Scrapie dans un boeuf: 1883 full text: French or English
Vets say maybe it was just Aujeszky's disease (pseudo-rabies)
Detwiler on differential diagnosis of Aujeszky's disease
French vache folle: more work needed -- webmaster
1920's Alzheimer's case: diagnosis confirmed
nvCJD from mononucleosis and tonsilectomies?
Domain-swapping and fibril formation
Reported scrapie in US: 1,117 cases (1947-1992).
Sheep ApoE alleles: no connection to scrapie
From helix to sheet after proteolysis
Contaminated lots implicated in French human growth hormone recipients
DMSO: does it dissociate amyloid fibrils?
24 Mar 98 webmasterBelow is the full text of the 1881 case of 'scrapie in a cow' of 8 years age from an 1883 French medical veterinary journal article. It has no list of citations at the end as was typical for scientific articles until after WWI. I have no idea when peer review came into play as we understand it today. A professional translation to English is being appended.
Did this cow in fact exhibit symptoms of a bovine TSE? What favors this over Aujeszky's disease (pseudorabies)? The quality of supporting evidence is open for discussion. Please let us not fault the veterinarian for not doing a western blot, electron micrsoscopy, or prion gene sequencing.
If yes, did it have an origin in scrapie? One scenario is that the cow was exposed to scrapie in co-pastured sheep, ie, horizontal transmission. This may have occured earlier in the herd with subsequent cow-to-cow transmission so that the cow of the article was not the primary passage. This might be called scrapie-BSE or scrapie-in-a-cow to indicate origin, keeping in mind that the cow prion causes the problem, not the long-gone sheep prion of different sequence. It is not scrapie any more, scrapie is a disease only sheep can get.
A second scenario is a validation of the Gibbs Principle, familial bovine TSE, that is, the cow had a familial CJD-type mutation in its prion gene as expected from the one per million background mutational rate. Other variants are somatic mutation bovine TSE or sporadic bovine TSE. These might be called familial BSE or sporadic BSE, keeping in mind that:
Neither scenario makes the ailment of this cow equivalent to either modern day UK BSE or Stetsonville BSE. This would be an unlikely coincidence because of the many possible strain types. Both scenarios are supportive, but certainly not proof, of the concept that some sporadic CJD in humans might long have had a dietary origin.
Par M. Sarraet, veterinaire a Carbone (Haute-Garonne). Revue médicale vétérinaire, 7, 310-312 1883
La tremblante est consideree comme une maladie exclusive du mouton; le fait suivant prouve que cette nevrose peut aussi attaquer les animaux de l'espece bovine.
Le sujet sur lequel il m'a ete donne de faire cette observation interessante est un boeuf de race gasconne sous poil gris clair, age de 8 ans, apparienant a M. Menville, fermier a Rieux.
Dans les dernier jours du mois de novembre 1881, cet animal fut en proie a un prurit si intense de la base de la queue, qu'il se grattait contre tous les objets qui se trouvaient a sa portee. A l'ecurie, il se frottait avec une veritable fureur contre la stalle ou contre son voisin, a la prairie, contre tous le arbres qu'il pouvait rencontrer; attele, contre la partie anterieure de la charrette ou, s'il ne pouvait y atteindre, il se contournait pour se frotter contre le timon.
Cette violente demangeaison avait cause une excoriation large et profonde et, par moment, une hemorrhagie assez abondante de la base de la queue.
Du reste, a part ce prurit incommode qui torturait sans cesse l'animal et un certain degre d'amaigrissement facile a expliquer, il ne presentait pas d'autre symptome digne d'etre note.
Il en fut ainsi jusqu'au 13 decembre. Le matin de ce jour, le prurit toujours tres vif semblait avoir reagi sur l'etat general du boeuf en question. L'appetit avait diminue, la rumination etait lente et rare. Il tenait la tete tres basse ou enfoncee dans la mangeoire; dans cette position, il appuyait parfois le front contre le mur et poussait a la facon d'un cheval atteint du vertige. Il ne sortait de cet etat comateux que pour frotter sa queue avec frenesie.
En meme temps que ces symptomes s'etaient manifestes du cote de l'encephale, une paralysie evidente commencait a envahir le train posterieur; dans les mouvements auxquels il se livrait pour satisfaire le prurit qui le devorait pour ainsi dire, l'animal tombait de l'arriere-train et ce n'etait qu'avec peine qu'il parvenait a se relever. La demarche etait mal assuree; les members posterieurs etaient vacillants et trainaient sur le sol.
Le 16, tous ces symptomes se sont aggraves; l'appetit et la rumination sont entierement suspendus; la paralysie a fait des progres remarquables; l'animal peut a peine se tenir sur ses jambes. Enon [I don't know what this word is supposed to be. Perhaps, "alors," or " et puis," or an earlier version that's no longer in common parlance], vers les trois heures du soir; il tombe pour ne plus se relever. Il est etendu sur le cote droit en decubitus lateral; dans cette situation, l'oeil est pirouettant dans l'orbite, la pupille fortement dilatee et la conjonctive tres injectee; la panse est tres meteorisee par suite l'inrumination et de la position du malade. La respiration est tres lente; sans quelques legers mouvements convulsifs des quatre membres et une certain conservation de la sensibilite generale, l'animal semblerait mort.
Diagnostique. -- Au debut, alors que le prurit existait seul, il etait aise de prendre cette affection pour un simple prurigo. Mais lorsqu'est survenue la complication de phenomenes cerebraux et surtout la paralysie, un rapprochement s'est fait instinctivement dans mon esprit entre la maladie dont je viens de faire la symptomatologie et la tremblante du mouton.
J'ai analyse comparativement ces deux affections et j'ai trouve entre elles des rapports si intimes, que je n'hesite pas a affirmer que ja'ai eu affaire a la forme prurigineuse de la tremblante.
Pronostique. -- La tremblante, chez le mouton, consitutue une maladie grave, puisqu'elle guerit rarement. D'apres le cas que j'ai eu la bonne fortune d'observer, elle semblerait encore plus grave sur le boeuf; elle parcourrait plus rapidement ses periodes et se terminerait d'une facon aussi malheureuse.
Dans l'espece, l'etat m'a paru desespere; aussi j'ai cru toute medication inutile et j'ai conseille au proprietaire l'abatage du boeuf qui a ete vendu pour la basse boucherie.
By M. Serraet, veterinary at Carbone in Haute-Garonne, France Medical Veterinary Review 7: 310-312 1883
Scrapie is considered an illness exclusive to sheep; the facts below prove that this nervous condition may also attack animals of the bovine species.
The subject on which these interesting observations were made is an 8-year-old steer of the Gasconne breed with a light gray hide, belonging to M. Menville, a farmer in Rieux, France.
In the last days of the month of November 1881, this animal experienced an itching so intense at the base of his tail that he scratched himself against all nearby objects. In the stable, he rubbed with a veritable furor against the stall or against his neighbor; in the pasture, against all the trees he could find; harnessed, against the front part of the cart, or, if he could not reach that, he would twist himself around to scratch against the shaft.
This violent scratching caused a wide and deep abrasion and, after time, substantial bleeding at the base of the tail.
Apart from this annoying pruritis which tormented this animal without let up and a certain degree of easily explained weight loss, he did not exhibit any symptoms worthy of note.
This went on until 13 Dec 1881. In the morning of that day, the itching as intense as ever appeared to have affected the general state of the steer in question. His appetite was diminished, and his rumination was slow and sporadic. He held his head very low or plunged it into his manger; in this position, he pressed his forehead against the wall and pushed in the same manner as a dizzy horse. He only came out of this comatose state to scratch his tail [rear] with frenzy.
At the same time that these symptoms were manifested in the head [brain] area, an obvious paralysis began to affect the hindquarters; during the movement he used to relieve his itching which consumed him, so to speak, the animal fell on its hindquarters and could get up only with difficulty. His gait was unsteady; his hind limbs wobbled and dragged on the floor.
On the 16th, all of these symptoms became more acute; his appetite and rumination stopped entirely; his paralysis progressed remarkably; the animal could barely stay on his feet. Then, towards three p.m., he fell, never to rise again. He lay stretched out on his right side; in this position, his eye was spinning in its orbit, the pupil intensely dilated and the conjunctiva very bloodshot; the rumen strongly inflated as a consequence of his ceased rumination and his [lateral] position. Respiration was very slow; were it not for some mild convulsive movements of the four limbs and a certain preservation of general sensibility, the animal would appear dead.
Diagnosis: In the beginning, when there was only the itching, it was easy to think this affliction was merely a simple pruritis. But once the complication of the cerebral phenomena set in and especially the paralysis, a connection was instinctively made in my mind between the illness whose symptomatology I have just described and scrapie in sheep.
I made a comparative analysis of the two afflictions and I found such a close a resemblance between them that I don't hesitate to affirm that I was dealing with the pruritic form of scrapie.
Prognosis: Scrapie, in sheep, is a serious disease because recovery is rare. According to the case which I had the good fortune to observe, scrapie seems even more serious in cattle; it runs its course more rapidly and ends in just as bad a manner.
In the species [cattle], the condition appeared to me to be hopeless; I also believed any medication was useless, and I advised the owner to butcher the steer that was sold for cheap [low class] meat.
Bovine Spongiform Encephalopathy: Clinical Signs In Swiss Bse Cases B. Hoernlimann and U. Brown; 1994This article states that 5% of the Swiss BSE cattle showed severe scratching symptoms, 17% milder ones.The authors state that this sign was typical for Swiss BSE cases. Scratching may indicate that the agent has wandered from the central nervous system to the periphery (skin). This would imply an increased risk for the gelatine production of skins.
[Thanks to Jeanne Brugere-Picoux, M. Savey et F. Moutou, John Kluge and Jane Pritchard]1. Usually the course of Aujeszky disease in cattle is very short 2 or 3 days and the description of the case of Sarradet is more than 2 weeks (first symptoms seen by Sarradet at the end of November, with decision for slaughter on the 16th of December).
Scrapie was very well known by this veterinarian and I remember, when I made the first videotape for a description of BSE for French veterinarians in 1990 (with the description of 5 cases of BSE in a videotype given [to us] by MAFF) I was very surprised by the similarities of clinical signs of scrapie (I was working on natural scrapie in sheep at the veterinary school of Alfort with Jacqueline Chatelain and Jean-Louis Laplanche, hopital St-Louis) with the clinical signs of BSE. For this reason, I have presented also two cases of scrapie in the French videotape on BSE; this videotape was utilized for the official surveillance of BSE in France.
Without confirmation by the histology we cannot be sure of the diagnosis of Sarradet but we cannot exclude the hypothesis of a "cas de tremblante chez un boeuf"
2. This paper is not a scientific article but rather a short paper about a unique clinical observation. This disease for today's vet looks very much like Aujeszky's or Pseudo-Rabies Diseases (PRD) (short duration, acute clinical stage, intense itching of the base of the tail, death). This hypothesis is further support by the fact that at this time (1883) in the South West Region of France, there was close contact between cattle and pig herds. The main source of PRDV in natural conditions is domestic pigs and wild boars.
The seminal works for scientific characterization of any TSE, mainly scrapie, was done between 1898 and 1939, precisely in Toulouse, France, in coordination between veterinary and medical institutions. The first essential contribution was given in 1898 by Benoit (professor in Toulouse Medical University) and Morel (professor in Toulouse Veterinary School) in the same journal as Sarradet's paper (Rev. Med. Vet. 1898, 23, 397 - 400). They characterized for the very first time, the nature and specificity of microscopic neuronal vacuolization in TSE diagnosis. That's to say that before that time (1898) nobody, even performing gross necropsy and microscopic examination, could really characterize scrapie from a scientific point of view. Sarradet was not able to perform such additional investigation, and he cannot investigate PRD virus, not yet discovered at that time.
Just for information, the transmissibility of scrapie was first proven by Cuillé and Chelle (Toulouse Veterinary School) between 1936 and 1939 (C.R. Acad. Sciences, Paris, 1936, 203, 1552 - 1554 et 1939, 208, 1058 - 1060). The whole story can be read in an article (in French !) from M. SAVEY (Bull. Acad. Vet. de France, 1989, 62, 25 - 32).
It is, then, fair to say that Sarradet's case is probably not a BSE-like disease and that it is more probably a PRD case.
Nevertheless, the scientific hypothesis of a sporadic BSE-like disease having existed in cattle for many years all over the world as does exist CJD in man (incidence rate of 0,5 to 1 case by million per annum), though not supported by Sarradet's observations, continues to be a sound one. It has been even more and more accepted since 1992 (SAVEY M. et all, Vet. Res, 1993, 24, 213 - 225) as an alternative hypothesis to the scrapie origin of BSE epidemic in UK.
3. At a minimum, the author should have discussed Aujeszky's disease (pseudorabies) and said why it wasn't, leaves us wondering whether perhaps a rural vet was not familiar with it.
The diagnosis is based strictly on clinical signs of this 1883 ox, there is no pathology reporte. A stonger case could be made for another differential diagnosis for pruritis and nervous signs in a cow infected with suid herpesvirus 1. This is refered to as Aujeszky's Disease for Pseudo Rabies. The presenting clincial sign is intense focal pruritits. Aujeszky's disease is known to cross from swine to cows, scrapie is not.
The clinical signs described in the paper are typical of Aujeszky's disease (pseudorabies) in cattle. The disease was first called pseudorabies by the Swiss in 1849 and the etiologic agent isolated by Aujeszky (Hungary) in 1902. In Cutlip's work at the National Animal Disease Center, in which he produced experimental scrapie in cattle, the affected cattle lacked pruritus which is often the chief clinical sign of pseudorabies in cattle.
Swine are the natural host; the US is nearing the end of a national eradication program in swine. As with many other herpesviruses, in the natural host swine you usually only see death loss in young animals. Many adults become infected, do not develop clinical signs, and become latently infected and a source of virus for young susceptable animals. Under old livestock management where swine were allowed in pasture, it was a common practice to isolate swine from cattle to prevent interspecies spread. This virus causes intense pruritus leading to self mutilation and death in cattle. It is also a fatal disease in most species except swine and humans.
On third to the fifth day of disease in the cattle clinical signs appeared in six of seven workers which had direct contact with diseased cattle. A pruritus of the palms, which spread onto the lower and upper arms, shoulders and back lasted several days.
See also: Lancet 1987 Feb 28;1(8531):501-502 Pseudorabies in man.
Taken from Large Animal Internal Medicine, 2nd ed., 1996, Bradford P. Smith ed., pg. 1017."The incubation period ranges from 90 to 156 hours, and the duration of illness ranges from 8 to 72 hours. Because of the short incubation period, animals may die suddenly, without premonitory signs.
In more slowly developing cases the first clinical signs are often paraesthesia. Dermal abrasions, swelling, pruritis, and alopecia occur at the site of virus inoculation. Affected animals also have fever and may bellow, bloat, stamp their feet, salivate and chew the tongue.
Other signs include ataxia, conscious proprioceptive deficits, circling, nystagmus and strabismus. Aggression may be seen in some instances, but most affected animals become depressed. Progression of the disease is associated with additional signs of diffuse cerebral dysfunction, which include twitching, hyperesthesia, tenesmus, wild spasmodic kicking, licking the nostrils, continuous mastication, sweating, vocalization, semicoma, coma, convulsions, opisthotonos, hyperpnea, tachypnea, or slow, irregular respirations.
The duration of clinical disease is longest in animals with pruritus of the head. Most affected animals die by 2 days after the first onset of clinical signs."
translated by Mary Nuppensmith 24 Mar 98"It would seem improbable, given its highly infectious and quickly lethal nature, that an animal infected with rabies would find its way into any food chain without relatively immediate and obvious consequences to someone along that chain (farmer, slaugherhouse, butcher, consumer). Could there be a native French "vache enragée" to match the UKs "vache folle," as the French translate mad cow disease; one which was once so common that its presence has fallen into the lexicon in an abstract expression? Certainly eating a mad cow now and then a 100 or more years ago probably presented little risk of dying from any form of CJD - few people, and almost no one in the lower socio- economic level which would have been reduced to eating enraged cows, would live beyond the age of 45 anyway."
"The ox mentioned in 1881/83 was found in the Haute-Garonne. Two of the most recent cases of BSE in France were located in the Haute-Loire and Haute-Saone regions. From my limited map, it appears there could be as little as 150 miles (and 117 years) separating the Haute-Garonne and Haute-Loire locations. I wonder what the geographic distribution of the 34 reported BSE cases in France is?"
It appears that the ox in question [1881/83 scrapie in an ox] was sold as cheap meat. Maybe that's what the French expression: "To eat enraged cow" means. [Note: The French word for rabies is la rage, however, the verb enrager has pretty much the same meaning in French as English - to be enraged, angry, agitated]. It's an expression in and of itself. It's used when people are poor and can't afford good meat. Other similar expressions are "to be in mashed potatoes" and "to pull the devil by the tail" or "to be broke."
But why an enraged cow? Why not a dog, or a horse?
Because rich people wouldn't be reduced to buying them to eat meat. They have the means to buy safe meat (if that exists. I sometimes wonder).
"Differential DiagnosisCommentary (webmaster): Cows of course are ruminants. The disease lasted at least 18 days. This rules out pseudorabies according to this diagnostic protocol. This long and fascinating article had other items of interest:
The clinical signs of many cases of scrapie are quite distinct and can be easily recognized (see chapter entitled "Clinical signs"). They include beharioural changes, tremor, pruritus and incoordination, progresing to recumbency and death. However, in the early stages of the disease, there are several other conditons which could be confused with scrapie including: * Ectoparasites (lice and mites): can be eliminated by parasitological examination;
* Pseudorabies (Atujezky's Disease): can be ruled out by an extremely short clinical course in ruminants (36-48 h) and the finding of a high fever.
* Rabies: ... should be considered if the clinical course of the suspect has been shorter than ten days...
* Ovine progressive pneumonia...
* Pregnancy toxaemia...
* Chemical and plant toxins...
* I have never seen anything published about scrapie in bighorns, yet we see "An equivalent gene of Sip (short incubation time allele sA) in sheep has been identified in Argali and Rocky Mountain Bighorn sheep (A Maciulis, Utah State, personal communication). The Sip (short incubation time allele sA) in sheep mentioned was later attributed to valine 112 in the prion gene though in hindsight many of the original Sip studies were done in unknown backgrounds. Reed Holyoak writes that Alma Maciulis and Dr. Tom Bunch simply looked at RFLP patterns of fibroblasts and blood from Argali and RM-Bighorn sheep to see if there was an equivalent gene or if there were any similarities in the RFLP patterns; and there was. Not surprising considering what we know now about the PrP gene. This had nothing to do with scrapie in these sheep.
The moufflon business has been improperly represented in the scientific literature as an independent natural occurence of a TSE. In fact, these are not wild moufflon at all: ten cases were seen in two tiny captive flocks in the UK. One flock was kept apart from domestic sheep for 20 years although animals were traded in and out to other moufflon flocks. The second flock was maintained with a Soay sheep flock (with no known scrapie but known susceptibility) but the first moufflon to succumb had been a Belgian import. No protein supplement was ever used. The moufflon prion gene has not been sequenced. No pathology was seen in wild moufflon on Cyprus. In my opinion, this is an open and shut case of scrapie horizontally transmitted across a minor species barrier.
I learned that Canada acquired scrapie back in 1938 in Ontario from British imports and that these were the source over several years of the 1947 Michigan outbreak. New Zealand's last reported case of scrapie was 1952.
"Some flocks may exist with an annual scrapie mortality rate of 3-5% Yet, it has been reported that within a flock it is not uncommon to have an incidence of 10-20%....21% of sheep 'found dead' in another study had scrapie" So CWD in free-ranging deer and elk in Colorado is not all that high considering winter concentration.
Iceland is making a monumental effort to eradicate scrapie, screening up to 15,000 brains a year and decontaminating farms with hypochlorite. Ten per cent of clinicially normal sheep from heavily infected sheep showed evidence of vacuolation. Fifteen infected flocks were identified thruough this surveillance effort _prior_ to an appearance of clinical disease....Observers reported a change in clinical signs over the years, scrapie manifesting itself as tremor and ataxia prior to 1968 but subsequently pruritus was more commonly seen and often became the predominant sign. 2 of 397 re-introduced flock had scrapie by 1992.
28 Mar 98 webmaster opinionI have not come to an opinion on what the problem was with this French ox myself. There is time for that after determining the historical context for the article. We should not restrict diagnostic alternatives solely to Aujeszky's disease.
Many vets commenting seem to lack any personal clinical experience with proven AD crossed to cattle; it is basically a matter of textbook cites from Large Animals 101. I am not sure how often AD in cattle is seen any more; the US practically has it eradicated even from pigs. Somewhere out there in listserve land is an expert with extensive clinical experience with AD in cattle, its international range of presentation, and its historical scientific literature.
Many people said, well, the ox had CNS symptoms and pseudorabies has CNS symptoms, end of story and never mind that the incubation period was wrong. However, the nub of it is in the specifics of gait disturbances, hindlimb dragging, ataxia, and terminal recumbancy. Show me one article on Medline where this specific syndrome has ever been seen with AD in cattle and I will show you 500 articles where it has been specifically described for TSEs. That is where the diagnostic nuances are.
And that, in my opinion, is why Sarraet [and the journal editors] had no doubt it was BSE.
Biographical data for Sarraet would be good. There is nothing on the Internet or Pubmed. I am thinking of when and where did he go to vet school, what textbooks were used in those days, what weight was given to scrapie versus pseudorabies in them, did he go on to eminance or remain a rural vet, what did he publish before or after, where they favorably cited.
What people learn at vet or med school is often what they go by for the rest of their careers, then and now, unfortunately.
Contemporary veterinary thinking of the era. This was published in Review Medicale Veterinare. Is this a Parisian journal, an eminent one by its seventh year? Who were the editors, what veterinary references were they likely to have had on the shelf, what did these books say about differential diagnosis of scrapie and pseudorabies, how often this article of Sarraet later cited and in what light, who came across this ancient reference in the modern era and what else did they find in their searches.
There is nothing said in the 1883 paper one way or another about other animal species present or affected on the farm such as pigs. Possibly, the farmer and vet might have noted a prior outbreak with affected cattle, sheep with scrapie, or pigs with AD, on this farm, on neighboring farms, or in the region. No one researched Menville's farm to see what sort of operation it was.
Aujeszky's disease is basically a disease of pigs that occasionally gets into co-pastured cows and sheep and into carnivores eating pig carcasses such as coyotes, foxes, and bears. It has also crossed to humans in Poland.
Disappointingly, no one researched earlier or later papers by Sarraet, nor contemporary papers by other vets: did some one publish a letter disagreeing? Further research might establish rough incidences of scrapie and AD in this region of France and whether or not Sarraet was familiar with both diseases in his practise and publications.
Many people commenting did not see that the illness began in the "last days of November" and was not yet terminal on 16 December. Let's call this 18 days duration of symptoms (severe enough to get the farmer's attention, beyond some animal just scratching itself repeatedly). I don't find this consistent with any published description of AD in cattle on Medline.
Scrapie came in 127 years before pseudorabies in pigs and even longer before pseudorabies in cattle. I believe there had been some very substantial outbreaks of scrapie and that it, while rare, was a fairly well known disease that large animal vets would have seen. I would like to see some data on the extent of pseudorabies in the nineteenth century, especially in cattle. Why do the pseudorabies enthusiasts stop short when they could go on to argue that all earlier scrapie reports in sheep were misdiagnoses as well?
When was the first published observation of confirmed or suspected pseudorabies in cattle (not pigs)? My guess is that it was well into the 20th century and that it went with intensified confinement agriculture. Perhaps there are some interesting citations in the earliest Medline articles:
Monatsh Veterinarmed 1966 Mar 15;21(6):201-203 [Comments on the incidence of Aujeszky's disease in sheep]
Monatsh Veterinarmed 1966 Jan 15;21(2):58-64 [Experiences with Aujeszky's disease with special reference to some cases in sheep and cattle].
Sarradin P., Lantier F., Elsen J.M., 1996. La tremblante des bovins. Note interne INRA-ESR & ENA.
Listerve and correspondence 23 Mar 98
"Would not mononucleousis stimulate T and B cells that are intermediates in prion replication and could this explain why nvCJD has mostly been found in young people?
And what about all those tonsillectomies that are still (occassionally still) done?! Given the tonsil component shouldn't disposable instuments be being use for that procedure in the UK/EU." This could be a very effective way to transmit and AMPLIFY the nvCJD in UK/EU. Has anyone thought about this!? I hope so. I saw a study on Tonsil Bx and an astute observation that disposable tonsil bx kits should be available for that.I think ipso facto, the use of disposable surgical instruments should mandatory at least in the UK/EU."
Neil Cashman responds:
"Thanks for noticing our Blood article. What we have found is that the normal cellular isoform of the prion protein is expressed on mononuclear cells (lymphocytes and monocytes), and by the bone marrow stem cell precursor cell (CD34+ cells). This suggests that prion infection could be supported by these cells, as expression of PrPC is essential for prion agent replication. Our study does not address which cell brings the prion agent to the brain -- although it is interesting that B cells are also "mononuclear".
Mononucleosis does not make monocytes proliferate, but it causes widespread activation of B and T cells. We have previously shown (Cashman et al, Cell 1990) that activation of mononuclear cells is accompanied by ~4-fold increase in surface PrPC, potentially making these cells better hosts for prion infection. It would be interesting to ask Robert Will if he has gathered information on the frequency of mononucleosis in nvCJD -- this could be important."
26 March 98 Science Martin EnserinkEnding a 2-year-long search, German scientists have uncovered a piece of science history: brain samples from Auguste D., the first Alzheimer's patient ever to be described in medical literature. The finding, published this week in Neurogenetics, is likely to put an end to lingering doubts about the cause of Auguste's dementia. Some scientists had argued that she may have suffered not from Alzheimer's, but from another, rarer brain disease.Researchers have been hunting for Auguste's brain since psychiatrist Konrad Maurer and two colleagues from the University of Frankfurt found her original hospital file at an institute of the university (Science, 5 July 1996, p. 28).
When they published their findings last year, the trio still nursed hopes of also finding her brain somewhere in Frankfurt. But they were looking in the wrong place. Last September, a rival team led by neuropathologist Manuel Graeber of the Max Planck Institute for Neurobiology in Martinsried, near Munich, discovered more than 250 slides of Auguste's brain in a basement of the University of Munich. Graeber's team had also found the brain of Johann F., the second case described by Alzheimer, just a few months earlier.In searching for Auguste D.'s brain, both teams had studied the history of her case and the movem
Auguste D. was admitted to the Hospital for the Mentally Ill and Epileptics in Frankfurt in 1901. Then only 51 years old, she did not understand the world around her, had hallucinations, and was disoriented, paranoid, and hardly able to speak. Alzheimer, who had been a doctor at the hospital since 1888, studied her intensively and continued to follow her progress from a distance after his research career took him to the Royal Psychiatric Clinic in Munich in 1903. After Auguste's death in April 1906, the hospital's director sent her brain to Alzheimer in Munich for investigation. He presented her case at a psychiatry meeting in Tübingen 7 months later and published it in 1907, thus assuring Auguste a place in medical history.
Nobody knew what happened to the brain slices after Alzheimer died. Graeber says he was convinced they had remained somewhere in Munich, but Maurer hoped at least part of the samples might have been returned to Frankfurt. "It would have been nice to have found [them] here, of course," he says. "But that's life." There is no doubt about the brain's authenticity, says Graeber: The arrival of the brain at Alzheimer's clinic was recorded in the hospital's autopsy book, and every single slide is labeled with Auguste's last name--a very rare one in Germany.
A fresh look at Auguste's brain dispels allegations that she may have suffered from something other than Alzheimer's, Graeber says. Some neurologists have speculated that she was ailing from a rare metabolic disorder called metachromatic leukodystrophy. But Graeber says the rediscovered slides show no evidence of this, although her cortex does display the two classic pathological signs of Alzheimer's disease: amyloid plaques and neurofibrillary tangles.
"It's exactly what you would expect" in a classical case, Maurer says.The Max Planck researchers were even able to extract and test Auguste's DNA from a few of the slides. They discovered that she did not carry the E4 allele of the APOE gene, which would have predisposed her to Alzheimer's. They would also like to screen for mutations in other genes involved in Alzheimer's, but these tests would require lots of tissue. Rather than destroy many of Alzheimer's meticulously conserved slides, Graeber prefers to await a new generation of tests that can do the job as economically as possible.
To Graeber, there is more to these analyses than just science history. As a neuropathologist, he is interested in the genetics of brain disease. And with fewer and fewer autopsies being carried out worldwide, he says, archived, well-studied brain tissue will become an important resource in studying the relationship between known genetic defects and disease symptoms. If a brain as old as Auguste's can relinquish its secrets, so can many others. "We have to run genetic tests on the best diagnosed cases there are. And many of them are old."
The discovery also has a bearing on the definition of Alzheimer's disease. According to neuropathologist Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, there is still a debate about what it takes to confirm a case of Alzheimer's in a post-mortem: just amyloid plaques, or both plaques and neurofibrillary tangles. The finding stresses that "Alzheimer originally described it as having tangles as well," Dickson says. "So it's an important paper in terms of ... understanding the historic base of the term Alzheimer's disease."
Neurology 1998 Mar;50(3):684-688 Brown P, Cervenakova L, McShane L, Goldfarb LG, Bishop K, Bastian F, Kirkpatrick J, Piccardo P, Ghetti B, Gajdusek DC
A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.
See also an earlier article on this same subject, possiblly on the same couple:
Cervenakova, L, Brown, P,Piccardo, P, ... Gajdushek, DC, Goldfarb, LG in Transmisablle Subacute Spongiform Encephalopathies: Prion Diseases pp 433-444L Court, B Dodet, editors. Elsevier, Paris 1996 Article notes by webmaster 20 Sept 1997This is an interesting case where clinical, pathological, and immunocytochemical data strongly support the diagnosis of CJD in both husband and wife. The wife was the only caregiver during the husband's illness. The husband had died at age 54, after a 9 month illness of progressive mental and physical decline five years before the onset of clinical symptoms in his wife, who died at age 54, after subacute onset of agitation, confusion and mental slowness progressing to ataxic gait and myoclonic jerks, with severe gliosis and punctate prion imunoreactivity.
Genetically, the husband's prion gene was normal: no changes and homozygous methionine at codon 129. The wife had an R3/R4 deletion in one repeat region (a common polymorphism) and was also met/met. This allele may provide genetically determined susceptibility to environmentally CJD but is not normally causative.
The couple evidently lived in the US. The case record is consistent with horizontal transfer from husband to wife. There is no information provided as to occupation, dietary preferences, or travel history. Strain-typing was not reported -- however, this would not be expected to distinguish between horizontal transfer and common dietary exposure. Two unrelated cases of sporadic CJD at such early ages seems unlikely if the incidence is 250 cases per year in the entire US.
I should like to clarify 'normal' as used above. Basically, a new allele makes substantial inroads into a population because it is of positive value (natural selection), because it is more or less neutral (but genetic drift, founder effect), or because it is a high frequency de novo result at a hotspot (rate of new mutations fast relative to rate of loss to negative selection).
Deletions in the repeat region of the prion protein are clearly of type 3. That's why it is not safe to infer from 1-2% incidence that it is a harmless variation for normal prion function. There are several inequivalent ways of getting to a prion repeat deletion that result in the same amino acid sequence (the wife carried an R3/R4 type); the 1-2% number refers to all of these pooled.
The norm in mammals is five repeats. However four or six seem tolerated in numerous species and for a time can even be the dominant allele, though five never goes away and seems to re-assert itself over longer periods. The 5-6 polymorphism has evidently bridged speciation events in recent bovids. Three has never been seen; longer repeats occur and are associated with disease (new Antwerp family 7x?). Propensity or susceptibility to TSE is probably only a very minor component of the overall evolutionary forces shaping the time course of this gene's sequence.
I mentioned earlier that all the common point mutations causing familial CJD are classical CpG hotspots. There was also a hotspot on the cow that is a good candidate for familial BSE, perhaps even for the index case of the UK situation. The other half of familial CJD is due to changes in the repeat region. Here the unit of change is not the single nucleotide but a repeat unit of 24 and the hotspot mechanism is classical replication slippage; it is operative at both individual and phylogenetic scales. This mechanism is often studied in mitochondria, which lack [unequal] recombination.
Note these repeat mutations have 3-4 times the incidence of nearby CpG hotspot mutations (which themselves are hugely elevated over generic point mutations, causing 30-40% of all human germline mutations despite 80% depletion) in this gene.
So it is this hyper hotspot origin coupled with 100 million years of drift back to five repeats that suggest the 4-repeat allele is moderately dysfunctional. The data are equivocal for CJD propensity (no particular familial association) and unknown for CJD susceptibility from external sources (could vary depending on source).
They could properly say here that the deletion did not markedly enhance the probablility of the wife having CJD on her own, they could not properly speak to whether the deletion enhanced the susceptibility to an external source (husband?) relative to the susceptibility of a five-repeat wife, and they could not properly say that the wife had a normal prion sequence nor a normally functioning prion protein.
The codon 129 allele, where valine has made substantial inroads into European populations at least, is probably of type 2: not at a hotspot, locus and embedding region extremely well conserved over long periods, yet some softness is tolerated in elk (partial leu), ostrich (val) and neognathes (ala) at codon 129 and similarly at codon 130, suggest approximate neutrality (slight negativity) and drift or founder effects within a somewhat permissive two-residue stretch.
While met and val no doubt have dramatic effects on external susceptibility incubation times and in internal symptomatic couplings to other mutations, codon 129 per se has not been shown to be special in these regards: it is just the only point allele readily studied, in a very subtle process. (There are some effects seen in E210K in Japan.) No one has looked, say, at codon 130 or many others. No one has substituted the other 18 amino acids into codon 129 that I can recall.
So it is wrong to say at this point that codon 129 is especially fundamental among codons in regards to understanding the recruitment or conversion process; for all we know, variations of many other residues are of much greater structural signficance. For these however, there will not be real-world in vivo data.
Univ.-Prof. Dr. Herbert Budka"This couple from Vienna was reported in the papers by Garzuly F, Jellinger K, Pilz P: Subakute spongiose Encephalopathie (Jakob-Creutzfeldt-Syndrom). Klinisch-morphologische Analyse von 9 Fallen. Arch Psychiatr Nervenkr 1971;214:207-227 (cases 7 & 8), and Jellinger K, Seitelberger F, Heiss WD, Holczabek W: Konjugale Form der subakuten spongiose Enzephalopathie. Wien Klin Wochenschr 1972;84:245-249.
According to the rather limited experience of that time, these cases were considered to be compatible clinicopathologically with CJD. Both spouses fell ill almost simultaneously and died after 2 and 4 months, respectively. An initial psychiatric stage was followed by progressive dementia with cerebellar, pyramidal and extrapyramidal signs and symptoms and terminal decerebration. None had a CJD-typical EEG or myoclonus.
Although some intoxication, especially from organic pesticides, was suspected, it could not be verified by forensic chemistry. We recently reexamined archival brain tissue from both spouses; histopathology was not convincing for TSE, especially unequivocal spongiform change was lacking, and immunocytochemistry for PrP was negative (Hainfellner JA, Jellinger K, Budka H: Testing for prion protein does not confirm previously reported conjugal CJD. Lancet 1996;347:616-617). Although this rules out CJD, I cannot give now a definite diagnosis for this couple. My guess is some sort of toxic encephalopathy, but this is not a mere neuropathological diagnosis."
Robert A. LaBudde responds:
1. 1:1,000,000 incidence per general pop per year. Check.
2. All caused by a narrower window of reported population, say 1:5 falling in the range of > 45+ years. Check.
3. Reporting general population: 500,000,000.
Probability of CJD per person per yr in reporting population:
5:1,000,000 = 1:200,000
Expected number of cases annually:
500,000,000 x 1/1,000,000 = 500
(500,000,000/5) x 1/200,000 = 500 (check.)
Consider now spousal pairs:
x = 1/200,000 = 0.000005 = expected spouse CJD rate
y=500 x 0.000005 = 0.0025 = annual joint CJD rate
If we say we're looking for such a pair in a 20-year period, we would expect 20 x 0.25% = 0.05 pairs in such a period. The probability of observing at least 1 such pair is 1 - exp(-.05) = 4.9%. The chance of two such pairs is 1:827. This is a far cry from my small number, but it's still not high. Particularly when you factor in the dying within 5 years of each other, as all 2-3 reported spousal pairs have done.
If you then factor in a possible 10x higher discovery rate in spouses, given the prior CJD case, then
x = 1/20,000 = 0.00005
y = 0.025
and the expected number of spousal pairs in 20 yrs of observation becomes 0.5. The chance of observing such pairs in 20 years is then:
n 0 1 2 3 4 Pr 60.7% 30.3% 7.6% 1.3% 0.2%Recall 15% of all CJD reported is familial; 2) CJD strikes at a distribution of ages from 30 to 80, not just to a narrow band from 60-70. In consequence, the occurrence of spousal CJD pairs would be mainly suggestive of marriage within a limited gene pool group rather than an as yet undiscovered cause, particularly when they occur at closely similar ages.
31 Mar 98 PNAS 1998 95: 3437-3442This is an article about unrelated protein in which prions come up in the discussion section.
There are two main ideas in the paper: they have a clear example of monomer growth by domain swapping and an interesting case of a smaller proteolytic fragment 'promoting' recruitment of the normal conformation.
Domain swapping has been around for a while, eg, tryptophan synthase. Here there is a helical domain attached to a loop with weakly contrained configuration. When that hinge is open, the helical domain from a second monomer can swing in and take its place. The key idea is that the second helical domain fits in a native way (ie, the way the original domain did). In the protein studied here, the process was reciprocal and the end product was a face-to-face 'terminal' dimer. Domain swapping is an attractive way for a monomeric protein to become multimeric. If the end product had been front-to-back (daisy-chain), then the process does not terminate and a fibril results, with growth points at both ends.
In their protein, protease sensitivity was lost after aggregation. They did not get congophilic birefringence though CR did get into the crystal.
The authors note that one of classic cross-beta fibrils (AL-amyloidosis of yesterday) originated as "reduction of disulfide bonds in the Bence Jones protein DIA led to the formation of amyloid-like fibrils. A mechanism identical to domain swapping was proposed for the fibril formation in Biol. Chem. Hoppe-Seyler 374, 1117-1122 (1993)."
The authors propose a general mechanism for amyloid formation: "The process is initiated by proetolytic cleavage of a fragment or domain of a protein [eg, S-peptide, beta 1-43 in Alzheimer, or perhaps 106-126 in CJD]. Under reductive or destabilizing conditions, this fragment or domain can bind to an intact molecule of the same protein, replacing the intact counterpart domain and permitting it in turn to insert into another molecule, and so on, to form a fibril." This is mostly easily understood from a picture from the article:
J Am Vet Med Assoc 1998 Mar 1;212(5):713-718 Wineland NE, Detwiler LA, Salman MDRecords for scrapie-positive sheep flocks and sheep with clinical signs consistent with scrapie reported to the USDA from 1947 through 1992. Records from the USDA's scrapie control and eradication program were abstracted, entered into a computer database, and statistically analyzed.
1,117 sheep from 657 flocks located in 39 states were scrapie positive during the study period. Seasonal or spatial trends were not evident. Mean yearly proportion of scrapie-positive flocks increased slightly from 1965 through 1992.
One hundred sixty-eight rams and 949 ewes were reported to be scrapie positive during the study period, which was slightly more rams than expected if the disease was equally likely to affect rams and ewes. Suffolks (972/1,117; 87%) and Hampshires (68/1,117; 6%) were most commonly affected.
The prevalence of scrapie in sheep in the United States is unknown. Bias in this study may have resulted from inconsistencies in available information, misclassification of sheep with clinically suspicious signs of scrapie, and changes in the national scrapie control and eradication program that likely affected willingness of owners and veterinarians to report potentially infected sheep.
Gene 1998 Feb 27;208(2):131-138 Komatsu Y, Horiuchi M, Ishiguro N, Takane Matsui, Shinagawa M]Apolipoprotein E (ApoE) plays a central role in lipid transport and is suggested to be involved in neuronal repair. Human ApoE epsilon4 allele is known as a risk factor for Alzheimer's disease, and an association of the human ApoE genotype with the human prion disease, Creutzfeldt-Jakob disease, is suggested, albeit controversial.
We analyzed the sheep ApoE gene to determine whether any association between the sheep ApoE genotype and the sheep prion disease, scrapie, existed. The sheep ApoE cDNA contained an open reading frame (ORF) consisting of 948 base pairs (bp) that encoded 316 amino acids (aa). The sheep ApoE gene was composed of four exons separated by three introns, and the ORF was encoded by three exons, designated exons 2, 3, and 4. Nucleotide sequence analysis also showed the presence of one G/T nucleotide polymorphism in the ORF that resulted in an Ala/Ser amino-acid substitution at codon 258.
PCR-restriction fragment length polymorphism analysis of genomic DNA showed the presence of three sheep ApoE genotypes that were the result of the homologous and heterologous combinations of the two alleles. We analyzed the sheep ApoE genotypic and the allelic frequencies in scrapie and control Suffolk sheep, but they did not significantly differ from those in the control sheep, even though PrP genotype-matched populations were compared.
The ApoE genotype appeared not to be associated with the progression of the disease when looking at the age at death. These results indicated that in Suffolk sheep, none of the ApoE genotypes was associated with scrapie.
Biochemistry 1998 Mar 24;37(12):4288-4298 Hwang PM, Zhou N,Shan X, Arrowsmith CH, Vogel HJThe solution structure of bovine lactoferricin (LfcinB) has been determined using 2D 1H NMR spectroscopy. LfcinB is a 25-residue antimicrobial peptide released by pepsin cleavage of lactoferrin, an 80 kDa iron-binding glycoprotein with many immunologically important functions.
The NMR structure of LfcinB reveals a somewhat distorted antiparallel beta-sheet. This contrasts with the X-ray structure of bovine lactoferrin, in which residues 1-13 (of LfcinB) form an alpha-helix. Hence, this region of lactoferricin B appears able to adopt a helical or sheetlike conformation, similar to what has been proposed for the amyloidogenic prion proteins and Alzheimer's beta-peptides.
LfcinB has an extended hydrophobic surface comprised of residues Phe1, Cys3, Trp6, Trp8, Pro16, Ile18, and Cys20. The side chains of these residues are well-defined in the NMR structure. Many hydrophilic and positively charged residues surround the hydrophobic surface, giving LfcinB an amphipathic character. LfcinB bears numerous similarities to a vast number of cationic peptides which exert their antimicrobial activities through membrane disruption.
The structures of many of these peptides have been well characterized, and models of their membrane-permeabilizing mechanisms have been proposed. The NMR solution structure of LfcinB may be more relevant to membrane interaction than that suggested by the X-ray structure of intact lactoferrin. Based on the solution structure, it is now possible to propose potential mechanisms for the antimicrobial action of LfcinB.
Am J Epidemiol 1998 Mar 15;147(6):597-604 Huillard d'Aignaux J, Alperovitch A, Maccario JFrom 1970 to 1988, thousands of children have been treated with human growth hormone (hGH) to supply pituitary gland deficiency. In France, 51 of the 968 children treated by hGH lots produced between January 1984 and March 1985 had developed Creutzfeldt-Jakob disease (CJD) by the end of 1996.
The authors' objective was to investigate which of the 13 hGH lots produced during this period might be implicated in the iatrogenic transmission of CJD. In this paper, the authors describe a model that was developed to compute the probability for each lot of being contaminated. The validity of the model was assessed by a simulation study that showed a good agreement between the estimated and the simulated number of contaminated lots.
The model suggested that about half of the lots distributed during this period might have been contaminated by the infectious agent that causes CJD. The risk of iatrogenic CJD for patients exposed to contaminated hGH lots was estimated to be 0.06 (95% confidence interval 0.05-0.07).
Webmaster comment 7 Apr 98A new paper reports dimethyl sulfoxide, the common solvent, DMSO, may affect prion fibrils. This was observer earlier in a human renal amyloidosis. Renal amyloidosis seems to be a catch-all topic involving a number of unrelated proteins that includes fibrinogen A alpha-chain gene, AA type anti-human amyloid-A amyloidosis, AL type, light chain deposition disease. The latter are cross-beta conformational disorders (prion-like) and already in Glenner's set of congophilic cross-beta diseases.
It is one thing to dissociate a polymer in the kidney and flush it away; it is another to do so in the brain and flush the dissociating reagent away. Potentially, this just results in a vast multiplication of seed crystals from the fragmentation. See 1, 2
Alex Bossers comments on 7 Apr 98:
"If DMSO is a potential therapeutic, why then are persistently scrapie infected neuroblastoma cells NOT cured when frozen and thawed to/from liquid N2??? Better targeting of DMSO to the place to be is almost not possible, maybe longer. At freezing stage final concentration is 10% DMSO in culture medium while at thawing (first passage) final concentration is generally 0.5%.
Neuroscience Letters 1997; 1997(S48): S 45-45 Shaked,G.; Taraboulos,A.; Gabizon,R. No abstract available
Vet Res Commun 1981 Sep;5(1):21-32 Gruys E, Sijens RJ, Biewenga WJData from the literature on DMSO therapy for amyloidosis in laboratory animals and man are reviewed and found to be inconclusive. In hamsters with casein-induced amyloidosis, as well as in dogs with spontaneous amyloidosis, therapeutic experiments with DMSO were performed. In these investigations no effect of DMSO on amyloid and amyloidosis was found.
Hiroshima J Med Sci 1996 Mar;45(1):11-14 Taniguchi Y, Yorioka N, Yamashita K, Oda H, Nie LF, Ye Yeu XF, Okushin S, Nishida Y, Kushihata S, Yamakido MTo clarify the role of apolipoprotein E (apo E) in the formation of amyloid deposits, we examined specimens from 11 patients with renal amyloidosis who underwent renal biopsy by an immunohistochemical method using a monoclonal antibody (murine IgG1). Apo E was distributed in the amyloid deposits of all patients in a pattern similar to that obtained with Congo red staining. Strong positive staining for apo E was found on the amyloid deposits in the glomeruli. These results suggest that apo E is a common constituent of amyloid fibrils and that it may be a useful marker for immunohistochemical studies of systemic amyloidosis including renal amyloidosis.