Publications

chemical chaperones interfere with the formation of scrapie prion protein.	the fundamental event in prion diseases involves a conformational change in one or more of the alpha-helices of the cellular prion protein (prp(c)) as they are converted into beta-sheets during the formation of the pathogenic isoform (prp(sc)). here, we show that exposure of scrapie-infected mouse neuroblastoma (scn2a) cells to reagents known to stabilize proteins in their native conformation reduced the rate and extent of prp(sc) formation. such reagents include the cellular osmolytes glycerol ...	1996	8978663
detection of scrapie agent in the peripheral nervous system of a diseased sheep.	in an attempt to determine whether scrapie infectivity can be found in the peripheral nervous system of a scrapie-diseased sheep, mice were inoculated intracerebrally or intraperitoneally with 10-fold dilutions of homogenates of nervus (n.) axillaris, n. ulnaris, n. medianus, n. ischiadicus, n. tibialis, n. fibularis, and n.saphenus. mice were observed for clinical signs of scrapie for 700 days and their brains were analyzed for accumulation of pathological prion protein by immunoblot. substanti ...	1996	8980019
recombinant scrapie-like prion protein of 106 amino acids is soluble.	the n terminus of the scrapie isoform of prion protein (prpsc) can be truncated without loss of scrapie infectivity and, correspondingly, the truncation of the n terminus of the cellular isoform, prpc, still permits conversion into prpsc. to assess whether additional segments of the prp molecule can be deleted, we previously removed regions of putative secondary structure in prpc; in the present study we found that deletion of each of the four predicted helices prevented prpsc formation, as did ...	1996	8986833
separating the environmental and genetic factors that may be causes of bovine spongiform encephalopathy.	the initial cause of the bovine spongiform encephalopathy (bse) epidemic is generally accepted to have been the feeding of infected animal protein to cattle. the proportion of animals affected in any year in a particular herd has generally been low. this suggests either considerable variation in the extent of challenge of the individual animals or variation in their susceptibility to challenge or both. there is known to be genetic variation in susceptibility in other spongiform encephalopathies, ...	1996	8856808
endosome-lysosomes, ubiquitin and neurodegeneration.	before the advent of ubiquitin immunochemistry and immunogold electron microscopy, there was no known intracellular molecular commonality between neurodegenerative diseases. the application of antibodies which primarily detect ubiquitin protein conjugates has shown that all of the human and animal idiopathic and transmissible chronic neurodegenerative diseases, (including alzheimer's disease (ad), lewy body disease (lbd), amyotrophic lateral sclerosis (als), creutzfeldt-jakob disease (cjd) and s ...	1996	8861020
mad cow disease and creutzfeldt-jakob disease--is there a link?	the report of the creutzfeldt-jakob surveillance unit from march 1996 regarding 10 cases of a new variant of creutzfeldt-jakob disease (cjd) in young adults caused a great deal of uproar when it was suggested that a possible link with bovine spongiform encephalopathy (bse) could not be excluded. bse was first noticed in 1986 after the introduction of modified rendering systems in the manufacture of meat and bone meal containing animal wastes contaminated with scraple-like agents. this article re ...	1996	8863351
how do neurons degenerate in transmissible spongiform encephalopathies?	neuroaxonal dystrophy is a feature of neuronal degeneration encountered in all subacute spongiform virus encephalopathies including scrapie and creutzfeldt-jakob disease (cjd). by immunohistochemical techniques, the accumulation of 200 kda neurofilament protein was demonstrated in affected neurites in human cjd. these neurites exhibited the ultrastructural features of dystrophic neurites encountered in other neurodegenerative disorders, particularly alzheimer's disease. these findings support th ...	1996	8871966
partial unfolding and refolding of scrapie-associated prion protein: evidence for a critical 16-kda c-terminal domain.	the conversion of the normal form of prion protein (prpc) to a disease-specific form (prpsc) is a central event in scrapie and other transmissible spongiform encephalopathies. prpsc is distinguished from prpc by its insolubility and its resistance to proteolysis. prpsc is also capable of converting 35s-prpc, in vitro, into a form which is indistinguishable from prpsc with respect to its protease-sensitivity. both the "converting activity" and the protease-resistance of isolated hamster prpsc can ...	1996	8873612
electrophoretic analysis of nucleic acids isolated from scrapie-infected hamster brain.	the purpose of this study was to investigate previous reports of a scrapie-specific 1.2 kb single-stranded dna observed in alkaline agarose electrophoresis gels. protocols were developed to be as consistent as possible with those used previously. partial subcellular fractionation was applied to the brains of hamsters clinically affected by the 263k strain of scrapie. nucleic acids were then isolated, and compared electrophoretically to nucleic acids isolated from equivalent fractions, made from ...	1996	8811040
the m22 antibody identifies highly activated reactive astrocytes responding to central nervous system disease.	astrocytes respond vigorously to diverse neurological insults. it is still not clear, however, whether this response is stereotypic following different insults or varies according to the injury. we have used a novel immunocytochemical marker of reactive astrocytes, termed m22, together with antibodies to glial fibrillary acidic protein (gfap), to analyze region- and insult-specific differences in reactive astrocytosis in the murine central nervous system (cns). pathology was variously induced by ...	1996	8834543
differential effects of a new amphotericin b derivative, ms-8209, on mouse bse and scrapie: implications for the mechanism of action of polyene antibiotics.	mice were infected intracerebrally with the bovine spongiform encephalopathy (bse) or the scrapie agent and treated during 8 weeks postinfection to test the protective effect of a new amphotericin b (amb) derivative, ms-8209, in experimental transmissible spongiform encephalopathies. the results show that (i) the treatment prolonged the incubation period of both bse-infected and scrapie-infected mice, (ii) ms-8209 and amb were much more efficient in delaying the onset of scrapie than that of bse ...	1996	8837228
evidence for an early inflammatory response in the central nervous system of mice with scrapie.	in alzheimer's disease, the most prevalent of the neurodegenerative diseases, inflammation of the cns contributes to the pathology and is a target for therapy. in contrast, the group of neurodegenerative conditions known as the prion diseases have been widely reported as lacking any inflammatory elements despite the many similarities between the pathologies of alzheimer's disease and prion diseases we have found evidence for an inflammatory component in mouse scrapie, characterized by microglial ...	1996	8843071
histopathological changes in the islets of langerhans in hamsters infected with the 139h strain of scrapie: semi-thin section study.	using histopathological analysis of semi-thin sections stained with toluidine blue, we observed profound pathological changes in the islets of langerhans of hamsters infected with the scrapie agent (strain 139h). these included cytoplasmic vesicles, nuclear swelling, and vacuolization in the islet cells. two types of vacuolization were seen. "localized vacuolization" (lv) has a distinct edge and is restricted or confined within the cell. "diffuse vacuolization" (dv) has no distinct edge and is s ...	1996	8720460
immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie.	the scrapie-associated form of the prion protein (prpsc) accumulates in the brain and lymphoid tissues of sheep with scrapie. in order to assess whether detecting prpsc in lymphoid tissue could be used as a diagnostic test for scrapie, we studied the localization and distribution of prpsc in various lymphoid tissues collected at necropsy from 55 sheep with clinical scrapie. samples collected from the spleen, palatine tonsil, ileum, and five different lymph nodes were immunohistochemically staine ...	1996	8727908
ultrastructural immuno-localization of synthetic prion protein peptide antibodies in 87v murine scrapie.	disease specific forms of a host encoded cell surface sialoglycoprotein called prion protein (prp) accumulate during this incubation period of the transmissible spongiform encephalopathies. a 33-35 kda disease specific form of prp is partially resistant to protease digestion whereas the normal form of prp can be completely digested. proteinase k digestion of the murine disease specific form of prp produces diverse forms of low molecular weight prp, some of which are n-terminally truncated at ami ...	1996	8731389
the uk epidemic of bse: slow virus or chronic pesticide-initiated modification of the prion protein? part 2: an epidemiological perspective.	this paper elucidates the flaws in the official hypothesis that bovine spongioform encephalopathy originated from alterations in the way that scrapie-contaminated cattlefeeds were manufactured in the uk. an alternative hypothesis is proposed that cites exposure of the bovine embryo to various specific high-dose lipophilic formulations of organophosphates, such as the high-dose phthalimide containing organophosphate phosmet, (which were applied compulsorily and exclusively in the uk during the 19 ...	1996	8735882
mouse inoculation studies reveal no transmissible agent in amyotrophic lateral sclerosis.	amyotrophic lateral sclerosis (als) resembles the spongiform encephalopathies in its dual pattern of inherited and sporadic cases, its uniform prevalence in different populations, its late onset (suggestive of a long incubation period) and its pathological picture of neuronal degeneration without inflammation. there is a well-established protocol for primary transmission of scrapie and related diseases to mice. using this, we inoculated four longlived, inbred, mouse strains with cord material fr ...	1996	8737921
prion protein amyloidosis.	the prion protein (prp) plays an essential role in the pathogenesis of a group of sporadic, genetically determined and infectious fatal degenerative diseases, referred to as "prion diseases", affecting the central nervous system of humans and other mammals. the cellular prp is encoded by a single copy gene, highly conserved across mammalian species. in prion diseases, prp undergoes conformational changes involving a shift from alpha-helix to beta-sheet structure. this conversion is important for ...	1996	8737929
infectivity in extraneural tissues following intraocular scrapie infection.	intraocular (i.o.) infection of mice with scrapie produces strain-specific targeting of replication and subsequent pathology within the visual system projection areas in the cns, but also initiates an extraneural infection. following i.o. infection with me7 scrapie, infectivity was detected 24 h later in the harderian gland, the superficial cervical lymph nodes (sclns) and the spleen, but not until 20 days in peyer's patches and inguinal lymph nodes (ilns). persistent low levels of infectivity w ...	1996	8887504
prp genotype contributes to determining survival times of sheep with natural scrapie.	several allelic variants of the sheep prp gene are associated with scrapie susceptibility. however, it is not known whether, and to what extent, the prp genotype contributes to determining survival times of scrapie sheep. we therefore determined the prp genotype and life spans of over 50 flemish and swifter sheep within a single scrapie-affected flock. eighty-three per cent of the scrapie sheep were homozygous for the prp(vq) allele (polymorphic amino acids at codons 136 and 171 are indicated) a ...	1996	8887505
reduction of the infectivity of scrapie agent as a model for bse in the manufacturing process of trasylol.	the trasylol manufacturing process was investigated with respect to its capacity for the inactivation/removal of infectivity causing bovine spongiform encephalopathy (bse). four process steps were selected for this investigation and scaled down to laboratory scale. authentic samples of bovine lungs used in the trasylol manufacturing plant were taken and spiked in laboratory scale experiments with high infectious titres of the rodent adapted scrapie strain me 7 which served as model for bse. afte ...	1996	8889056
a neurotoxic prion protein fragment enhances proliferation of microglia but not astrocytes in culture.	the scrapie isoform of the prion protein (prpsc) induces pathological changes in the central nervous system including neurodegeneration and gliosis. a synthetic prion protein (prp) peptide corresponding to amino acid residues 106-126 has been shown to be toxic to neurons that express prpc, the cellular isoform of prp. here we show that in mixed glial cultures prp106-126 induces astroglial proliferation that is dependent on cellular prpc expression. in purified cultures of glial subtypes only mic ...	1996	8891692
no maternal transmission?		1996	8900261
aberrant induction of neuropeptide y mrna in hippocampal ca3 pyramidal neurones in scrapie-infected mice.	the neurochemical alterations preceding neurological dysfunction and neuronal death in prion diseases are not well characterized. here we examined, using in situ hybridization histochemistry, the expression of neuropeptide y (npy), an inducible and abundant neuropeptide in mammalian brain with known neuroregulatory functions, and glial fibrillary acidic protein (gfap), a marker for astroglial activation, in the hippocampus at different time points following intracerebral prion inoculation in mal ...	1996	8905686
comparison of biochemical extraction techniques for the detection of scrapie-associated fibrils in the central nervous system of sheep naturally affected with scrapie.	standardized samples of brain material from four sheep naturally affected with scrapie and from four healthy control sheep were subjected to six different extraction techniques used for the detection of scrapie-associated fibrils by negative-contrast transmission electron microscopy. the six methods were compared in respect of fibril yield and clarity of ultrastructure. the simplest method consisting of a single n-lauroylsarcosine detergent extraction and differential centrifugation, followed by ...	1996	8910745
prion protein amyloid: separation of scrapie infectivity from prp polymers.	the prion protein (prp) undergoes a profound conformational change when the cellular isoform (prpc) is converted into the scrapie form (prpsc). limited proteolysis of prpsc produces prp27-30 which readily polymerizes into amyloid. to study the structure of prp amyloid, we employed organic solvents that perturb protein conformation. 1,1,1,3,3,3-hexafluoro-2-propanol (hfip), which promotes alpha-helix formation, modified the ultrastructure of rod-shaped prp amyloids, producing flattened ribbons wi ...	1996	8915611
normal host prion protein (prpc) is required for scrapie spread within the central nervous system.	mice devoid of prpc (prnp%) are resistant to scrapie and do not allow propagation of the infectious agent (prion). prpc-expressing neuroectodermal tissue grafted into prnp% brains but not the surrounding tissue consistently exhibits scrapie-specific pathology and allows prion replication after inoculation. scrapie prions administered intraocularly into wild-type mice spread efficiently to the central nervous system within 16 weeks. to determine whether prpc is required for scrapie spread, we ino ...	1996	8917559
margination and diapedesis of inflammatory cells in the islets of langerhans in hamsters infected with the 139h strain of scrapie.	the islets of langerhans in hamsters infected with the 139h strain of scrapie contain large masses of red blood cells not surrounded by the usual arterial, venous or capillary wall cells. we have referred to these structures as "blood vessel cores" (bvcs). bvcs were almost always centrally located within the islets and surrounded by pancreatic b cells. margination and diapedesis of inflammatory cells were observed at the bvc walls in 139h-infected hamsters. the cells consisted of the following t ...	1996	8920215
improvement of prpsc-detection in mouse spleen early at the preclinical stage of scrapie with collagenase-completed tissue homogenization and sarkosyl-nacl extraction of prpsc.	scrapie in sheep has recently become again a target of control measures and eradication programs. crucial for the effectiveness of these measures is the detection of infected sheep during the long and potentially hazardous incubation period. however, routine-diagnosis is mostly limited to clinical examinations when disease becomes apparent, and to postmortem investigations. through the detection of the scrapie-specific isoform of the prion protein (prpsc) by western blot in the spleen and lymph ...	1996	8920821
intracellular calcium rise through l-type calcium channels, as molecular mechanism for prion protein fragment 106-126-induced astroglial proliferation.	the infectious prion protein (prpsc) is the etiologic agent of transmissible neurodegenerative conditions such as scrapie or creutzfeldt-jakob disease. its fragment 106-126 (prp106-126) has been reported to maintain most of the pathological features of prpsc. we report here the intracellular mechanisms mediating the proliferative effects of prp106-126 on rat cortical type i astrocytes. the proliferative effects of prp106-126 started after 24h of treatment and lasted up to 9 days and was antagoni ...	1996	8920926
novel polymorphisms in the caprine prp gene: a codon 142 mutation associated with scrapie incubation period.	age at disease onset and rate of progression of transmissible spongiform encephalopathies in man, sheep and mice are modulated by the host genome, in particular by the prp gene and its allelic forms. analysis of the caprine prp gene revealed several different alleles. four prp protein variants were found, three of which were goat specific with single amino acid changes at codons 142, 143 and 240. the fourth was identical to the most common sheep prp protein variant (ala136-arg154-gln171). the di ...	1996	8922485
polymorphism at codon 129 of the prion protein gene determines cerebellar pathology in creutzfeldt-jakob disease.	creutzfeldt-jakob disease (cjd) is a transmissible neurodegenerative disorder characterized by the accumulation of proteinase-resistant prion protein (prp) in the brain. pathological changes in the cerebellum are common and include atrophy of the granular layer, spongiform change in the molecular layer, and astrocytic gliosis of the cerebellar cortex and white matter. in most cases of sporadic cjd immunohistochemistry for prp shows widespread granular deposits of the scrapie isoform of the prion ...	1996	8937783
scrapie: recent trends.		1996	8941420
how many phenotypes from one genotype? the case of prion diseases.	the usual assumption, namely that the underlying biochemical reactions in an organism tend to a unique steady-state, is shown to be not always correct. there are certain pathway mechanisms (e.g. positive feedback) which allow the system to exists in two alternative stable steady states. this bistability implies that environmental perturbations can "switch" the system from either state to the other. such a switch takes place at the metabolic level and hence a single genotype can display two diffe ...	1996	8944151
immunolocalisation of the prion protein (prp) in the brains of sheep with scrapie.	cheviot sheep from the neuropathogenesis unit flock were examined for prp in brain sections using immunocytochemistry in order to aid scrapie diagnosis. brains were collected from sheep which had been naturally or experimentally infected with scrapie and fixed in periodate-lysine-paraformaldehyde or in formalin. immunolabelling was achieved using a monoclonal antibody (fh11) raised to the n-terminus of recombinant prp protein. several pre-treatments were studied in an effort to enhance prp immun ...	1996	8953691
sleep, genes and death: fatal familial insomnia.	over the past 30 years, significant progress has been made in understanding the physiologic mechanisms of sleep. insomnia, a common complaint in general medical practice, and other sleep disorders have become increasingly recognized. in 1986, a heritable total insomnia was described and termed fatal familial insomnia; since then, the pathology of this disease has been shown to involve an accumulation of prion particles in the brains of affected patients. prions have been more commonly associated ...	1996	8957563
subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains.	results of transgenetic studies argue that the scrapie isoform of the prion protein (prpsc) interacts with the substrate cellular prp (prpc) during conversion into nascent prpsc. while prpsc appears to accumulate primarily in lysosomes, caveolae-like domains (clds) have been suggested to be the site where prpc is converted into prpsc. we report herein that clds isolated from scrapie-infected neuroblastoma (scn2a) cells contain prpc and prpsc. after lysis of scn2a cells in ice-cold triton x-100, ...	1996	8962161
[several problems concerning bovine spongiform encephalopathy].		1996	8965331
[studies on prion diseases].		1996	8966477
eu stops fiddling while cows burn.		1996	8966596
activation effects of a prion protein fragment [prp-(106-126)] on human leucocytes.	prion-related encephalopathies are characterized by the intracerebral accumulation of an abnormal isoform of the cellular prion protein (prpc) named scrapie prion protein (prpsc). the pathological forms of this protein and its cellular precursor are not only expressed in the brain but also, at lower concentrations, in peripheral tissues. we recently showed that a synthetic peptide corresponding to residues 106-126 [prp-(106-126)] of the human prp is toxic to neurons and trophic to astrocytes in ...	1996	8973567
a review of the epidemiology of scrapie in sheep.	the aim of this review is to summarise and evaluate the data available about the aetiology of scrapie in naturally affected sheep flocks, particularly data concerning the possible transmission of infection between related animals. the author examines data taken from various relevant studies carried out over the last thirty years. the main conclusions are that scrapie is an infectious disease with a genetic influence on the incubation period. the increased risk of disease in the offspring of affe ...	1996	9025137
bovine spongiform encephalopathy: an update.	a specialist group of the office international des epizooties met in may 1996 to prepare updated information on bovine spongiform encephalopathy (bse): in particular on the development of the epidemic, geographical incidence, nature of the disease, transmission, precautions and control measures. a revised chapter 3.2.13. of the international animal health code dealing with bse, and an outline of the spongiform encephalopathies, are appended, along with a comprehensive bibliography.	1996	9025153
scrapie prions: a three-dimensional model of an infectious fragment.	a conformational change seems to represent the major difference between the scrapie prion protein (prpsc) and its normal cellular isoform (prpc). we recently proposed a set of four helix bundle models for the three-dimensional structure of prpc that are consistent with a variety of spectroscopic and genetic data.	1996	9079359
transmissible encephalopathies and biopharmaceutical production.	the use of post-mortem tissues as sources for the production of biologicals, vaccines and feedstuffs has led to the transmission or generation of transmissible encephalopathies in some recipients. for example, the use of pituitary-derived human growth hormone and gonadotropins has resulted in the transmission of creutzfeldt-jakob disease to other humans [1], the use of formalin-inactivated sheep brain as a source for louping ill vaccine led to the transmission of scrapie to over 1,000 sheep from ...	1996	9119144
analysis of risk to biomedical products developed from animal sources (with special emphasis on the spongiform encephalopathy agents, scrapie and bse).	factors that must be considered in estimations of risk from exposure to adventitious contaminants of animal derived biologicals include: (i) the use of the product; (ii) the routes of administration and exposure to potential pathogens; (iii) the source of animal(s) and their history and maintenance; (iv) the tissue(s) used in the product and their likelihood of harbouring or being contaminated by an agent; (v) the methods by which the animal is slaughtered and the tissue(s) collected; (vi) the p ...	1996	9119146
transmissible spongiform encephalopathies (tse): minimizing the risk of transmission by biological/biopharmaceutical products: an industry perspective.	several guidelines and recommendations have been published on assessing the potential risk of a biological product being contaminated with an agent causing a transmissible spongiform encephalopathy (tse). basic principles which can be used during the manufacturing of biological products to minimize the risk of transmission of tse agents include the following: (i) obtaining animals, tissues or animal-derived raw materials from countries in which the relevant tse agent is reported to be absent; (i ...	1996	9119148
minimization of viral contamination in human pharmaceuticals produced in the milk of transgenic goats.	the minimization of viral contamination in therapeutic proteins produced in transgenic goats' milk can be achieved by a combinatorial approach. it begins with reduction in the risk in the starting material followed by appropriate clearance/inactivation steps in the purification process. to minimize risk in the starting material, genzyme transgenics corporation (gtc)'s closed goat herds are subjected to routine serological surveillance for known viral diseases, especially those transmitted throug ...	1996	9119149
[prion diseases and a new variant of creutzfeldt-jakob disease].	the causal link of a new variant of cjd (v-cjd) with bovine spongiform encephalopathy (bse) has led to world-wide panic. bse emerged in 1986 through dietary products contaminated with scrapie pathogen, bse case reports increased in number up to 37,000/year in 1993, then declined in 1994 when the first case of v-cjd emerged. there is a 3-year gap between the emergence of bse and the introduction of a ban on the use of specified bovine offal in human food. people might have consumed dietary produc ...	1996	9128415
[bovine spongiform encephalopathy. second update of data collected since the report of february 6, 1996].	the observation in 1995 and 1996 of 12 cases of a new variant of creutzfeldt-jakob disease (v-cjd) in u.k. suggested a possible relation between this human cases and bovine spongiform encephalopathy (bse). recent papers about this topic are reviewed: bse transmission to macaques, transmission of scrapie with embryo transfer, incidence of maternal transmission, prp protein released by platelets, diagnostic test by detection of prp protein in tissues of sheep, epidemiology of bse, french regulatio ...	1996	8991617
the effect of dry heat on the me7 strain of mouse-passaged scrapie agent.	partial survival of lyophilized scrapie agent has been reported previously following exposure to dry heat at 360 degrees c for 1 h, and led to speculation that scrapie-like agents might not be completely inactivated by incineration. however, it is known that dried infectivity is more difficult to inactivate by heat than that in hydrated samples. in this present study it was shown that the infectivity in macerates of mouse-brain infected with the me7 strain of scrapie agent was not completely ina ...	1996	9000112
prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations.		1996	9246476
the role of prp in pathogenesis of experimental scrapie.		1996	9246477
medical microbiology	subacute progressive degenerative diseases of the nervous system are important because they appear to be caused by infectious agents that are smaller than conventional viruses and composed mainly of protein related to a cell protein. few, if any, of these diseases are curable. although some are genetically determined, most occur sporadically, and a history of the disease does not appear in close relatives. therefore, ...	1996	21413288
prion protein and the transmissible spongiform encephalopathies.	transmissible spongiform encephalopathies (tses) are fatal neurodegenerative diseases that occur in a wide variety of mammals. in humans, tse diseases include kuru, sporadic and iatrogenic creutzfeldt-jakob disease (cjd), gerstmann-sträussler-scheinker syndrome (gss), and fatal familial insomnia (ffi). so far, tse diseases occur only rarely in humans; however, scrapie is a widespread problem in sheep, and the recent epidemic of bovine spongiform encephalopathy (bse or mad cow disease) has seriou ...	1997	17708907
blockade of glycosylation promotes acquisition of scrapie-like properties by the prion protein in cultured cells.	the conformational conversion of the prion protein, a sialoglycoprotein containing two n-linked oligosaccharide chains, from its normal form (prpc) to a pathogenic form (prpsc) is the central causative event in prion diseases. although prpsc can be generated in the absence of glycosylation, there is evidence that oligosaccharide chains may modulate the efficiency of the conversion process, and may also serve as molecular markers of diverse prion strains. in addition, mutational inactivation of o ...	1997	9261166
prp genetics in sheep and the applications for scrapie and bse.	the strong links between prp genotype and the occurrence of scrapie in sheep strengthen evidence supporting the central importance of the prp protein in the development of transmissible spongiform encephalopathies, despite the fact that the cattle prp gene has, so far, failed to show any association between prp alleles and susceptibility to bse.	1997	9263413
engineering peptides and proteins that undergo alpha-to-beta transitions.	in the 'protein-only' hypothesis, prion diseases are proposed to be the result of conformational changes of the normal form of the prion protein (prpc) with a highly alpha-helical conformation to a pathogenic scrapie form (prpsc) with a predominantly beta-sheet conformation. recent studies examining the folding process of proteins, as well as the amyloidogenesis of peptides and proteins including prion proteins, alzheimer's beta-peptides and other pathogenic protein mutants, have provided insigh ...	1997	9266171
huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo.	the mechanism by which an elongated polyglutamine sequence causes neurodegeneration in huntington's disease (hd) is unknown. in this study, we show that the proteolytic cleavage of a gst-huntingtin fusion protein leads to the formation of insoluble high molecular weight protein aggregates only when the polyglutamine expansion is in the pathogenic range. electron micrographs of these aggregates revealed a fibrillar or ribbon-like morphology, reminiscent of scrapie prions and beta-amyloid fibrils ...	1997	9267034
the scrapie enigma: insights from radiation experiments. 1993.		1997	9273353
[expanded illness spectrum of human spongiform encephalopathies or prion diseases].	since its first description by h.g. creutzfeldt and a. jakob, six forms of human spongiform encephalopathies have been described. besides creutzfeldt-jakob disease (cjd), a new variant cjd (nvcjd), gerstmann-sträussler-scheinker syndrome (gss), fatal familial insomnia (ffi) and potentially familial progressive subcortical gliosis have been reported. the most likely causative agent of these and at least six animal-transmissible spongiform encephalopathies (tse) is a structurally altered form of a ...	1997	9273460
natural scrapie and prp genotype: case-control studies in british sheep.	natural scrapie in sheep is associated with polymorphisms of the prp gene, particularly at amino acid codons 136, 154 and 171. this paper reports the results of nine scrapie case-control studies in bleu du maine, herdwick, merino x shetland, poll dorset, scottish halfbred, shetland, soay, suffolk and swaledale sheep from british flocks affected by scrapie. in some outbreaks, scrapie was found to occur only in animals with at least one prp allele encoding valine at codon 136 (v136), usually a rel ...	1997	9280041
[prion disease in animals and experimental prion disease].		1997	9282362
prp-expressing tissue required for transfer of scrapie infectivity from spleen to brain.	much available evidence points to a pathological isoform of the prion protein prp being the infectious agent that causes transmissible spongiform encephalopathies, but the mechanisms controlling the neurotropism of prions are still unclear. we have previously shown that mice that do not express prp (prnp[o/o] mice) are resistant to infection by prions, and that if a prnp(+/+) neurograft is introduced into such animals and these are infected intracerebrally with scrapie, the graft but not the sur ...	1997	9288968
the 139h scrapie agent produces hypothalamic neurotoxicity and pancreatic islet histopathology: electron microscopic studies.	neuronal degeneration, along with astrocytosis, spongiform vacuolation, and amyloid (prpsc) formation, have long been regarded as neuropathological hallmarks of transmissible spongiform encephalopathies (tses). in animals, these diseases include; scrapie, transmissible mink encephalopathy, chronic wasting disease, bovine and feline spongiform encephalopathies, and in humans; kuru, creutzfeldt-jakob disease (cjd), and gerstmann-sträussler-scheinker syndrome (gss). the abnormal amyloid protein, (p ...	1997	9291501
immunodetection of prpsc in spleens of some scrapie-infected sheep but not bse-infected cows.	the development of diagnostic tools for transmissible spongiform encephalopathies (tses) would greatly assist their study and may provide assistance in controlling the disease. the detection of an abnormal form of the host protein prp in noncentral nervous system tissues may form the basis for diagnosis of tses. using a new antibody reagent to prp produced in chickens, prp can be readily detected in crude tissue extracts. prp from uninfected spleen had a lower molecular mass range than prp from ...	1997	9292029
the nature of transmission in prion diseases.	replicating biological information is usually stored only within nucleic acid. the existence of 'strains' of agent in prion disease (scrapie, bse, cjd) has been taken to indicate an independent genome within the transmissible agent. other replicable information exists, however, both in biology and elsewhere, including, for example, the 'meme' (the neutral correlate of ideas which replicate in human brains by communication) and the computer virus. from this broader viewpoint, we explore the possi ...	1997	9292865
the key must fit: macrophages transport prion infection to the central nervous system and may determine the sites of infection within it.	it is suggested that the agent for transmissible spongiform encephalopathies is transferred from an original peripheral site of infection into the brain by recruited and selected circulating macrophages/monocytes. it is because of this selection that strains of disease appear to be different when infecting separate species, but retain characteristics when infecting a single species.	1997	9293465
evidence for protein x binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation.	studies on the transmission of human (hu) prions to transgenic (tg) mice suggested that another molecule provisionally designated protein x participates in the formation of nascent scrapie isoform of prion protein (prpsc). we report the identification of the site at which protein x binds to the cellular isoform of prp (prpc) using scrapie-infected mouse (mo) neuroblastoma cells transfected with chimeric hu/moprp genes even though protein x has not yet been isolated. substitution of a hu residue ...	1997	9294164
solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform.	the scrapie prion protein (prpsc) is the major, and possibly the only, component of the infectious prion; it is generated from the cellular isoform (prpc) by a conformational change. n-terminal truncation of prpsc by limited proteolysis produces a protein of approximately 142 residues designated prp 27-30, which retains infectivity. a recombinant protein (rprp) corresponding to syrian hamster prp 27-30 was expressed in escherichia coli and purified. after refolding rprp into an alpha-helical for ...	1997	9294167
differential allelic expression of prp mrna in carriers of the e200k mutation.	creutzfeldt-jakob disease (cjd) linked to the e200k mutation of the prion protein (prp) gene presents with a wide range of age at disease onset. since most patients are heterozygous for the mutation, we tested whether differential expression of mutant versus wild-type (wt) prp may affect the age at disease onset in carriers of the mutation. we measured wt and mutant prp protein and mrna in epstein-barr virus (ebv)-transformed b cells of either e200k cjd patients or healthy e200k carriers. our re ...	1997	9305353
the risk of bovine spongiform encephalopathy ('mad cow disease') to human health.	some human cases of the transmissible neurodegenerative disorder creutzfeldt-jakob disease recently seen in great britain are thought to have resulted from eating beef infected with the agent of bovine spongiform encephalopathy. reasons for and against this presumption are explained, and the question of a similar situation occurring in countries other than britain-in particular, the united states-is discussed in terms of the existence of scrapie (in sheep) or unrecognized bovine spongiform encep ...	1997	9307349
astrocyte-specific expression of hamster prion protein (prp) renders prp knockout mice susceptible to hamster scrapie.	transmissible spongiform encephalopathies are characterized by spongiosis, astrocytosis and accumulation of prpsc, an isoform of the normal host protein prpc. the exact cell types responsible for agent propagation and pathogenesis are still uncertain. to determine the possible role of astrocytes, we generated mice devoid of murine prp but expressing hamster prp transgenes driven by the astrocyte-specific gfap promoter. after inoculation with hamster scrapie, these mice accumulated infectivity an ...	1997	9321385
prion protein and scrapie susceptibility.	this article presents briefly current views on the role of prion protein (prp) in transmissible spongiform encephalopathies or prion diseases and the effect of prp polymoryhisms on the susceptibility to these diseases, with special emphasis on sheep scrapie. the prp genotype of sheep appears to be a major risk factor for scrapie, and polymorphisms at codons 136, 154, and 171 modulate the susceptibility of sheep for scrapie. nevertheless, scrapie is not a spontaneous genetic disease alone. we des ...	1997	9323849
control of scrapie eventually possible?	after a brief description of the scrapie situation in the netherlands, the technical progress made in aspects of scrapie diagnosis is reported. emphasis is placed on the use of immuno-histochemistry (ihc) in the post-mortem histological diagnosis and on the recently published preclinical test for scrapie, in which ihc is applied to tonsillar biopsies. these two approaches use the same ihc technique and enable us to confirm suspected scrapie in individual animals, and for certain genotypes even i ...	1997	9323850
health hazards to the small ruminant population of the middle east posed by the trade of sheep and goat meat.	meat consumers in the middle east traditionally prefer meat from freshly slaughtered animals to that from chilled or frozen carcasses. consequently, meat trade in the middle east is based mainly upon the importation of large quantities of live animals rather than of sheep and goat carcasses. furthermore, as it seems that pathogens remain viable for longer periods of time in live animals than in meat, the probability of pathogens spreading in the middle east as a result of contaminated small rumi ...	1997	9329108
bovine spongiform encephalopathy: the causal role of ruminant-derived protein in cattle diets.	although bovine spongiform encephalopathy (bse) has occurred in other european countries, the major epidemic has been in the united kingdom (uk), where there have been more than 163,000 cases so far. bse has been linked to the practice of feeding meat-and-bone meal (mbm), putatively contaminated with scrapie agent, to cattle. a ban on the feeding of mbm to ruminants in the uk has resulted in a significant decline in the number of reported cases. it is considered that bse in other european countr ...	1997	9329116
risks of transmitting scrapie and bovine spongiform encephalopathy by semen and embryos.	this paper reviews current knowledge on transmission of scrapie and bovine spongiform encephalopathy (bse) by semen and embryos. in sheep, in particular, it is difficult to distinguish between the genetic transmission of susceptibility to scrapie and vertical transmission of the infection. nevertheless, there is evidence that vertical transmission of infection does occur, probably across the placenta, but none to suggest a significant scrapie risk from semen. two teams have studied scrapie trans ...	1997	9329121
amyloid angiopathy and blood-brain barrier changes in alzheimer's disease.	evidence is accumulating that suggests that increased permeability of the bbb to blood-borne proteins is favorable for the development of neuropathologic changes such as amyloid angiopathy and formation of amyloid plaques in the ad brain. to study this problem, we applied a quantitative immunocytochemical procedure that enables evaluation of the barrier function of brain microvasculature to endogenous albumin. this procedure was successfully used on scrapie-infected mice, which represent a uniqu ...	1997	9329688
use of capillary sodium dodecyl sulfate gel electrophoresis to detect the prion protein extracted from scrapie-infected sheep.	scrapie in sheep and in goats is the prototype of a group of transmissible spongiform encephalopathies (tse). a feature of these diseases is the accumulation in the brain of rod shaped fibrils that form from an aggregated protein that is a protease-resistant form of a modified normal host cell protein. in this study, we compared sds gel capillary electrophoresis to conventional sds-page and western blot to detect the monomer of this aggregated protein. this prion protein was extracted from the s ...	1997	9342673
rna aptamers specifically interact with the prion protein prp.	we have isolated rna aptamers which are directed against the recombinant syrian golden hamster prion protein rprp23-231 (rprpc) fused to glutathione s-transferase (gst). the aptamers did not recognize the fusion partner gst or the fusion protein gst::rprp90-231 (rprp27-30), which lacks 67 amino acids from the prp n terminus. the aptamer-interacting region of prpc was mapped to the n-terminal amino acids 23 to 52. sequence analyses suggest that the rna aptamers may fold into g-quartet-containing ...	1997	9343239
a hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis.	neuronal death and vacuolation are characteristics of the cns degeneration found in prion diseases. relatively few cultured cell lines have been identified that can be persistently infected with scrapie prions, and none of these cells show cytopathologic changes reminiscent of prion neuropathology. the differentiated neuronal cell line gt1, established from gonadotropin hormone releasing-hormone neurons immortalized by genetically targeted tumorigenesis in transgenic mice (p. l. mellon, jj. wind ...	1997	9343242
syrian hamster prion protein (prp(c)) is expressed in photoreceptor cells of the adult retina.	prp(c), the cellular isoform of the prion protein (prp) serves as a precursor to abnormal prp isoforms which accumulate in diseases such as scrapie in sheep, and creutzfeldt-jakob disease in humans. since prions can replicate in photoreceptors we surmised that prp(c) must be expressed in these cells. accordingly, monoclonal antisera directed against two epitopes of hamster prp(c) produced retinal immunostaining in hamsters, and in mice bearing a hamster prp transgene. immunostaining was most pro ...	1997	9347934
severely combined immunodeficient (scid) mice resist infection with bovine spongiform encephalopathy.	following combined intraperitoneal and intracerebral injection with bovine spongiform encephalopathy (bse) cow brain homogenate, scid mice show a resistance to infection in comparison with immunocompetent cb20 mice. bse occurred in only five out of 22 challenged scid mice, with a mean incubation period of 573 days, whereas all the cb20 mice developed the disease with a mean incubation period of 456 days. in contrast, previous studies have shown that intracerebral infection of scid mice with a mo ...	1997	9349494
a conformational transition at the n terminus of the prion protein features in formation of the scrapie isoform.	the scrapie prion protein (prpsc) is formed from the cellular isoform (prpc) by a post-translational process that involves a profound conformational change. linear epitopes for recombinant antibody fab fragments (fabs) on prpc and on the protease-resistant core of prpsc, designated prp 27-30, were identified using elisa and immunoprecipitation. an epitope region at the c terminus was accessible in both prpc and prp 27-30; in contrast, epitopes towards the n-terminal region (residues 90 to 120) w ...	1997	9356250
chemical inactivators as sterilization agents for bovine collagen materials.	the use of collagen as a biomedical implant raises safety issues with regard to viruses and prions. specific chemical agents that inactivate prion infectivity could be applied to collagen implants. the physicochemical changes and the in vitro and in vivo biocompatibility of collagen treated by formic acid (fa), trifluoroacetic acid (tfa), tetrafluorethanol (tfe), and hexafluoroisopropanol (hfip) were investigated. in addition, the effects of these treatments on nucleic acids incorporated in coll ...	1997	9358314
stress-induced transcription of the clusterin/apoj gene.	clusterin/apoj is an intriguing gene frequently isolated by differential screening in laboratories from different areas of molecular biology, since it is overexpressed in numerous cases of degenerative diseases such as alzheimer's disease and scrapie. while the dramatic increase of clusterin expression in injured tissues is well established, the molecular basis of the gene induction remains unclear. in this study, we have focused our attention on the only dna region strictly conserved between cl ...	1997	9359832
allele identification using immobilized mismatch binding protein: detection and identification of antibiotic-resistant bacteria and determination of sheep susceptibility to scrapie.	a novel method for detection and identification of specific alleles has been developed utilizing immobilized mismatch binding protein (imbp). the assay involves the use of biotin-labeled probes, which are prepared by pcr amplification of cloned fragments with known sequence. the use of probes avoids many of the problems associated with the extreme sensitivity of imbp assays to errors in pcr amplification. the method can be used to monitor pcr fidelity and to genotype both diploid and haploid org ...	1997	9365263
the prion hypothesis is finally accepted by the establishment.		1997	9365293
yeast prions: inheritance by seeded protein polymerization?		1997	9368740
propagation of prion strains through specific conformers of the prion protein.	two prion strains with identical incubation periods in mice exhibited distinct incubation periods and different neuropathological profiles upon serial transmission to transgenic mice expressing chimeric syrian hamster/mouse (mh2m) prion protein (prp) genes [tg(mh2m) mice] and subsequent transmission to syrian hamsters. after transmission to syrian hamsters, the me7 strain was indistinguishable from the previously established syrian hamster strain sc237, despite having been derived from an indepe ...	1997	9371560
late treatment with polyene antibiotics can prolong the survival time of scrapie-infected animals.	amphotericin b (amb) is one of the few drugs able to prolong survival times in experimental scrapie and delays the accumulation of prpres, a specific marker of this disease in the brain in vivo. previous reports showed that the amb effect is observed only if the drug is administered around the time of infection. in the present study, intracerebrally infected mice were treated with amb or one of its derivatives, ms-8209, between 80 and 140 days postinoculation. we observed an increased incubation ...	1997	9371634
marked decrease of neuropeptide y y2 receptor binding sites in the hippocampus in murine prion disease.	using autoradiographic binding methodology with monoiodinated peptide yy together with the agonists neuropeptide y (npy) and npy (13-36), as well as in situ hybridization with oligonucleotide probes complementary to the npy y2 receptor (y2-r) mrna, we have studied whether or not intracerebral prion inoculation affects y2-rs in male cd-1 mice. monoiodinated peptide yy binding, mainly representing y2-rs, was down-regulated by 85% in the ca1 strata oriens and radiatum and by 50-65% in the ca3 strat ...	1997	9371835
[slow virus infections: mad cow disease and the debate about a disease not transmitted by a virus].		1997	9376398
scrapie strains retain their distinctive characteristics following passages of homogenates from different brain regions and spleen.	the molecular basis of differences among scrapie strains is unknown. the prion theory posits that there are differences in the conformation of the host protease-resistant protein (prp) molecules and that these differences are responsible for scrapie strains. a corollary of this theory is that the origin of host prp variation resides in different neuronal cell types. to assess this concept, preparations from three brain regions (cerebrum, cerebellum and olfactory bulb) and from spleen were passag ...	1997	9010315
characterisation of two promoters for prion protein (prp) gene expression in neuronal cells.	the neuronal membrane protein, prp, has a key role in the development of the transmissible spongiform encephalopathies and the level of expression of the prp gene has been shown to affect the disease profile. in order to define the sequences that are responsible for the normal expression of the prp gene we have isolated and sequenced a 5' region of the murine prp gene, which includes 1.2 kb upstream from exon 1, intron i and exon 2. sequencing of this region from several strains of mice identifi ...	1997	9016962
association between natural scrapie and prp genotype in a flock of suffolk sheep in scotland.	the incidence of natural scrapie in sheep is associated with polymorphisms of the prp gene, particularly those at codons 136, 154 and 171. in many breeds, the prp allele encoding valine at codon 136 confers an extremely high risk of scrapie, but in suffolk sheep this allele is vanishingly rare. in this study of a single closed flock of suffolk sheep in scotland, scrapie occurred primarily in animals which were homozygous for glutamine at codon 171, a genotype which was significantly less frequen ...	1997	9023905
neuronal vacuolation in raccoons (procyon lotor).	microscopic vacuolar changes in neuronal perikaryon are described in two free-ranging raccoons (procyon lotor) from different geographic locations in the united states. both animals were negative for rabies and scrapie-associated antigens. microscopically, lesions were not seen in the neuropil. neuronal vacuolations have previously been documented in brains of normal animals and in diseases such as rabies and prion-associated encephalopathies. although experimental transmission of a spongiform m ...	1997	9163886
prp deposition, microglial activation, and neuronal apoptosis in murine scrapie.	the present study investigated the relationship among prp deposition, microglial activation, vacuolation, and neuronal death in the hippocampus of the 301v/vm murine scrapie model (mean incubation period 117 +/- 1 days). prp deposition was first detected after 30 days and microglial activation after 60 days. vacuolation in the ca1 and ca2 pyramidal layer was present from 90 days onward. only occasional in situ end labeling (isel)-positive neurons were present in the hippocampus of scrapie-infect ...	1997	9168844
expression of prp mrna is regulated by a fragment of mrp8 in human fibroblasts.	prion protein (prpc) is expressed in many tissues, both in human and animals. the scrapie isoform of prpc has been shown to cause neurodegeneration. in other studies it has been demonstrated that overexpression of the prp gene can result in nonneuronal tissue degradation. little is known, however, about the normal function of prpc and prion protein gene regulation. using cultured periodontal ligament cells as an experimental model, we have demonstrated the stimulation of prp mrna expression by m ...	1997	9168960