The conference celebrating ‘The end of kuru: 50 years of research into an extraordinary disease’
1: Related Articles Collinge J, Alpers MP.
Introduction. Philos Trans R Soc Lond B Biol Sci. 2008 Jul 31. [Epub ahead of print] No abstract available. PMID: 18672464 [PubMed - as supplied by publisher]
The conference celebrating ‘The end of kuru: 50 years of research into an extraordinary disease’ was held in the Kohn Room of the Royal Society, London on 11–12 October 2007. It was an extraordinary meeting that is reflected in the proceedings published in this issue of the Philosophical Transactions of the Royal Society. There were 90 participants from around the world (figure 1). The first day was devoted to reminiscences and reflections, personal and scientific, about kuru, about working and living in the kuru-affected region, and about undertaking research on kuru, from the perspectives of both medical scientists and the Fore people. On the second day, the results of contemporary research on kuru and their ever widening implications in neurodegeneration and beyond were presented, with discussions on bovine spongiform encephalopathy (BSE), its human counterpart variant Creutzfeldt– Jakob disease (vCJD) and other prion diseases. The fundamental molecular processes involved in propagation of the transmissible agent or prion are now known to be of relevance in understanding the common degenerative brain diseases (such as Alzheimer’s and Parkinson’s diseases) and possibly normal brain ageing, and may explain a range of biological phenomena as evidenced by the emergence of the field of yeast and fungal prions. Indeed, the existence of multiple strains of prions implies non-Mendelian protein-based inheritance, with major evolutionary implications. The proceedings represent the full diversity of the meeting and, unusually, include a good measure of history as well as science. This Introduction gives an account of the meeting; an account of kuru itself may be found in these proceedings in the introduction to the paper by Collinge et al. (in press). All the scientists currently working on kuru attended the conference. The two Nobel laureates in the field, D. Carleton Gajdusek and Stanley Prusiner, both participated. There were 15 Papua New Guinean participants, 12 of whom were from the Fore linguistic group, the principal sufferers from kuru since the epidemic began about a century ago. Also attending were Peter Siba, the Director of the Papua New Guinea Institute of Medical Research, which has been involved in research on kuru since its inception in 1968, Adolf Saweri, the Chairman of the Council of the Institute, who as a young doctor had worked at Okapa, the government station at the centre of the kuru-affected region (Saweri in press), and Ken Boone, a doctor in Goroka, capital of the Eastern Highlands Province, who in 2003 performed the last autopsy on a kuru patient (Boone in press). Although many of those who had worked on kuru in the field or laboratory were unable, owing to death or infirmity, to attend the conference, representatives of every era of kuru research participated. Systematic research on the disease began when Carleton Gajdusek joined Vincent Zigas in March 1957 (Gajdusek & Zigas 1957). They teamed up with Jack Baker, the patrol officer in charge of the government station at Okapa, and lived in his house (see fig. 1 in Reid in press). Vin, sadly, has died and Jack was unable to attend the meeting, but Carleton was there in full force (Gajdusek in press a,b). Other members of this team in 1957 were Lois Larkin Baker, who was unable to attend, and Lucy Hamilton Reid, who talked about her studies on the nutrition of the Fore (Reid in press). Unfortunately, no members of the Adelaide group who had worked on kuru in the early years were able to be present, though we are fortunate to have the reminiscences of J. Henry Bennett and Donald Simpson in these proceedings (Bennett in press; Simpson in press). Cyril Curtain, who contributed to the first laboratory studies on kuru (Curtain in press), took part in the meeting, which was very pleasing, though we missed the presence of Chev Kidson and the late Roy Simmons from this era of kuru research. The research workers who followed next were Robert Glasse and Shirley Lindenbaum, who studied the anthropology of the Fore people and their neighbours, and Michael Alpers. hough Bob, sadly, has died, we were pleased that Shirley could attend and contribute to the proceedings of both the days (Lindenbaum in press a,b). Of the doctors who worked at the Okapa Hospital at this time, Jonathan Hancock attended the meeting and Werner Sto¨cklin contributed to these proceedings (Sto¨cklin in press). The next group to undertake research in the field included RichardW.Hornabrook andAlexNilsson,who were unable to attend; however,Dickwas represented by Annette Beasley and we are pleased to have some reflections on kuru from himin the proceedings (Beasley in press). John Mathews, Ray Spark and Coralie Mathews all participated in the meeting. Coralie gave her own reminiscences and reflections, which were, moreover, intended to be representative of the experiences of other wives who had not only supported their scientist husbands in the field but also made their own independent relationships with the Fore people that are still affectionately remembered in the area today (Mathews, C. in press). Inamba Kivita, who had worked closely with Shirley Lindenbaum and John Mathews, was delighted to see his old friends again after so many years (Kivita in press). Richard Hornabrook became the first Director of the Papua New Guinea Institute of Medical Research and the Institute thereafter assumed the main responsibility for kuru epidemiological surveillance. John Cochrane, Margaret Cochrane, Donald Moir and
Hilary King worked in the field during the late 1960s and early 1970s. Throughout the period from 1957 to 1985, Carleton Gajdusek made many return visits to the kuru-affected region and Michael Alpers, working from Perth in Australia, made annual field excursions during the early years of the institute. They both contributed to kuru field surveillance and assisted all fieldworkers with updated printouts from the kuru database maintained at the National Institutes of Health in Bethesda by Judith Farquhar (who attended the meeting) and Steven Ono. In 1977, Michael Alpers took over as Director of the Papua New Guinea Institute of Medical Research and the field surveillance intensified; Stanley Prusiner, Robert Klitzman and Phillip Tarr attended from these years (Prusiner in press; Klitzman in press; Tarr in press). Phil Tarr conducted a village-based autopsy during his time in the field. Another autopsy was carried out by Euan Scrimgeour (in press) in Rabaul, since a Fore man came down with kuru after living there for many years and decided that he would die there (Scrimgeour in press). The four most experienced field officers from that period, Auyana Winagaiya, the late Anua Senavaiyo, Igana Alesagu and Kabina Yaragi, were unable to attend but Anua’s wife Andemba took part (Anua in press). Finally, in 1996, field activities were enhanced by a collaboration between Michael Alpers and John Collinge, initially supported by the Wellcome Trust in London (of which John was then a Principal Research Fellow), and Jerome Whitfield was recruited to work in Papua New Guinea (Collinge in press; Whitfield in press). This collaboration then formed part of the newly formed MRC Prion Unit in London from 1998, directed by John Collinge. Dafydd Thomas and Edward McKintosh were involved in the fieldwork from the MRC Unit. Henry Pako outlined the current field activities of the kuru project (Pako in press). Bridget Ogilvie, former Director of the Wellcome Trust, described the Trust’s enthusiastic and flexible attitude to the project and their early support for John Collinge. Of the neuropathologists who made the early significant observations on the histopathological features of kuru, Malcolm Fowler, E. Graeme Robertson and Elisabeth Beck had died and Igor Klatzo, who was invited to the meeting, died before it began. Their contributions were recognized by many participants during the course of the conference. As a consequence of seeing the neuropathological features of kuru at an exhibition in the Wellcome Medical Museum in London in 1959, William J. Hadlow made the seminal connection between kuru and scrapie. Though he was unable to attend, we are pleased to have his reminiscences and reflections in these proceedings (Hadlow in press). A carefully planned experiment to test the transmissibility of kuru to chimpanzees followed from Hadlow’s observations within a few years and led to a successful outcome, which was reported in 1966 by Carleton Gajdusek, C. Joseph Gibbs and Michael Alpers (Gajdusek et al. 1966). Sadly, Joe Gibbs has died but his major contribution was honoured at the meeting. This work initiated our understanding of the human transmissible spongiform encephalopathies. Subsequent work by Stanley Prusiner and others led to the unifying concept of the prion diseases. In October 2007, the epidemic of kuru may not have been entirely over but the end was certainly in sight. There was no patient with kuru in 2006 nor, as we now know, in 2007. The continuing field surveillance (Pako in press) will tell us whether we have seen the last case; at the most we can expect only one or two more. This dramatic decline from 200 deaths a year over the first 5 years of kuru investigation is a cause for celebration. To be able to celebrate the disappearance of a fatal disease, especially one so distressing in its manifestations and so well documented, is an extraordinary experience and there was a sense of elation throughout the meeting. We were uniquely privileged at this celebration to have a good representation of the people who had suffered fro the disease. The Fore participants had all lost close family members to kuru, including husbands, wives, children and mothers. Their suffering and resilience were expressed in their talks, which symbolized for the whole conference what all the people of the kuru-affected region over the span of a century (a population of approx. 40 000 at the peak of the epidemic) had endured (Bavasa in press; Mabage in press; Ombeya in press; Poki in press; Puwa in press). The burden of kuru at its peak would be equivalent in the US, for example, to well over a million deaths per annum. Moreover, since the deaths were not evenly distributed in the total affected population and since most of the deathswere in adult women, in communities of high incidence the cumulative burden of mortality affected every family: in Fore society, nobody was untouched by kuru. Many of the scientific talks also paid tribute to the Fore people and their neighbours affected by kuru. A brief film by Rob Bygott and Ben Alpers, from a larger documentary in the making, showed Fore perspectives on kuru and gave a moving portrayal of both the suffering and the resilience exhibited by dying kuru patients and their many carers. To enhance the Fore participants’ involvement in the meeting, at the end of each session, the talks and discussion were briefly summarized, with typical Papua New Guinean oratory, in Tok Pisin (by Peter Siba or Ray Spark) and Fore (by Henry Pako or Anderson Puwa). The meeting celebrated 50 years of scientific research on kuru and its many achievements. These achievements were reviewed within their historical context and their contemporary implications were analysed during the scientific presentations of the meeting. Social and behavioural studies of the Fore people, the interactions between the resident research workers and the local people, and the creative cross links that were established between disciplines during the field research were discussed in two papers, one on each day of the meeting, by Lindenbaum (in press a,b). Mathews, J. D. (in press) described how kuru had spread among the Fore, the trajectory of which has now been reasonably well established. The two factors that may have affected the probability of transmission are variations in mortuary practices (since the mode of transmission of the prion agent was through the consumption of dead relatives by the women and young children) and human genetic variation. Jerome
Whitfield described recently acquired knowledge about Fore mortuary practices and their links with Fore cosmology (Whitfield et al. in press). Much new work has been done on genetic variation and selection in relation to prion diseases, and the work on kuru, though it may not explain the local geographical spread of kuru, has produced results in population genetics that have been far-reaching and exciting (Mead et al. 2003, in press). Historical aspects of the epidemiology of kuru, including his own many significant contributions, were presented on the first day by Mathews, J. D. (in press). The sweep of the kuru epidemic from 1957 to the present, and the essential clues it has provided to solve the puzzle of kuru, were recounted on the second day by Michael Alpers from his personal experiences over the last 46 years (Alpers in press a). John Collinge discussed the contemporary implications of kuru, in particular for the vCJD, the human form of BSE (Collinge et al. in press). When the recent detailed clinical and epidemiological findings on kuru, including evidence that incubation periods after oral transmission may be greater than 50 years, are combined with new genetic information a powerful dataset is created for exploring the wider implications of kuru for other human diseases (Collinge et al. in press). Broad vistas of science were opened up by Prusiner on prions, Gajdusek (in press a) on self-propagating proteins and other entities, Per Westermark on amyloidosis (Westermark & Westermark in press) and Colin Masters on kuru and Alzheimer’s amyloid plaques (paper not available for publication). Though research on kuru has been ongoing for 50 years, only recently has it been possible to undertake molecular and biological strain typing of the prion agent of kuru. Studies at the MRC Unit have shown that kuru is caused by prion strains closely similar to those causing sporadic and iatrogenic CJD and quite distinct from that causing variant CJD (Wadsworth et al. in press). The neuropathology of the most recent autopsied case of kuru was presented in comprehensive detail by Sebastian Brandner (Brandner et al. in press). We were fortunate to have other neuropathologists at the meeting, including Byron Kakulas and Catriona McLean. Byron’s work was done during the second wave of the neuropathological study of kuru (Kakulas in press) and Catriona’s work was published during the last decade, from the examination of archival material held in Melbourne, which she has re-examined for these proceedings (McLean in press). In 1967, Gabriele Zu Rhein produced the first electron micrographs of kuru. Though she was unable to attend the meeting, she has submitted a brief account of her early findings (Zu Rhein in press). We were privileged to have at the meeting not only Carleton Gajdusek in excellent form, despite recent illhealth, but also many of his associates ranging over a wide span of years of kuru research. The oldest were Taka Gomea, Tiu Pekiyeva, Tarubi Taguse and Koiye Tasa from the earliest years of research in the field, and their reunion with Carleton was an emotional experience shared by all who were fortunate to be witnesses (Gomea in press; Pekiyeva in press; Taguse in press; Tasa in press). We sorely missed the ebullience of Vin Zigas at the meeting but were delighted that his second wife (and widow) Jettie Zigas was able to attend and speak. Of Carleton’s later associates Michael Alpers, David Asher, richard Benfante, Judith Farquhar and Robert Klitzman participated (Alpers in press b; Asher in press; Benfante in press; Farquhar in press; Klitzman in press) and Franc¸oise Cathala, though unable to be present, submitted her reminiscences (Cathala in press). Ceridwen Spark gave an animated account of Carleton’s adopted family, with its strong Melanesian connections and links to kuru research. Kuru has historical significance, not only for those who lived through the epidemic and experienced its horrors but also for historians of science (Anderson in press), particularly those interested in human behaviour, in the transiti n from a traditional mode of life to the modern world, in the relationship of scientists to the people they are studying or whose diseases they are studying, and in the international politics of science (Scragg in press). Kuru has a scientific significance that has never been lost over the years, though its focus has changed, from the challenge of an exotic new disease reaching epidemic proportions in a restricted area of the tropics, to the first human transmissible spongiform encephalopathy, which led very quickly to the transmission of Creutzfeldt–Jakob disease (Gibbs et al. 1968), to a model for multidisciplinary epidemiological enquiry, to a model for intraspecies recycling, a lesson not learned that allowed the same augmenting mechanism to cause the cattle BSE epidemic, and to a model for the oral transmission of prion disease to humans (vCJD). The intracerebral transmission to chimpanzees had an incubation period of 2 years (Gajdusek et al. 1966), which halved on first chimpanzee-to-chimpanzee passage (Gajdusek et al. 1967): these were considered extraordinarily long incubations when they were first reported. Now we have recent work demonstrating incubation periods exceeding half a century after intraspecies oral transmission, with a strong dependence on host genetics. These findings in kuru will continue to have long-standing significance for neurology, infectious disease and public health. Kuru is indeed an extraordinary disease. Many people were involved in the planning and organization of the meeting and its associated activities. These include many staff of the MRC Prion Unit (particularly Simon Mead and Caroline Potter) and other meeting participants who also hosted and guided our Fore guests. Remarkable effort was put in by Jerome Whitfield in arranging Papua New Guinea documentation and passports to enable the participation of the Fore and for accompanying them from their remote villages in the Eastern Highlands via Goroka, Port Moresby and Singapore to London and the Royal Society. Special thanks also go to Ray Young for superb audiovisual support at the meeting and for preparing many, and processing all, of the images and figures in this volume. The meeting would not have happened without the ceaseless effort, dedication, and logistical skill of Frank Cooper MBE, who maintained his flawless courtesy and good humour despite often extraordinary challenges in the best tradition of the Royal Navy. We would like to thank the following organizations for their generous support for the meeting. Without their generosity, this event could not have taken place: the Medical Research
Council, the Wellcome Trust, Wyeth Europa Ltd, Novartis Vaccines and Diagnostics, Inc., Dupont, University College London and University of Wisconsin. The following provided additional support for the participation of Papua New Guineans at the meeting: Michael Alpers, Ross Anderson, Stewart Gray Anderson, Richard Benfante, Gloria Chalmers, John Collinge, Cyril Curtain, Helen Fenbury, Skip Jackson, Deborah Lehmann, Shirley Lindenbaum, John and Coralie Mathews, Cedric Raine, Barbara Sherwood, Donald Simpson, Werner Sto¨ cklin, Margaret Spencer, Phillip Tarr, Gunilla Westermark, Per Westermark, Jerome Whitfield and Jettie Zigas. John Collinge1,* Michael P. Alpers1,2 1MRC Prion Unit, The National Hospital for Neurology and Neurosurgery, Institute of Neurology, Queen Square, University College London, London WC1N 3BG, UK E-mail address: email@example.com 2Centre for International Health, ABCRC, Curtin University, Health Research Campus, Shenton Park, GPO Box U1987, Perth, WA 9845, Australia *Author for correspondence. REFERENCES Alpers, M. P. In press a. The epidemiology of kuru: monitoring the epidemic from its peak to the end. Phil. Trans. R. Soc. B 363. (doi:10.1098/rstb.2008.0071) Alpers, M. P. In press b. Some tributes to research colleagues and other contributors to our knowledge about kuru. Phil. Trans. R. Soc. B 363. (doi:10.1098/rstb.2008.0098) Anderson, W. H. In press. Early perceptions of an epidemic. Phil. Trans. R. Soc. B 363. (doi:10.1098/rstb.2008.0082) Anua, A. In press. ‘My late husband Mr Anua was a hardworking man.’ Phil. Trans. R. Soc. B 363. (doi:10.1098/ rstb.2008.0098) Asher, D. M. In press. 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Title Kuru - fifty years later. Author(s) Liberski PP, Brown P Institution Laboratory of Electron Microscopy and Neuropathology, Department of Molecular Pathology and Neuropathology, Chair of Oncology, Medical University Lodz, 8/10 Czechos³owacka Street, 92-216 Lodz, Poland. Source Neurol Neurochir Pol 2007 November-December; 41(6):548-556. Abstract Kuru, the first human neurodegenerative disease classified as a transmissible spongiform encephalopathy, prion disease or, in the past, slow unconventional virus disease, was first reported to Western medicine in 1957 by D. Carleton Gajdusek and Vincent Zigas. Thus, this year marks the 50th anniversary of kuru discovery, highlighted by the symposium The end of kuru: 50 years of research into an extraordinary disease organized by John Collinge and Michael Alpers at the Royal Society, London, November 11-12, 2007. In this review, we summarize some data on the epidemiology, neuropathology and clinical picture of kuru. Language ENG Pub Type(s) JOURNAL ARTICLE
PubMed ID 18224577
Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice
Jonathan D. F. Wadsworth, Susan Joiner, Jacqueline M. Linehan, Melanie Desbruslais, Katie Fox, Sharon Cooper, Sabrina Cronier, Emmanuel A. Asante, Simon Mead, Sebastian Brandner, Andrew F. Hill*, and John Collinge†
Medical Research Council Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom
Communicated by Charles Weissmann, The Scripps Research Institute, Jupiter, FL, January 10, 2008 (received for review October 10, 2007)
Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD.
In the present study, we have compared the transmission properties of kuru prions with sporadic, iatrogenic, and variant CJD prions in transgenic mice expressing human PrP valine 129 and in wild-type mice. These data establish that kuru prions have transmission properties equivalent to those of classical CJD prions and are distinct from vCJD prions. In agreement with this finding, the molecular strain types of PrPSc seen in kuru brain correspond to those seen in classical CJD rather than the distinct PrPSc types seen in vCJD or inherited prion disease. These collective data establish that kuru and classical CJD prions have closely similar prion strain properties and are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD (43). Human prion diseases with distinct etiologies are associated with a range of clinical presentations that are now seen as clinicopathological syndromes rather than individual disease entities (4, 55, 56). The central clinical feature of kuru is progressive cerebellar ataxia, and, in sharp contrast to sporadic CJD, dementia is a late and less prominent feature. A prodrome and three clinical stages consisting of an ambulatory stage, a sedentary stage, and a tertiary stage have been described in ref. 20. In this regard, the natural history of kuru is more reminiscent of vCJD in which early symptoms of distal sensory disturbance, joint pains, and psychiatric and behavioral changes are common before forthright dementia (4, 23, 25, 28). Despite these similarities in early clinical presentation, the molecular and neuropathological features of kuru are distinct from vCJD. In contrast to the occurrence of abundant florid PrP plaques that are the neuropathological changes seen in kuru lie within the spectrum of those seen in sporadic CJD. Unicentric PrP plaques, however, are unusually prominent and widespread (58, 59). This pattern of neuropathology most closely resembles a relatively rare subtype of sporadic CJD associated with long clinical duration and PRNP codon 129 heterozygosity in which kuru-type PrP plaques are also observed (10, 11, 46). Although PrP plaques are not a prominent feature of the most common subtypes of sporadic CJD, where diffuse synaptic PrP deposition predominates (10, 11, 46, 60), kuru-type plaques are a notable feature of iatrogenic CJD resulting from peripheral inoculation, most conspicuously after cadaveric pituitaryderived hormone exposure (61). This form of iatrogenic CJD also typically presents with a progressive cerebellar syndrome reminiscent of kuru, whereas cases of iatrogenic CJD arising from intracerebral or ocular inoculation usually manifest clinically as sporadic CJD, with a rapidly progressive dementia (62–65). These observations suggest that cerebellar onset and subsequent neuropathological changes may be determined in part by a peripheral route of exposure. The similarity of prion strain type in kuru and sporadic CJD demonstrated here now clearly suggests that peripheral routes of infection (predominantly dietary), rather than prion strain type, may be an important determinant of the clinicopathological phenotype of kuru. In this regard, the etiology of sporadic CJD remains unclear, although its remarkably uniform worldwide incidence and apparently random distribution suggest involvement of a stochastic process such as somatic PRNP mutation (2, 48, 66, 67). It is thus possible that part of the phenotypic and neuropathological heterogeneity seen in sporadic CJD could be related to peripheral versus central initiation of prion replication. Aside from route of exposure, additional factors may also influence the neuropathology and clinical features of kuru. A number of genetic modifiers of prion disease have been mapped in mice (16, 17). Although the genes responsible for mouse incubation time quantitative trait loci have not yet been identified, orthologous human genes are likely to be globally polymorphic with significant differences within and between Europe and the Fore. Furthermore, age is an important dete minant of youth may be associated with an atypical sporadic CJD neuropathology (70). The marked difference in mean age of kuru and sporadic CJD patients might thus account for some of the neuropathological differences that distinguish kuru from the majority of sporadic CJD cases. Our finding that kuru prions and vCJD prions have very different transmission properties supports previous molecular (9, 45–47, 49, 50), neuropathological (25, 57, 58), and transmission (14, 15, 26, 27) data indicating that vCJD is a highly distinct human prion strain. The pathogenesis of vCJD differs significantly from that of other forms of human prion disease. PrPSc is readily detectable in lymphoreticular tissues in vCJD and not in classical CJD or inherited prion disease (29, 32, 47, 71–76). Because kuru, iatrogenic CJD, and vCJD are caused by a peripheral route of exposure to infectious prions, it is possible that extensive lymphoreticular pathogenesis may result from this common route of exposure. However, the fact that tonsillar prion infection has not been detected in iatrogenic CJD associated with use of human cadaveric derived pituitary hormone (72, 75) or kuru (unpublished data) suggests that the distinct peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection. Although distinct from the vCJD prion strain, kuru is critically important as our only precedent of an orally acquired human prion disease epidemic. There remain striking parallels between the two outbreaks in terms of their clinical features, restricted temporal and geographic distribution, and the long and variable incubation times observed. Profound disease susceptibility is conferred by PRNP codon 129 in both diseases (4, 5, 15, 22). Because mouse models of prion disease demonstrate the importance of a small number of non-Prnp genetic factors in control of incubation time, it will be important to understand how the orthologous human genes modify susceptibility or incubation to both kuru and vCJD. ...snip...end...tss
Fig. 2. Molecular strain typing of human prion transmissions to mice. Immunoblots of proteinase K-digested brain homogenates from wild-type mice, human patients, or transgenic mice analyzed by enhanced chemiluminescence with ant i-PrP monoclonal antibodies ICSM35 (A) or 3F4 (B–D) are shown. The provenance of each brain sample is designated above each lane, and the type of human PrPSc detected in each sample (B–D) is designated below. (A) Transmission of vCJD prions (I344) and sporadic CJD prions (I764) to FVB/NHsd mice. (B) Transmission of vCJD prions (I348) to 129VV Tg152 mice. (C) Transmission of sporadic CJD prions with type 3 PrPSc (I4855) and kuru prions with type 3 PrPSc (I516) to 129VV Tg152 mice. (D) Transmission of kuru prions with type 2 PrPSc (I518) to 129VV Tg152 mice revealing a change in molecular strain type.
Fig. 3. Neuropathological analysis of transgenic mouse brain. Equivalent patterns of neuropathology are seen in 129VV Tg152 mice that propagate type 3 PrPSc after primary transmission of kuru prions or sporadic CJD prions that are distinct from 129VV Tg152 mice that propagate type 5 PrPSc after primary transmission of vCJD prions. Sketches represent the regional distribution of abnormal PrP deposition in transgenic mouse brain: diffuse synaptic PrP deposition (bars) and PrP plaques (circles). The bottom images show PrP immunohistochemistry with ICSM 35 (from the areas delineated by the blue boxes in the sketches) demonstrating nonflorid PrP plaques in the corpus callosum and diffuse synaptic PrP deposition in the thalamus. (Scale bar, bottom images: 100 m.)
Wadsworth et al. PNAS March 11, 2008 vol. 105 no. 10 3887
Materials and Methods
www.pnas.orgcgidoi10.1073pnas.0800190105 Wadsworth et al. http://www.pnas.org/cgi/reprint/0800190105v1.pdf
Kuru in the 21st century—an acquired human prion disease
Thu Jun 22, 2006 19:44 18.104.22.168
The Lancet 2006; 367:2068-2074
Kuru in the 21st century—an acquired human prion disease with very long incubation periods
John Collinge a , Jerome Whitfield a b, Edward McKintosh a, John Beck a, Simon Mead a, Dafydd J Thomas a and Michael P Alpers a c
Summary Background Kuru provides the principal experience of epidemic human prion disease. Its incidence has steadily fallen after the abrupt cessation of its route of transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of infection after the extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru. We investigated possible incubation periods, pathogenesis, and genetic susceptibility factors in kuru patients in Papua New Guinea.
Methods We strengthened active kuru surveillance in 1996 with an expanded field team to investigate all suspected patients. Detailed histories of residence and exposure to mortuary feasts were obtained together with serial neurological examination, if possible.
Findings We identified 11 patients with kuru from July, 1996, to June, 2004, all living in the South Fore. All patients were born before the cessation of cannibalism in the late 1950s. The minimum estimated incubation periods ranged from 34 to 41 years. However, likely incubation periods in men ranged from 39 to 56 years and could have been up to 7 years longer. PRNP analysis showed that most patients with kuru were heterozygous at polymorphic codon 129, a genotype associated with extended incubation periods and resistance to prion disease.
Interpretation Incubation periods of infection with human prions can exceed 50 years. In human infection with BSE prions, species-barrier effects, which are characteristic of cross-species transmission, would be expected to further increase the mean and range of incubation periods, compared with recycling of prions within species. These data should inform attempts to model variant CJD epidemiology.
a. MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK b. Papua New Guinea Institute of Medical Research, Goroka, EHP, Papua New Guinea c. Centre for International Health, Curtin University, Perth, Australia
Correspondence to: Prof John Collinge
Listen to The Lancet This week's audio summary discusses an Article entitled "Kuru in the 21st century - an acquired human prion disease with very long incubation periods". Also covered is a Lecture assessing climate change and its impact on health, and an Editorial about the roll-out of cervical cancer vaccines worldwide. >>
further into this study;
The early clinical, epidemiological, and anthropological study of kuru; the recognition of its neuropathological, and then causal parallels to ovine scrapie;20 and then crucially, the experimental transmission of the disease
to primates,21 originated the concept of the human transmissible spongiform encephalopathies, which was followed in turn by the eventual unifying concept of the mammalian prion diseases. However, in addition to the central historical importance of kuru, study of the end-stage of this epidemic offers a unique opportunity to study the variables of a near-complete epidemic of human prion disease. In particular, recognition of the incubation periods possible after natural prion infection in people is important in providing an insight (from actual case histories rather than from mathematical models) into the probable span of the vCJD epidemic in the UK. Although estimation of kuru incubation periods early in the epidemic was difficult, and the timing of the actual infecting event for an individual can rarely be determined, the abrupt and permanent interruption of the source of infection, endocannibalism, in the late 1950s, has progressively allowed recognition of an enormous span of possible incubation periods, at its shortest extreme bracketed by the rare onset of disease in children as young as 5 years and extending up to (and perhaps beyond) the incubations covering more than half a century, as we describe here.In our field studies, we have interviewed many individuals who participated in traditional mortuary feasting or who described the participation of family members from the preceding generation. These detailed descriptions will be published elsewhere but have reaffirmed the oral histories of endocannibalism in the Fore recorded previously12,22–24 and that this practice ceased abruptly at the time of Australian administrative control over the kuru areas. Although isolated events might have occurred for a few years after this prohibition, we are confident that new exposures of individuals to kuru at mortuary feasts would not have occurred after 1960. Not only have no cases of kuru been recorded in people born after 1959 (and only nine were recorded in those born after 1956); but also all the 11 last recorded cases of kuru that we report here were born before 1950. If any source of infection remained, whether from surreptitious cannibalism, possible ground contam-ination with human prions at sites where food was prepared, or other lateral routes, we would expect individuals born after this period to have kuru—especially since children are thought to have had shorter incubation periods than adults. However, no such cases have been observed. Additionally, although a fraction of hamster-adapted scrapie prions have been shown to survive in soil for at least 3 years,25 the mortuary feast practices (during which the entire body would be consumed) were undertaken so that any substantial contamination of soil would not have occurred, and traditional bamboo knives and leaf plates were burned after the feast. Furthermore, no clusters of kuru cases, as seen earlier in the epidemic,26 have been recorded for many years. We have also reviewed the assertion that maternal transmission of kuru did not occur, and saw no evidence for maternal transmission from kuru archives, interviews of colleagues who have practised medicine in the Fore, or local oral history. Again, any possible vertical route of kuru transmission would have resulted in the presence of kuru in children born after 1960, especially since kuru was common in women of childbearing age; no such cases have occurred.With respect to extrapolation of incubation periods of BSE prion infection in people, we should recognise that the kuru epidemic arose from intraspecies recycling of infectious prions. However, transmission of prions between different mammalian species is associated with a species barrier, which is better described as a transmission barrier, because of the importance of within-species prion strain type, in addition to species-specific differences in its determination.27 The biological effects of such a barrier are: extended mean incubation period; increased spread of incubation periods in individual animals; and reduced attack rate (in which only a fraction of inocu ated animals will succumb), by comparison with the 100% mortality generally associated with within-species inoculation with high-titre infectivity. Incubation periods approaching the natural lifespan of the inoculated species are often seen in such primary cross-species transmissions of prions. Second and subsequent passage of prions within the new species is always associated with adaptation involving a considerable shortening of the mean and spread of incubation periods and high or total lethality to high-titre inocula. Thus, estimation of the range of possible incubation periods in human BSE infection needs superimposition of the effect of a transmission barrier onto these findings of natural human incubation periods. The mean incubation period for kuru has been estimated to be around 12 years,27 with a similar estimate in iatrogenic CJD associated with the use of human-cadaver-derived pituitary growth hormone.28 As shown here, maximum incubation periods in kuru can exceed 50 years. The transmission barrier of BSE between cattle and human beings is unknown and cannot be directly measured. However, the cattle-to-mouse barrier for BSE has been well characterised experimentally by comparative endpoint titration. BSE prions transmit readily to laboratory mice, including after oral dosing.29 The murine LD50 (lethal dose causing 50% mortality) in C57Bl/6 mice is about 500-fold higher than that in cattle;30 this barrier also results in a three-fold to four-fold increase in mean incubation period.27 Mean incubation periods of human BSE infection of 30 years or more should therefore be regarded as possible, if not probable,27 with the longest incubation periods approaching (and perhaps exceeding) the typical human lifespan. The shortest incubation periods in kuru were estimated from the age of the youngest patients—suggesting that the shortest incubation period was Articles www.thelancet.com Vol 367 June 24, 2006 2073 4–5 years. Similarly in vCJD, although the total clinical caseload so far has been small, the youngest onsets of vCJD have been at age 12 years or above, providing an early estimate of a minimum incubation period. Furthermore, prion disease in mice follows a well-defined course with a highly distinctive and repeatable incubation time for a specific prion strain in a defined inbred mouse line. In addition to the PrP gene, a few additional genetic loci with a major effect on incubation period have been mapped.4,31,32 Human homologues of such loci could be important in human susceptibility to prion disease, both after accidental human prion exposure and after exposure to the BSE agent. By definition, patients identified so far with vCJD are those with the shortest incubation periods for BSE. These patients could have received an especially high dose of BSE prions. However, no unusual history of dietary, occupational, or other exposure to BSE has been reported from case-control studies. Because of the powerful genetic effects on incubation period in laboratory animals, vCJD patients identified could represent a distinct genetic subpopulation with unusually short incubation periods to BSE prions, with vCJD so far occurring predominantly in those individuals with short incubation time alleles at these multiple genetic loci, in addition to having the homozygous PRNP genotype of codon 129 methionine. Therefore, a human BSE epidemic may be multiphasic, and recent estimates of the size of the vCJD epidemic based on uniform genetic susceptibility could be substantial underestimations.33,34 Genes implicated in species-barrier effects, which would further increase both the mean and range of human BSE incubation periods, are also probably relevant. In this context, a human epidemic will be difficult to accurately model until such modifier loci are identified and their gene frequencies in the population can be measured.4Heterozygosity at PRNP codon 129 is a major determinant of susceptibility to and incubation time of human prion diseases.5,7,9,35 As expected, most of these recent kuru cases with extended incubation periods (ei ht of ten) were heterozygotes. We have reported previously that most elderly survivors of exposure to traditional mortuary feasts are heterozygous.9 Although the study included a small number of patients with kuru with long incubation periods, we saw no evidence of association with PRNP haplotype,10 HLA-DQ7,18 APOE,36 or PRND alleles.13
J Whitfield led the field patrol team throughout the study and investigated all suspect cases; E McKintosh provided assistance during this time. J Beck and S Mead undertook the molecular genetic studies. J Collinge, M P Alpers, E McKintosh, and D J Thomas did field neurological examinations. J Collinge and M P Alpers supervised the study and drafted the manuscript. All authors contributed to and approved the final version of the manuscript. .........
Prion infections, blood and transfusions
Adriano Aguzzi* and Markus Glatzel
Prion infections lead to invariably fatal diseases of the CNS, including
Creutzfeldt–Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), and scrapie in sheep. There have been hundreds of instances in which prions have been transmitted iatrogenically among humans, usually through neurosurgical procedures or administration of pituitary tissue extracts. Prions have not generally been regarded as bloodborne infectious agents, and case–control studies have failed to identify CJD in transfusion recipients. Previous understanding was, however, questioned by reports of prion infections in three recipients of blood donated by individuals who subsequently developed variant CJD. On reflection, hematogenic prion transmission does not come as a surprise, as involvement of extracerebral compartments such as lymphoid organs and skeletal muscle is common in most prion infections, and prions have been recovered from the blood of rodents and sheep. Novel diagnostic strategies, which might include the use of surrogate markers of prion infection, along with prion removal strategies, might help to control the risk of iatrogenic prion spread through blood transfusions. ...
Prion diseases, also termed transmissible SPONGIFORM ENCEPHALOPATHIES, constitute a group of neurodegenerative conditions that are transmissible within and between mammalian species. A characteristic of these diseases is the accumulation of a misfolded prion protein, PrPSc, which is a post-translationally modified form of the host-encoded prion protein (PrPC). The processes underlying PrPSc formation remain enigmatic, but there is little doubt that a conformer of PrPC, which might exist in an oligomeric form,1 is identical to the infectious entity.2 Prions damage the brain by transmitting toxic signals to cells expressing PrPC.3 Although genetic evidence has been taken to indicate that human prion diseases have been with us since prehistoric times,4 the first documented cases of Creutzfeldt–Jakob disease (CJD) date back only 85 years.5–7 Since then, it has become obvious that human prion diseases have three distinct etiologies: they can arise in the absence of any documented exposure to infectious prions as sporadic CJD (sCJD), as an autosomal dominantly inherited disease in the case of genetic, or familial, CJD (gCJD/fCJD), or as an acquired condition in the case of IATROGENIC and variant CJD (iCJD, vCJD), or kuru, which resulted from cannibalism.8
Some prion diseases that occur in animals might have been recognized several centuries ago, as suggested by early descriptions of sheep diseases that seem to correspond to scrapie. Most prion diseases affecting animals, however, were discovered relatively recently.6 A transmissible spongiform encephalopathy affecting cattle (bovine spongiform encephalopathy, or BSE) has caused a massive epidemic in European countries, affecting around 2 million animals.9 Epidemiological, biochemical, neuropathological and transmission studies have substantiated the concern that BSE prions might have crossed the species barrier between cattle and humans, resulting in a novel form of human prion disease, vCJD.10–13 During 1996–2001, the incidence of vCJD in the UK rose year upon year, evoking fears of a large upcoming epidemic.
Since 2001, however, the incidence of vCJD in the UK appears to have been stabilizing, indicating that the extent of the epidemic might be limited.14 As might be expected for in frequent stochastic events, the numbers of new cases of vCJD fluctuate from year to year. For example, data available on the web page of the National CJD Surveillance Unit15 show that the number of onsets of vCJD was higher in 2004 than it was in 2003, but this is not necessarily indicative of an upward trend. It must be assumed that a number of asymptomatic carriers of vCJD exist in human populations that have been exposed to BSE. The existence of such a chronic carrier state is a logical and unavoidable consequence of the long incubation time of prion diseases, which is typically in the order of several years and—in the case of oral exposure to prions—can reach several decades. Consequently, anybody who has contracted the infection but has not developed clinical signs and symptoms might be consider ed a carrier. Some of these carriers are likely be ‘preclinical’, and will proceed, in due course, to the development of disease.
Alternatively, it is conceivable that the carrier state can persist for an indefinite period of time, in which case infected individuals could be regarded as ‘permanent asymptomatic (sub clinical) carriers’. Studies performed in rodents indicate that the permanent subclinical carrier state might be a common phenomenon, such as occurs when immune deficient mice are exposed to prions.16 Unlinked anonymous screens for hallmarks of prion infection in archival tissues have suggested that the prevalence of individuals with sub clinical vCJD might be higher than previously antici pated, and could reach 237 cases per million individuals.17
The recent discovery of transmission of vCJD via blood in three individuals indicates with near certainty that blood-borne prion transmission, in conjunction with an unknown prevalence of vCJD-infected carriers, leads to secondary transmission of host-adapted prions.18 Consequently, the vCJD epidemic might be prolonged, or, in the worst-case scenario, vCJD be rendered endemic and selfsustained. In this article, we review how prions could act as blood-borne infectious agents, and consider strategies aimed at minimizing the risk of secondary trans mission of prion diseases.
TRANSMISSION OF PRION DISEASES IN HUMANS
The cause of most human prion diseases is unknown. In the case of sCJD, the term ‘sporadic’ is used as a euphemism, meaning that we have no idea about the origin of this form of CJD. By contrast, gCJD always segregates within families with mutations in the gene encoding the prion protein (PRNP), suggesting that these mutations are causally involved in disease pathogenesis. As no families have been described in which gCJD segregates with mutations in genes other than PRNP, it has been difficult to use human genetics to understand the pathogenesis of prion diseases. The discovery of PRNP mutations in gCJD has led to the proposal that at least some cases of sCJD might be due to somatic PRNP mutations analogous to those found in the germline of gCJD patients. It is equally possible, however, that some of the cases of alleged sCJD derive from hitherto unrecognized infectious causes. In apparent agreement with the ‘intrinsic’ origin of sCJD, which accounts for more than 90% of all human prion diseases, epidemiological studies were not able to identify a conclusive link between this form of CJD and external risk factors.19 This fact is reflected in the pathological and biochemical features of these diseases. Although low levels of PrPSc and prion infectivity can be demonstrated in peripheral sites such as lymphoid organs or skeletal muscle,20,21 the highest levels of PrPSc and prion infectivity appear to occur in the CNS. These facts might account, at least in part, for the lack of evidence of sCJD transmission by labile or stable blood products.22 Indeed, several retrospective studies have failed to identify blood transfusion or exposure to plasma products as risk factors for the development of sCJD,19 and prion diseases appear to be exceedingly rare in hemophiliacs, a group of patients that is at particularly high risk of contracting emerging blood-borne infectious diseases. Although these studies cannot exclude the possibility that transmission of sCJD might have occurred through blood transfusions in rare cases, and despite the fact that the etiology of sCJD is unclear, it would appear that transmission of sCJD by trans fusion of blood or blood products does not play a major role in the pathogenesis of this disease entity.
In the case of acquired prion diseases, however, the situation is very different. For vCJD, high levels of prion infectivity and of PrPSc have been detected in lymphoid organs such as the appendix and tonsils (Figure 1).23,24 For this reason, it has been speculated for almost a decade that vCJD might be associated with a higher risk of blood-borne transmission than sCJD. It is important to be cautious, however, as the differences in the organ tropism of sCJD and vCJD might be quantitative rather than qualitative, and PrPSc has been detected in the lymphoid organs of both vCJD and sCJD patients.21 Initial studies have failed to detect PrPSc and prion infectivity in the blood of patients with vCJD, but these negative data are likely to be attributable to the lack of sensitivity of the assays available at the time.23
The recent identification of three individuals with probable transmission of vCJD via blood transfusion has provided tragic evidence that vCJD prions can indeed be transmitted through blood (Figure 2). On the basis of the epi demiological and pathogenetic considerations discussed above, it can only be a matter of time before further cases of blood-transfusion-associated cases of vCJD will ensue (Figure 3). In the first of the cases reported, a patient received a single unit of non-leukodepleted erythrocyte concentrate from an individual who went on to develop vCJD 3.5 years later, and was therefore likely to have been subclinically prion-infected at the time of the donation. The recipient developed vCJD 6.5 years following the transfusion.25
In the second case, transmission of prion disease occurred again via a single unit of nonleukodepleted red-blood-cell concentrate. The donor developed vCJD 2 years following blood donation, again raising the possibility of pre clinical infection at the time of the donation. 18 The recipient died of causes unrelated to the prion infection 5 years after the transfusion. Although this individual did not display overt signs of vCJD, PrPSc could be detected in lymphoid organs, enforcing the concept of subclinical prion disease in this individual. Recently, a third case of blood-borne prion transmission has been reported.26 In this case, the incubation time in the recipient was 8 years, whereas the donor showed vCJD symptoms 20 months following his blood donation. Until now, sequencing of the PRNP gene in all individuals who succumbed to vCJD revealed homozygosity for the sequence ‘ATG’, which encodes methionine, at codon 129. In the general population, only 33% of people are homozygous for ATG at this codon of PRNP, so this particular genetic trait, known as the MM genotype, has been regarded as a risk factor for vCJD.8 The second identified recipient of prioninfected blood, however, was heterozygous for methionine/valine at codon 129 (MV genotype).
The MV genotype is underrepresented in sporadic and acquired CJD, and has therefore been considered a protective genetic trait. The fact that this individual died of a cause unrelated to prion disease raises the question of whether MV heterozygotes might develop a permanent carrier status, in which the prion replicates within their body but clinical signs are absent for an indeterminate period of time. Of course, it would be imprudent to draw far-reaching conclusions on the basis of three cases of blood-borne prion infection. We deem it justified, however, to highlight a number of surprising details that have become clear on analysis of these cases.
First, vCJD prions can indeed propagate using blood as a vector. In the past, this idea has often been regarded as ‘worst-case scenario’, ‘highly speculative’, and ‘barely a theoretical possibility’. The wishful thinking of many physicians involved in blood transfusion has often conjured up a sense of safety, which, as we regrettably now know, is unwarranted.
Second, a single unit of vCJD-prion-infected blood is sufficient to cause transmission of the disease. This fact is particularly unsettling, as it can only be taken to signify that the concentration of ID50 units in blood is relatively high. One ID50 unit is defined as the infectious dose sufficient to establish infection in 50% of recipients; animal experiments indicate that the amount of prion infectivity needed to reach one ID50 unit is much higher when prions are administered intravenously than when they are inoculated intracerebrally.
Third, blood from preclinically vCJD-infected patients can be infectious. Although not unexpected, this aspect is particularly worrisome, as it suggests that preclinical donors might subjectively not consider themselves at risk. Consequently, the only way to identify such donors would be to subject the donation to a prion screen of satisfactory sensitivity, which is currently unavailable.
Last, despite all epidemiological evidence to the contrary, patients who are methionine/valine heterozygous at codon 129 of the PRNP gene are susceptible to infection with vCJD prions, which raises several important questions. Is the virulence of BSE prions enhanced when passaged from human to human, as opposed to the original bovine to human situation? Passaging experiments of scrapie infectivity between mice and hamsters indicate that this scenario is highly plausible.6 Even more importantly, can vCJD infection of heterozygous individuals establish a permanent subclinical carrier state? Although this situation might constitute a best-case scenario for the infected individuals, it could be disastrous from an epidemiological viewpoint, as it might lead to an unrecognized and possibly self-sustaining epidemic. ...
snip... full text ;
JUNE 2006 VOL 2 NO 6 AGUZZI AND GLATZEL NATURE CLINICAL PRACTICE NEUROLOGY 329
see full blog ;
Thursday, July 24, 2008
Prion diseases are efficiently transmitted by blood transfusion in sheep
Submitted April 18, 2008 Accepted June 28, 2008
Saturday, December 08, 2007
Transfusion Transmission of Human Prion Diseases
Saturday, January 20, 2007
Fourth case of transfusion-associated vCJD infection in the United Kingdom
CHRONIC WASTING DISEASE CWD
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY TME
TSE advisory committee for the meeting December 15, 2006
From: Terry S. Singeltary Sr.
Cc: firstname.lastname@example.org ; email@example.com
Sent: Friday, December 01, 2006 2:59 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION]
FDA FAILED US
Sunday, July 20, 2008 Red Cross told to fix blood collection or face charges 15 years after warnings issued, few changes made to ensure safety
10 people killed by new CJD-like disease
Public release date: 9-Jul-2008
Since Gambetti's team wrote a paper describing an initial 11 cases referred to his centre between 2002 and 2006 (Annals of Neurology, vol 63, p 697),
another five have come to light. "So it is possible that it could be just the tip of the iceberg," Gambetti says.
sporadic CJD, the big lie
Thursday, July 10, 2008 A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008
Thursday, July 10, 2008 A New Prionopathy update July 10, 2008
MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE
Saturday, June 21, 2008 HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory JUNE 2008
Tuesday, July 29, 2008
Heidenhain Variant Creutzfeldt Jakob Disease Case Report
Infection as the Etiology of Spongiform Encephalopathy (Creutzfeldt-Jakob Disease)
Abstract. Fatal spongiform encephalopathy occurred in four chimpanzees 12 to 14 months after inoculation with suspensions of brain from four patients, respectively. Chimpanzee to chimpanzee transmission was effected without reduction in incubation period. Retransmission of the disease to a second chimpanzee occurred when an inoculum that had been stored at -70°C for over 2 years was used.
C. J. GIBBS, JR.
D. C. GAJDUSEK
National Institute of Nelurological
Diseases and Stroke,
Bethesda, Maryland 20014
References and Notes
1. C. J. Gibbs, Jr., D. C. Gajduisek, D. M.
Asher, M. P. Alpers, E. Beck, P. M. Daniel,
W. B. Matthews, Science 161, 388 (1968).
2. The brain biopsy from patient 1 and the
brain autopsy from patient 4 were obtained
through the courtesy of Dr. W. B.
Matthews of Derby, England, and Dr. Peter
Daniel and Mrs. Elisabeth Beck of Maudsley
Hospital, London, England; frozen brain tissue
from patient 2 was obtained from Dr. E.
R. Ross of the Chicago Wesley Memorial
Hospital and Northwestern University, Chicago,
Illinois; and frozen brain tissue from
patient 3 was obtained from Dr. Alfred Pope
of McLean Hospital, Boston, Massachusetts.
3. D. C. Gaidusek, C. J. Gibbs, Jr., M. Alpers,
Natuire 209, 794 (1966).
4. - Science 155, 212 (1967).
5. E. Beck, P. M. Daniel, W. B. Matthews, D.
L. Stevens, M. P. Alpers, D. M. Asher, D.
C. Gajdusek, C. J. Gibbs, Jr., Brain, in press.
6. P. W. Lampert, K. M. Earle, C. J. Gibbs,
Jr., D. C. Gajdusek, J. Neutropathol. Exp.
Neurol. 28, No. 3, 353 (1969).
7. D. C. Gajdusek, C. J. Gibbs, Jr., D. M.
Asher, E. David,, Science 162, 693 (1968).
15 May 1969; revised 15 July 1969
Experimental Subacute Spongiform Virus
Encephalopathies in Primates and Other Laboratory Animals
Abstract. The host range of subacute spongiform virus encephalopathies is
described. The asymptomatic incubation period and the duration of the illnesses
in various species of animal hosts is discussed along with information on addi-
-tional species of Old World and New World monkeys and the domestic cat, which
have been shown to be susceptible to subacute spongiform virus encephalopathies.
References and Notes
1. D. C. Gajdusek, C. J. Gibbs, Jr., M. Alpers,
Nature 209, 794 (1966).
2. C. J. Gibbs, Jr., Curr. Top. Microbiol. 40,
44 (1967); -- and D. C. Gajdusek, Amer.
J. Trop. Med. Hyg. 19, 138 (1970).
3. C. J. Gibbs, Jr., D. C. Gajdusek, D. M.
Asher, M. P. Alpers, E. Beck, P. M. Daniel,
W. B. Matthews, Science 161, 388 (1968);
G. J. Gibbs, Jr., and D. C. Gajdusek, ibid.
165, 1023 (1969).
4. D. C. Gajdusek, C. J. Gibbs, Jr., D. M.
Asher, E. David, ibid. 162, 693 (1968); D. C.
Gajdusek and C. J. Gibbs, Jr., Nature 230,
588 (1971); ibid. 240, 351 (1972).
5. C. J. Gibbs, Jr., and D. C. Gajdusek, Nature
236, 73 (1972).
6. R. F. Marsh, thesis, University of Wisconsin
( 1968); D. Burger, R. Eckroade,
0. M. ZuRhein, R. P. Hanson, J. Infec. Dis.
120, 713 (1969); R. J. Eckroade, G. M.
ZuRhein, R. F. Marsh, R. P. Hanson, Scienc-
e 169, 1088 (1970).
7. N. G. Rogers, M. Basnight, C. J. Gibbs, Jr.,
The induction or transfer of enzyme
activity would be an attractive mode
of therapy for some of the enzyme
deficiency diseases. Rugstad and his
co-workers (1) have shown that bilirubin
uridine diphosphate (UDP)
glucuronyltransferase (E.C. 24.1.17)
activity could be transferred into enzyme
deficient homozygous Gunn rats.
This was accomplished by subcutaneous
transplantation of a clonal strain of
rat hepatoma cells (2). However, transplantation
of a viable neoplastic tissue
Fig. 1. Sequential histological appearance
of the tissues after grafting. (a) Three
weeks after the graft procedure. The pale
graft is surrounded by fibrotic tissues
and some inflammatory cells. (b) Six
weeks after the graft procedure. The graft
seems to be near the periphery. Fibrotic
tissues cannot be seen. (c) Nine weeks
after grafting. The size of the tissues
has diminished. (d) Twelve weeks after
grafting. No visible graft tissue can be
identified. The location of the graft can
be identified by the cleft.
D. C. Gajdusek, Nature 216, 446 (1967);
D. C. Gajdusek, C. J. Gibbs, Jr., N. G.
Rogers, M. Basnight, J. Hooks, ibid. 235,
8. E. J. Field, Lancet 1968-I, 981 (1968).
9. D. A. Peterson, L. G. Wolfe, F. Deinhart,
D. C. Gajdusek, C. J. Gibbs, Jr., Nature,
10. I. Zlotnik and J. C. Rennie, J. Comp. Pathol.
75, 147 (1965).
11. R. P. Hanson, R. J. Eckroade, R. F. Marsh,
G. M. ZuRhein, C. L. Kanitz, D. P. Gustafson,
Science 172, 859 (1971).
12. R. L. Chandler and B. A. Turfey, Res. Vet.
Sci. 13, 219 (1972).
13. W. J. Hadlow, personal communication
14. R. M. Barlow, J. Clin. Pathol. 25, 102 (1972).
15. J. L. Hourrigan and A. L. Klingsporn, personal
16. , H. A. McDaniel, M. N. Riemenschneider,
J. Amer. Vet. Med. Ass. 154, 538
30 April 1973; revised 12 June 1973
5 OCTOBER 1973 SCIENCE, VOL. 182
Subject: Human Tissues for Transplantation, Recall Nationwide and Internationally (CJD TSE RISK, among other infectious diseases risk)
Date: July 25, 2006 at 10:21 am PST
RECALLS AND FIELD CORRECTIONS: BIOLOGICS -- CLASS I
Human Tissues for Transplantation, Recall # B-0431-6
a) Patellar Tendon of varying sizes;
b) Patellar Tricortical Wedge;
c) Precision Graft of varying sizes;
d) RESERVE Cortical-Cancellous Ring of varying sizes;
e) Saphenous Veins of varying sizes;
f) SELECT Fibula Wedge of varying sizes;
g) SR Coritcal Block of varying sizes;
h) Tangent - Impacted Cortical Wedge of varying sizes;
i) Tibialis Anterior Tendon;
j) Tibialis Posterior Tendon;
k)TLIF of varying sizes;
l) Tricortical Block 9mm;
m) Unicortical Blocks of varying sizes;
n) Achilles Tendon W/ Calcaneus L=>180mm;
o) ACSR Coritcal Block of varying sizes;
p) ASR Cortical-Cancellous Block;
q) Bicortical Block of varying sizes;
r) BioCleanse® Patellar Tendon Hemi of varying sizes;
s) BioCleanse® Patellar Tendon Preshaped of varying sizes;
t) BioCleanse® Patellar Tendon Whole;
u) BioCleanse® Tibialis Anterior Tendon >= 200mm;
v) Cancellous Chips of varying sizes;
w) Cancellous Cubes of varying sizes;
x) Cornerstone L-ASR of varying sizes;
y) Cortical Cancellous Chips of varying sizes;
z) Cortical Strip of varying sizes;
aa) Corticocancellous Chips 40/60 Blend (1-3mm) 90cc;
bb) Dowel, Unicortical 14mm;
cc) Femoral Head W/O Cartilage;
dd) Femoral Shaft of varying sizes;
ee) FEMUR DISTAL (Left);
ff) Fibula Shaft, 50mm-75mm (L);
gg) FROZEN Impacted Cortical Wedge 8 x 20mm;
hh) HTO Wedge of varying sizes;
ii) Humeral Shaft, 50mm-100mm (L);
jj) HUMERUS WHOLE (Left);
kk) Iliac Block, Tricortical of varying sizes;
ll) Ilium Strip Tricortical 28-45mm x >24mm x 9mm;
mm) L-ACSR Cortical Block of varying sizes;
nn) Lordotic ASR Cortical-Cancellous Block of varying sizes;
oo) Lordotic MASR Cortical-Cancellous Block of varying sizes;
pp) Lordotic SR Cortical Block of varying sizes;
qq) Machined Cortical Ring of varying sizes;
rr) MASR Cortical-Cancellous Block of varying sizes;
ss) MD-II Dowel (Threaded) of varying sizes;
tt) MD-IV Threaded Cortical Dowel of varying sizes;
uu) Right/Left pulmonary hemi-artery;
vv) Semitendinosus Tendon, 200mm;
ww) Strips Cortical 090-110mm(L) x 18-20mm (W);
xx) Tibia Shaft, 50mm-75mm (L);
yy) Patellar Tendon (hemi)(International);
zz) Patellar Tendon Preshaped of varying sizes
Recalling Firm: Regeneration Technologies, Inc., Alachua, FL, by letters dated October 14 and October 26, 2005.
Responsible Firm: Biomedical Tissue Services, Ltd., Fort Lee, NJ. Firm initiated recall is ongoing.
Human tissues, recovered from donors without adequate donor eligibility, were distributed.
VOLUME OF PRODUCT IN COMMERCE
Nationwide and Internationally
Human Tissues for Transplantation, Recall # B-1091-6:
a) ASCR Cortical Block (10x14x11);
b) Assembled Cortical-Cancellous Block (07x14x11);
c) Bicortical Block (14 mm x 20 mm);
d) Cancellous Chips;
e) Cancellous Cubes of varying sizes;
f) Cortical Cancellous Chips 40/60 Mix (1-3 mm) 30 cc;
g) Dowel, Unicortical 14 mm;
h) Iliac Block, Tricortical (16 mm x 15 mm);
i) Ilium Strip Tricortical of varying sizes;
j) MD-II Dowel (Threaded) of varying sizes;
k) MD-IV Threaded Cortical Dowel of varying sizes;
l) Patellar Tricortical Wedge (20 mm(H) x 25 mm(L));
m) Precision Graft of varying sizes;
n) SELECT Fibula Wedge of varying sizes;
o) SR Cortical Block of varying size;
p) Tangent -- Impacted Cortical Wedge of varying sizes;
q) Unicortical Block of varying sizes;
r) Achilles Tendon Preshaped;
s) Achilles Tendon with Calcaneous;
t) Cancellous Block;
u) Femoral Head w/o Cartilage;
v) Femoral Shaft (166 mm -- 202 mm (L));
w) Fibula Shaft of varying sizes;
x) HTO Wedge of varying sizes;
y) Patellar Tendon (hemi) of varying sizes;
z) Patellar Tendon (Whole);
aa) Patellar Tendon Preshaped (International);
bb) Patellar Tendon Preshaped of varying sizes;
cc) Tibialis Anterior Tendon;
dd) Tibialis Posterior Tendon;
Recalling Firm: Regeneration Technologies, Inc., Alachua, FL, by letters dated October 14 and October 26, 2005.
Responsible Firm: Biomedical Tissue Services, Ltd., Fort Lee, NJ. Firm initiated recall is ongoing.
Human tissues, recovered from donors without adequate donor eligibility, were distributed.
VOLUME OF PRODUCT IN COMMERCE
Nationwide and Internationally
Human Tissue for Transplantation Tissues, Recall # B-1108-6:
a) Achilles Tendon;
b) Cancellous Chips 30cc, 4-10mm;
c) Tibialis Tendon, Anterior;
d) Tibialis Tendon, Posterior;
e) Patella Tendon, Hemi;
f) Ground Cancellous;
a) T2005-061-002, T2005-053-001, T2005-053-002, T2005-069-002, T2005-046-003, T2005-068-001, T2005-044-001, T2005-044-002, T2005-010-001, T2005-063-001, T2005-039-002, T2005-043-001, T2005-045-003, T2005-045-004, T2005-049-003, T2005-049-004, T2005-055-001, T2005-022-002, T2005-075-001, T2005-048-001, T2005-048-002, T2005-038-002, T2005-023-002, T2005-022-001, T2005-063-002, T2005-023-001, T2005-040-002, T2005-040-001, T2005-072-001, T2005-074-002, T2005-013-001, T2005-054-001, T2005-100-001, T2005-034-002;
b) T2005-018-004, T2005-018-003, T2005-024-001, T2005-024-002, T2005-024-003, T2005-025-001, T2005-013-003;
c) T2005-046-007, T2005-044-006, T2005-043-002, T2005-043-003, T2005-041-006, T2005-040-006, T2005-048-005, T2005-045-006, T2005-048-006, T2005-047-007;
d) T2005-048-004, T2005-044-003, T2005-040-004, T2005-047-010, T2005-041-005, T2005-045-005, T2005-047-009, T2005-049-005, T2005-040-003;
f) T2005-018-002, T2005-027-001, T2005-027-002, T2005-027-003, T2005-027-004, T2005-018-006, T2005-018-007, T2005-026-001
Recalling Firm: Tissue Management Solutions, LLC, Scottsdale, AZ, by telephone on October 5, 2005, and by letter dated October 28, 2005.
Manufacturer: Lost Mountain Tissue Bank, Kennesaw, GA. Firm initiated recall is complete.
Responsible Firm: Biomedical Tissue Services Ltd., Fort Lee, NJ
Human tissues, recovered from donors without adequate donor eligibility, were distributed.
VOLUME OF PRODUCT IN COMMERCE
CO, IL, AZ, CA, TX, NV, KA and WI
##################### Bovine Spongiform Encephalopathy #####################
----- Original Message -----
From: Terry S. Singeltary Sr.
Sent: Friday, September 01, 2006 2:49 PM
Subject: RE- FDA FORMS TASK FORCE ON HUMAN TISSUE SAFETY
FOR IMMEDIATE RELEASE
August 30, 2006
Paul Richards, 301-827-6242
FDA Forms Task Force on Human Tissue Safety
“The primary goal of the new task force is to identify whether any additional steps are needed to further protect the public health while assuring the availability of safe products,” said Jesse Goodman, MD, MPH, director of CBER. “The creation of this task force is part of the agency's overall plan to ensure that all human cells and tissues are as safe as possible.”
While the agency believes most firms involved in tissue manufacturing comply with the new regulations, FDA wants to explore where additional steps could help strengthen its approach to making sure firms follow required practices to prevent the transmission of communicable diseases. The agency continues to work diligently to identify and, where appropriate, take action against establishments and individuals that violate the rules. These actions may include both administrative and criminal proceedings.
“FDA is committed to rapidly identifying and stopping those establishments and individuals that risk endangering the public health by not complying with the regulations,” said Margaret O’K Glavin, Associate Commissioner of the Office of Regulatory Affairs. “We also will continue to work with professional and trade associations to support their ongoing efforts to assure quality oversight of manufacturing operations and product safety.”
“The creation of this task force underscores FDA’s recognition that compliance with the rules in place to ensure recipient safety is our highest priority,” Dr. Goodman said.
Within the next three months, the task force will develop an action plan, and where necessary, propose changes to existing policies, as well as generate a set of recommendations, identify what resources are needed to support these actions and report on how the agency can immediately implement its action plan.
THANK YOU DR. GOODMAN !!!
I only hope that you (FDA et al) are serious? ACTIONS speak louder than words, and only monetary damages AND jail will make some companies comply. I donated my mothers brain for the research of human TSE, she died 12-14-97 from the Heidenhain Variant of Creutzfeldt Jakob Disease, and since, have regretted ever doing it due to the various controversies that have taken place since, with tissue donations. I know others that feel the same way. Either get it under control now, or risk having less and less donated tissue to work with in science and the medical donor programs. ...
I am sincerely,
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
CJD WATCH MESSAGE BOARD
NIH BODY SNATCHERS AT IT AGAIN, SELLING TO HIGHEST BIDDERS
Wed Jun 14, 2006 09:07
Charged With Stealing Parts From Corpses
Parts Allegedly Removed Before Cremation
POSTED: 5:55 am CDT May 18, 2007
ROCHESTER, N.Y. -- Three funeral home directors and four former employees of a biomedical supply company secretly removed skin, bone and other body parts from dozens of corpses awaiting cremation at Rochester funeral homes, prosecutors said Thursday.
An indictment unsealed Thursday charges the seven with body stealing, unlawful dissection and other counts. The most serious charges carry maximum 20-year prison sentences.
"Put yourself in the position of one of the family members," said Monroe County District Attorney Michael Green. "What we've heard from them is that this is just absolutely devastating."
Four of those charged worked at a suburban Rochester branch of now-defunct Biomedical Tissue Services of Fort Lee, N.J.
Four other men, including the company's owner, former dentist Michael Mastromarino, were charged last year with removing bone and tissue from 1,077 bodies at funeral homes without the permission of families. All have pleaded not guilty.
Prosecutors said Mastromarino made millions of dollars by selling body parts to biomedical companies that supply material for common procedures, including dental implants and hip replacements.
In October, seven funeral home directors linked to the scheme pleaded guilty in New York City to undisclosed charges and agreed to cooperate with investigators. They included the director of a funeral home that took parts from the body of "Masterpiece Theatre" host Alistair Cooke, who died in 2004, defense attorneys say.
Biomedical Tissue Services operated its only satellite office in the Rochester suburb of Brighton and paid funeral homes a standard fee of around $1,000 to lawfully harvest body parts.
The indictment alleges that employees Darlene Deats, 46; Kevin Vickers, 53; Nicholas Sloyer, 34; and Kirssy Knapp, 29, removed bone and tissue from 36 corpses in 2005 without getting the proper consent.
Also charged were Jason Gano, 31, former funeral director of Thomas E. Burger Funeral Home in Hilton, Scott Batjer, 37, director of Profetta Funeral Chapel in Webster, and Serrell Gayton, 59, director of Serenity Hills Funeral Chapel in Rochester.
Five of the defendants pleaded not guilty Thursday and were released. Vickers, in England attending his brother's wedding, was ordered to appear next week, and an arrest warrant was issued for Knapp, who failed to show up in court.
Sloyer's attorney, Paul MacAulay, said he did not knowingly commit a crime.
"He had no reason to doubt that any of the bodies that they were involved in were being processed without a valid consent," MacAulay said.
Copyright 2007 by The Associated Press.
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518