Roland Heynkes email Home Page Erkwiesenstr.19 52072 Aachen Tel: 0241/93207-0 - Fax: 0241/93207-2 (oder -1)
Manipulated are the mean incubation time and the rate of BSE infected animals not with the intention of a manipulation, but simply because of the loss of retainability of a cow with decreasing condition.
The increase and decrease of the BSE epidemie is obviously caused mainly by changes in the titer of infectivity within the ruminant food. This is a further factor, totally independent from the possible factor milk productivity. You should not mix them in the statistical analysis
. The maternal transmission study will not give us much more evidence with respect to the BSE incidence of older cows, because they were killed when they became 7 years old."
Yes. Colin Whitaker, the vet that discovered the first cases of BSE, wrote in his report regarding the first 10 cases at the same farm outside Ashford, Kent:
"Milk yield gradually drops and there is loss of condition in the later stages." (Presentation at a meeting of the British Cattle Veterinary Association in July 1987)
"In my paper I had a list of differential diagnosis, and the last one was 'a new scrapie-like syndrome'. The Ministry (MAFF) asked us not to use that (at the meeting in '87) - or told us not to use the word 'scrapie-like'. I think they were concerned that it would effect the sheep market." (Sept 23 1996)
The word was blacked out at the meeting. Colin Whitaker's report was published one year later, in its original version.
It is legal to mix gelatine, fat from all animals and even blood products into the milk substitute for German calves. Furthermore meat bone meal does not have to be made with the famous German method with 133 degree Celsius at 3 bar pressure for 20 minutes. It only has to be dried if it comes from not obviously sick animals. I described that for Germany but as we all know the British circumstances are not better.
Every governmet that has to tighten its standards because they didn't follow any Precautionary Principle in the past."
Also remember the old article of Dickinson et al. in Nature 1975; 256 732-3. No test is sensitive only because of other less sensitive tests and tests are much more sensitive if there is no species barrier and if the normal life span of the inoculated animal is longer than that of mice. Cutlip et al. for example only have to wait 14-18 months after ther the inoculation of new born calves until the symptomes became visible (J.Inf.Dis. 1994; 169: 814-20). After that minimum incubation time you can wait more than 20 years for the symptomes if you are interested in a maximum of sensitivity with a biological functional test."
On the other hand the specialists lost a lot of time because it takes months or even years until an article has been accepted and finally published. This aspect is less important for the broader publicum, which can wait for the qualitiy proven articles. Therefor I do not want to replace the scientific journals, but I only want to get an additional tool for the specialists of a field of research, as physicists, chemicists, mathematicians and psychiologists have it. If many specialists discuss an article, they will find even more mistakes and erroneous ideas than only two reviewers.
Scientists may view peer review as an invaluable resource to confirm, clarify and substantiate research articles, but at the same time many of them suffer from the described delay. The quality of research will not suffer from APADS, because they do not replace the qualitiy check of scientific journals."
The Glycosylation influences the transport of the cellular prion protein to the surface (Lehmann,S.; Harris,D.A. - Effect of 2 pathogenic mutations on the cellular processing of the mouse prion protein - Journal of Cellular Biochemistry 1995; 1995(S21B): 104). Incorrect Glycosylation may cause artificial results of the Collinge experiments with transgenic mice. The article of Kocisko et al. demonstrates, that glycosylation is not required for the transmission of strain attributes to the normal prion protein.
Literature List: Atouf,F.; Scharfmann,R.; Lasmezas,C.; Czernichow,P. - Tight hormonal control of PrP gene expression in endocrine pancreatic cells - Biochemical and Biophysical Research Communications 1994 Jun 30; 201(3): 1220-6 Bendheim,P.E.; Brown,H.R.; Rudelli,R.D.; Scala,L.J.; Goller,N.L.; Wen,G.Y.; Kascsak,R.J.; Cashman,N.R.; Bolton,D.C. - Nearly ubiquitous tissue distribution of the scrapie agent precursor protein - Neurology 1992 Jan; 42(1): 149-56 Borchelt,D.R.; Koliatsos,V.E.; Guarnieri,M.; Pardo,C.A.; Sisodia,S.S.; Price,D.L. - Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems - The Journal of Biological Chemistry 1994 May 20; 269(20): 14711-4 Borchelt,D.R.; Rogers,M.; Stahl,N.; Telling,G.; Prusiner,S.B. - Release of the cellular prion protein from cultured cells after loss of its glycoinositol phospholipid anchor - Glycobiology 1993 Aug; 3(4): 319-29 Borchelt,D.R.; Scott,M.; Taraboulos,A.; Stahl,N.; Prusiner,S.B. - Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells - The Journal of Cell Biology 1990 Mar; 110(3): 743-52 Brown,H.R.; Goller,N.L.; Rudelli,R.D.; Merz,G.S.; Wolfe,G.C.; Wisniewski,H.M.; Robakis,N.K. - The mRNA encoding the scrapie agent protein is present in a variety of non-neuronal cells - Acta neuropathologica 1990; 80(1): 1-6 BTeler,H.; Fischer,M.; Lang,Y.; Bluethmann,H.; Lipp,H.P.; DeArmond,S.J.; Prusiner,S.B.; Aguet,M.; Weissmann,C. - Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein [see comments] - Nature 1992 Apr 16; 356(6370): 577-82 Castelnau,P.; Lazarini,F.; Deslys,J.P.; Dormont,D. - Prion protein gene expression in cultured astrocytes treated by recombinant growth hormone and insulin-like growth factor - Experimental Neurology 1994 Dec; 130(2): 407-10 Collinge,J.; Whittington,M.A.; Sidle,K.C.L.; Smith,C.J.; Palmer,M.S.; Clarke,A.R.; Jefferys,J.G.R. - Prion protein is necessary for normal synaptic function - Nature 1994 Jul 28; 370(6487): 295-7 Denman,R.; Potempska,A.; Wolfe,G.; Ramakrishna,N.; Miller,D.L. - Distribution and activity of alternatively spliced Alzheimer amyloid peptide precursor and scrapie PrP mRNAs on rat brain polysomes - Archives of Biochemistry and Biophysics 1991 Jul; 288(1): 29-38 Forloni,G.; Angeretti,N.; Chiesa,R.; Monzani,E.; Salmona,M.; Bugiani,O.; Tagliavini,F. - Neurotoxicity of a prion protein fragment - Nature 1993 Apr 8; 362(6420): 543-6 Fournier,J.G.; Escaighaye,F.; Devillemeur,T.B.; Robain,O. - Ultrastructural localization of cellular prion protein (PrPc) in synaptic boutons of normal hamster hippocampus - Comptes Rendus de l'Academie des Sciences Serie III - Sciences de la Vie 1995 Mar; 318(3): 339-44 Gabriel,J.M.; Oesch,B.; Kretzschmar,H.; Scott,M.; Prusiner,S.B. - Molecular cloning of a candidate chicken prion protein - Proceedings of the National Academy of Sciences of the United States of America 1992 Oct 1; 89(19): 9097-101 Halabi,G.; Morelon,E.; Lavery,P.; Loertscher,R. - Beta(2) microglobulin (beta(2)m) supports the transport of the cellular prion glycoprotein (prpc) to the cell-surface - Kidney International 1995; 48(N1): 298 Harmey,J.H.; Doyle,D.; Brown,V.; Rogers,M.S. - The cellular isoform of the prion protein, PrP(C), is associated with caveolae in mouse neuroblastoma (N(2)a) cells - Biochemical and Biophysical Research Communications 1995 May 25; 210(3): 753-9 Harris,D.A.; Lele,P.; Snider,W.D. - Localization of the mRNA for a chicken prion protein by in situ hybridization - Proceedings of the National Academy of Sciences of the United States of America 1993 May 1; 90(9): 4309-13 Harris,D.A.; Huber,M.T.; van-Dijken,P.; Shyng,S.L.; Chait,B.T.; Wang,R. - Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites. - Biochemistry 1993 Feb 2; 32(4): 1009-16 Harris,D.A.; Falls,D.L.; Johnson,F.A.; Fischbach,G.D. - A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity - Proceedings of the National Academy of Sciences of the United States of America 1991 Sep 1; 88(17): 7664-8 Horiuchi,M.; Yamazaki,N.; Ikeda,T.; Ishiguro,N.; Shinagawa,M. - A cellular form of prion protein (PrPC) exists in many non- neuronal tissues of sheep - Journal of General Virology 1995 Oct; 76(Part 10): 2583-7 Hornshaw,M.P.; McDermott,J.R.; Candy,J.M. - Copper binding to the N-terminal tandem repeat regions of mammalian and avian prion protein - Biochemical and Biophysical Research Communications 1995 Feb 15; 207(2): 621-9 Huang,Z.W.; Cohen,F.E.; Prusiner,S.B. - Structural basis of prion diseases - Journal of Cellular Biochemistry 1995; 1995(S21B): 103 Huang,Z.W.; Gabriel,J.M.; Baldwin,M.A.; Fletterick,R.J.; Prusiner,S.B.; Cohen,F.E. - Proposed three-dimensional structure for the cellular prion protein - Proceedings of the National Academy of Sciences of the United States of America 1994 Jul 19; 91(15): 7139-43 Kretzschmar,H.A.; Prusiner,S.B.; Stowring,L.E.; DeArmond,S.J. - Scrapie prion proteins are synthesized in neurons - American Journal of Pathology 1986 Jan; 122(1): 1-5 Kurschner,C.; Morgan,J.I. - Analysis of interaction sites in homomeric and heteromeric complexes containing bcl-2 family members and the cellular prion protein - Molecular Brain Research 1996; 37(N1-2): 249-58 Kurschner,C.; Morgan,J.I. - The cellular prion protein (PrP) selectively binds to Bcl-2 in the yeast two-hybrid system - Molecular Brain Research 1995 May; 30(1): 165-8 Lazarini,F.; Castelnau,P.; Chermann,J.F.; Deslys,J.P.; Dormont,D. - Modulation of Prion Protein Gene Expression by Growth Factors in Cultured Mouse Astrocytes and PC-12 Cells - Molecular Brain Research 1994 Mar; 22(1-4): 268-74 Loertscher,R.; Lavery,P.; White,M.; Lazarovits,A.I. - Cellular prion protein (prpc) clusters with beta(2) microglobulin (beta(2)m) on the cell-surface of human- lymphocytes - Kidney International 1995; 48(N1): 298 Manson,J.C.; Clarke,A.R.; Hooper,M.L.; Aitchison,L.; McConnell,I.; Hope,J. - 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal - Molecular Neurobiology 1994 Apr-Jun; 8(2-3): 121-127 Manson,J.C.; West,J.D.; Thomson,V.; McBride,P.; Kaufman,M.H.; Hope,J. - The prion protein gene: a role in mouse embryogenesis? - Development 1992 May; 115(1): 117-22 McBride,P.A.; Eikelenboom,P.; Kraal,G.; Fraser,H.; Bruce,M.E. - PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice - Journal of Pathology 1992 Dec; 168(4): 413-8 Moser,M.; Colello,R.J.; Pott,U.; Oesch,B. - Developmental expression of the prion protein gene in glial cells - Neuron 1995 Mar; 14(3): 509-17 Nakahara,D.H.; Lingappa,V.R.; Chuck,S.L. - Translocational pausing is a common step in the biogenesis of unconventional integral membrane and secretory proteins - The Journal of Biological Chemistry 1994 Mar 11; 269(10): 7617-22 Oesch,B.; Moser,M.; Coufal,F.; Prusiner,S.B.; DeArmond,S.J. - Distribution of the prion protein and its ligands - implications for spongiform encephalopathies - Journal of Cellular Biochemistry 1995; 1995(S21B): 106 Shyng,S.L.; Moulder,K.L.; Lesko,A.; Harris,D.A. - The n-terminal domain of a glycolipid-anchored prion protein is essential for its endocytosis via clathrin-coated pits - The Journal of Biological Chemistry 1995 Jun 1; 270(24): 14793-800 Stahl,N.; Baldwin,M.A.; Hecker,R.; Pan,K.M.; Burlingame,A.L.; Prusiner,S.B. - Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid - Biochemistry 1992 Jun 2; 31(21): 5043-53 Taraboulos,A.; Scott,M.; Semenov,A.; Avraham,D.; Laszlo,L.; Prusiner,S.B. - Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform - The Journal of Cell Biology 1995 Apr; 129(1): 121-32 Toh,B.H.; Gibbs,C.J. Jr; Gajdusek,D.C.; Tuthill,D.D.; Dahl,D. - The 200- and 150-kDa neurofilament proteins react with IgG autoantibodies from chimpanzees with kuru or Creutzfeldt-Jakob disease; a 62-kDa neurofilament-associated protein reacts with sera from sheep with natural scrapie. - Proceedings of the National Academy of Sciences of the United States of America 1985 Jun; 82(11): 3894-6 Whatley,S.A.; Powell,J.F.; Politopoulou,G.; Campbell,I.C.; Brammer,M.J.; Percy,N.S. - Regulation of intracellular free calcium levels by the cellular prion protein - Neuroreport 1995; 6(N17): 2333-7 Whittington,M.A.; Sidle,K.C.L.; Gowland,I.; Meads,J.; Hill,A.F.; Palmer,M.S.; Jefferys,J.G.R.; Collinge,J. - Rescue of neurophysiological phenotype seen in prp null mice by transgene encoding human prion protein - Nature Genetics 1995 Feb; 9(2): 197-201
1) The calfs of the negative control group came from the same herds as the calfs from obviously BSE affected cows. Nobody knows whether the mothers of the control group have been BSE infected or not. It is hard to believe, but they can even not exclude that their calves consumed infectious foodstuff. This was a really poor experimental design.
2) The shortened the time of observation from possible 20 years down to only 7. In my oppinion they did this in order to reduce the total number of affected animals and eventualy to hide an increase in the BSE incidence with the age of the animals. As I mentioned before the British BSE statistic shows a decline of the BSE incidence after the age of 6, which may be caused by a BSE driven drop of milk productivity. The aborted experiment was a singular opportunity to demonstrated the true development of the BSE incidence without any covering factor of selection. In eyes it was a crime against science and public health to kill the remaining animals.
What SEAC did with the Weybridge data was so stupid, that it not relly deserves a comment. They subtracted the less than 5% of BSE in the control group from the more than 15% in the other because allegedly 5% of all calves eat infectious foodstuff and died of that. Does anybody wonder why they didn't see the possibillity of infcted mothers in both groups? Than they concluded without data that the risk of maternal transmission has to be 10% within the last 6 months before the mother dies and 0% if this timespan is 1 day longer. Then they divided this 6 months by the never experimentally proofed 60 months of mean BSE incubation time to get a risk of only 1%. A cow gets its first calf after 27-30 months and that the BSE incidences are equally when they get their third, fourth or fifth calve. Are the members of SEAC scientists or what?
How long did they live after they have born the control calves? Even if they lived for additional 10 years this could not proof that they were not infected. But I am sure they were killed much earlier. Can you tell us why this dams did not live at least until the end of the study?
It is not possible to exclude BSE at early stages histopathologically. It is much better do use immunological tests, but I do not know any experiment that demonstrates the detection of early stages of BSE. Can you give us such a reference?
The WKeybridge experiment has not proven that the calves must have been infected by maternal transmission. Indeed it is impossible to proof something with statistics, but you can calculate probabilities and it is very likely that the reason for the difference of BSE incidences between both groups is a difference of the effectivity of maternal transmission in relation to the stage of BSE of the mother.They did not compare calves from BSE cows with calves from not infected cows, but calves from late stage BSE cows with calves from non late stage BSE cows."
I did that in July and sent my calculations to the British embassy in august. They were not very happy with that"
If the incidence of BSE does only decline with the age of older cows because of a selective slaughtering of cows with unsatisfactory milk production, than the rate of maternal transmission is not 9-14%. If the real BSE incidence only stays constant, then the rate of maternal tranmission is 30-45%. If I am right and the BSE incidence increases with the age of a cow, then the rate maternal transmission would be much higher."
In the USA Gibs et al. within the ministry of agriculture inoculated cattle with scrapie as early as 1979 and knew about the transmissibility of scrapie to cattle since 1980. Perhaps the british BSE epidemy could have been minimized if they had published that result. But they published it in 1990!"