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Estimation of Epidemic Size and Incubation Time Based on Age Characteristics of vCJD in the United Kingdom
Abstract and Figures
The size of the variant Creutzfeldt-Jakob Disease (vCJD) epidemic in the United Kingdom is a major public health concern and a subject of speculation. The cases are young (mean age = 28). Assuming that the risk of developing the disease in susceptible exposed subjects decreases exponentially with age after age 15, that all infections occurred between 1980 and 1989, and that the distribution of the incubation period is lognormal, we estimate that the mean duration of the incubation period is 16.7 years [95% confidence interval (CI): 12.4 to 23.2] and that the total number of cases will be 205 (upper limit of the 95% CI: 403).
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... Elle peut aussi se transmettre à d'autres animaux comme les grands félins ou les chats domestiques (encéphalopathie spongiforme féline (ESF)) (Valleron et al., 2001) Une grande épidémie d'ESB a eu lieu au Royaume Uni entrainant l'abattage d'environ 1 million de bovins et la mort d'environ 150 patients infectés (Prusiner., 1997 ;Andrews et al., 2003). ...
... ntation animal et des abas de bovin dans la chaine alimentaire, l'inscription de l'ESB dans les maladies à déclaration obligatoire, la mise en place de surveillance active et l'abattage systématique des troupeaux infectés, l'interdiction de la consommation des tissus les plus infectieux comme le cerveau, la moelle épinière, le thymus et l'intestin.(Valleron et al., 2001). ...
Les prions résultent d’un changement de conformation de la protéine PrP et sont responsables de maladies neurodégénératives fatales et transmissibles, chez l’homme et l’animal. Sous sa forme prion, la PrP devient insoluble, résistante aux protéases et forme des agrégats riches en feuillet bêta. Les prions convertissent la PrP cellulaire normale en un élément du prion par simple contact, se multipliant ainsi dans le cerveau. Nous montrons qu’une délétion raccourcissant l’hélice H2 de la PrP ovine réduit la stabilité de la protéine et induit sa conversion spontanée en un nouveau type de príon dans un modèle de culture cellulaire. Ce nouveau príon est capable de convertir la PrP mutante mais aussi son fragment C1. Le C1 est une forme raccourcie de la PrP, tronquée en NKterminal par les métalloprotéases, mais est présent avec la PrP entière à la surface cellulaire. Le fragment C1 n’est pas converti par les souches classiques de prion et est considéré comme trop court pour former un prion. Nous montrons au contraire que le C1 de la PrP mutée peut adopter une structure prion autoKréplicative, résistante aux protéases et infectieuse. De plus, les fibres amyloïdes produites in& vitro avec une PrP recombinante présentant la même délétion se sont comportées comme des prions synthétiques, induisant la conversion en prion de la PrP cellulaire homologue et de son fragment C1. L’analyse des fibres par RMN du solide a montré un changement de conformation de la région CK terminale vers une forme enrichie en feuillet bêta.
... During the 1980s the UK human population is estimated to have been extensively exposed to bovine spongiform encephalopathy (BSE) prions via contaminated food (Wilesmith, 1993;Valleron et al., 2001). Despite this widespread risk of zoonotic disease transmission, the numbers of definite and probable human cases of variant Creutzfeldt-Jakob disease (vCJD) due to the consumption of BSE-contaminated food have remained low (n = 178, March 2022), with no new cases recorded since 2016 (Unit, 2018). ...
Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep, are infectious and chronic neurodegenerative diseases to which there are no cures. Infection with prions in the central nervous system (CNS) ultimately causes extensive neurodegeneration, and this is accompanied by prominent microglial and astrocytic activation in affected regions. The microglia are the CNS macrophages and help maintain neuronal homeostasis, clear dead or dying cells and provide defense against pathogens. The microglia also provide neuroprotection during CNS prion disease, but their pro-inflammatory activation may exacerbate the development of the neuropathology. Innate immune tolerance induced by consecutive systemic bacterial lipopolysaccharide (LPS) treatment can induce long-term epigenetic changes in the microglia in the brain that several months later can dampen their responsiveness to subsequent LPS treatment and impede the development of neuritic damage in a transgenic mouse model of Alzheimer’s disease-like pathology. We therefore reasoned that innate immune tolerance in microglia might similarly impede the subsequent development of CNS prion disease. To test this hypothesis groups of mice were first infected with prions by intracerebral injection, and 35 days later given four consecutive systemic injections with LPS to induce innate immune tolerance. Our data show that consecutive systemic LPS treatment did not affect the subsequent development of CNS prion disease. Our data suggests innate immune tolerance in microglia does not influence the subsequent onset of prion disease-induced neuropathology in mice, despite previously published evidence of this effect in an Alzheimer’s disease mouse model.
... Si l'on analyse les cas d'ESB par rapport à leur année de naissance (Fig. 1, 2 et 3) on constate que la contamination du cheptel britannique suit une courbe exponentielle Lorsque, en mars 1996, on sut que l'ESB pouvait être transmise à l'Homme, là encore le consommateur a été inquiet face aux prévisions alarmistes des épidémiologistes qui essayaient d'évaluer le risque potentiel pour la santé publique, mais, qui se fondaient sur des données limitées (d'où certains intervalles de confiance présentant une zone d'incertitude de quelques cas à des millions de personnes contaminées par l'agent bovin). Ce n'est que 5 ans plus tard qu'il leur fut possible d'être plus précis, notamment grâce aux travaux de d'Alain-Jacques Valleron en 2001 annonçant 205 cas humains de variants de la MCJ (vMCJ) avec 16,5 ans d'incubation [10]. ...
Résumé
Le concept « une seule santé » lie étroitement la santé humaine et la santé animale car de nombreuses maladies sont des zoonoses. Les exemples historiques témoignant d’une collaboration efficace entre la médecine vétérinaire et la médecine humaine sont nombreux dans la mise au point des premiers vaccins utilisés dans le monde (variole, rage, tétanos, diphtérie, tuberculose, etc.). Mais lorsqu’une maladie nouvelle apparaît chez l’animal, le risque d’une transmission possible à l’Homme est difficile à estimer. Dans ce dernier cas, la perte de confiance du consommateur face aux incertitudes scientifiques peut provoquer une crise sanitaire (exemples de l’encéphalopathie spongiforme bovine et de la peste aviaire H5N1). Mais la plus grave crise que nous connaissons depuis le début de l’année 2020 est celle de la pandémie de Covid-19 qui confirme que la modification des écosystèmes de certaines espèces sauvages comme la chauve-souris fer à cheval peut avoir des conséquences importantes pour la santé publique. Les animaux ayant été malades de la Covid-19 ont été contaminés par l’Homme mais on ne peut pas exclure actuellement le risque de réservoir animal pour le SARS-CoV-2 qui a circulé dans le monde entier.
... Figure 2 shows that the incubation periods between transfusion and the onset of clinical symptoms varied from 6.5 to 8.5 years. This is broadly in line with incubation period for vCJD estimated from the lag between the peaks of the BSE and vCJD epidemics [100][101][102]. Shown as well is the time interval between the donation of blood and the onset of symptoms in the donor ( Figure 2). ...
Twenty-five years has now passed since variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom (UK). Early epidemiological, neuropathological and biochemical investigations suggested that vCJD represented a new zoonotic form of human prion disease resulting from dietary exposure to the bovine spongiform encephalopathy (BSE) agent. This hypothesis has since been confirmed though a large body of experimental evidence, predominantly using animal models of the disease. Today, the clinical, pathological and biochemical phenotype of vCJD is well characterized and demonstrates a unique and remarkably consistent pattern between individual cases when compared to other human prion diseases. While the numbers of vCJD cases remain reassuringly low, with 178 primary vCJD cases reported in the UK and a further 54 reported worldwide, concerns remain over the possible appearance of new vCJD cases in other genetic cohorts and the numbers of asymptomatic individuals in the population harboring vCJD infectivity. This review will provide a historical perspective on vCJD, examining the origins of this acquired prion disease and its association with BSE. We will investigate the epidemiology of the disease along with the unique clinicopathological and biochemical phenotype associated with vCJD cases. Additionally, this review will examine the impact vCJD has had on public health in the UK and the ongoing concerns raised by this rare group of disorders.
This report summarises donation testing data, and incidence and prevalence trends for transfusion transmissible infections among Australian blood donors. It relates to the occurrence of transfusion transmissible infections in Australia and the effectiveness of Lifeblood’s infectious disease blood safety strategy.
Prion diseases are a group of fatal, infectious neurodegenerative disorders affecting various species of mammals, including humans. The infectious agent in these diseases, termed prion, is composed exclusively of a misfolded protein that can spread and multiply in the absence of genetic materials. In this article, we provide an overview of the mechanisms of prion replication, interindividual transmission, and dissemination in communities. In particular, we review the potential role of the natural environment in prion transmission, including the mechanisms and pathways for prion entry and accumulation in the environment as well as its roles in prion mutation, adaptation, evolution, and transmission. We also discuss the transmission of prion diseases through medical practices, scientific research, and use of biological products. Detailed knowledge of these aspects is crucial to limit the spreading of existing prion diseases as well as to prevent the emergence of new diseases with possible catastrophic consequences for public health.
Prion diseases or transmissible spongiform encephalopathies (TSEs) are human and animal diseases naturally or experimentally transmissible with a long incubation period and a fatal course without remission. The nature of the transmissible agent remains debated but the absence of a structure evoking a conventional microorganism led Stanley B. Prusiner to hypothesize that it could be an infectious protein (proteinaceous infectious particle or prion). The prion would be the abnormal form of a normal protein, cellular PrP (PrPc) which will change its spatial conformation and be converted into scrapie prion protein (PrPsc) with properties of partial resistance to proteases, aggregation and insolubility in detergents. No inflammatory or immune response are detected in TSEs which are characterized by brain damage combining spongiosis, neuronal loss, astrocytic gliosis, and deposits of PrPsc that may appear as amyloid plaques. Although the link between the accumulation of PrPsc and the appearance of lesions remains debated, the presence of PrPsc is constant during TSE and necessary for a definitive diagnosis. Even if they remain rare diseases (2 cases per million), the identification of kuru, at the end of the 1950s, of iatrogenic cases in the course of the 1970s and of the variant of Creutzfeldt-Jakob disease (CJD) in the mid-1990s explain the interest in these diseases but also the fears they can raise for public health. They remain an exciting research model because they belong both to the group of neurodegenerative diseases with protein accumulation (sporadic CJD), to the group of communicable diseases (iatrogenic CJD, variant of CJD) but also to the group of genetic diseases with a transmission Mendelian dominant (genetic CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia).
Several neurodegenerative diseases of humans and animals are caused by the misfolded prion protein (PrP Sc), a self-propagating protein infectious agent that aggregates into oligomeric, fibrillar structures and leads to cell death by incompletely understood mechanisms. Work in multiple biological model systems, from simple baker's yeast to transgenic mouse lines, as well as in vitro studies, has illuminated molecular and cellular modifiers of prion disease. In this review, we focus on intersections between PrP and the proteostasis network, including unfolded protein stress response pathways and roles played by the powerful regulators of protein folding known as protein chaperones. We close with analysis of promising therapeutic avenues for treatment enabled by these studies.
Epidemiological data were collected on the slow virus disease, kuru, among the Fore cultural and linguistic group in Papua New Guinea from 65 kuru patients who died or were diagnosed between 1977 and 1981. From these, 3 episodes of cannibalistic feasts were identified, in each of which 2 or more participants were exposed to the infectious agent for the first time and died within weeks or months of each other 25–30 years later. Thus, it is shown that the natural incubation period of kuru could be as long as 25–30 years and is at times identical in 2 or more individuals infected at the same time, even over this span of years; also it is not determined by age at exposure. Further analysis of the episodes supports the concept on which the study was based, namely the transmission of kuru at the time of cannibalistic mourning with primary infection often occurring in infancy or early childhood.
Mathematical model that describe the key processes determining the pattern of the bovine spongiform encephalopathy (BSE) epidemic in British cattle are derived that allow for infection from feed as well as maternal and direct horizontal transmission. Heterogeneous susceptibility classes are also incorporated into the analysis. Maximum likelihood methods are used to estimate parameters and to obtain confidence intervals from available experimental and epidemiological data. A comprehensive sensitivity analysis of all model parameters and distributional assumptions is presented. Additional validation is provided by fitting the model to independent data collected in Northern Ireland. Model estimates and predictions based on BSE case data for Great Britain and Northern Ireland, together with their implications, are reviewed, and future research priorities discussed.
The aim was to develop a new approach for estimating the incubation period of acquired immunodeficiency syndrome (AIDS), based on age distributions.
Incubation period was expressed as the difference between age at time of diagnosis and age at time of contamination. Assuming independence between age at time of infection and incubation period, the age distribution of newly diagnosed AIDS cases is thus the convolution product between the distributions of the age of freshly infected patients and of the incubation times. AIDS incubation time can therefore be estimated from the age distribution of newly HIV infected subjects and newly diagnosed AIDS cases.
Subjects were 2220 AIDS cases diagnosed until 1987, reported to the Ministry of Health, France, and 172 subjects discovered to be HIV-1 seropositive during a blood donation in Paris between August 1985 and July 1988. In both groups, the only known risk factor was homosexuality.
The estimated median incubation time was 9.9 years (90% CI 9.0-10.9 years). Confidence intervals were narrow, even when taking into account the uncertainty in serodetection delay (90% CI 6.7-13.5 years).
The incubation estimate is as accurate as previous estimates based on other models. This technique could therefore be applied to other risk groups.
The first concern of this work is the development of approximations to the distributions of crude mortality rates, age-specific mortality rates, age-standardized rates, standardized mortality ratios, and the like for the case of a closed population or period study. It is found that assuming Poisson birthtimes and independent lifetimes implies that the number of deaths and the corresponding midyear population have a bivariate Poisson distribution. The Lexis diagram is seen to make direct use of the result. It is suggested that in a variety of cases, it will be satisfactory to approximate the distribution of the number of deaths given the population size, by a Poisson with mean proportional to the population size. It is further suggested that situations in which explanatory variables are present may be modelled via a doubly stochastic Poisson distribution for the number of deaths, with mean proportional to the population size and an exponential function of a linear combination of the explanatories. Such a model is fit to mortality data for Canadian females classified by age and year. A dynamic variant of the model is further fit to the time series of total female deaths alone by year. The models with extra-Poisson variation are found to lead to substantially improved fits.
Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because
of its high prevalence (e.g. 15–20% of the European and American populations). Although blood pressure is known to have a
strong genetic determination, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci
involved in blood pressure regulation have been found by linkage in experimental hereditary hypertensive rat strains, but
their relationship to human hypertension has not been extensively investigated. One of the principal blood pressure loci has
been mapped to rat chromosome 10 and we have undertaken an investigation of the homologous region on human chromosome 17 in
familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant
evidence of linkage (P <0.0001 in some analyses) near two closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal
to the ACE locus in the homology region. Our results indicate that chromosome 17q could contain a susceptibility locus for human hypertension
and show that comparative mapping may be a useful approach for identification of such loci in humans.
Blood pressure is a quantitative trait that has a strong genetic component in humans and rats. Several selectively bred strains of rats with divergent blood pressures serve as an animal model for genetic dissection of the causes of inherited hypertension. The goal is to identify the genetic loci controlling blood pressure, i.e., the so-called quantitative trait loci (QTL). The theoretical basis for such genetic dissection and recent progress in understanding genetic hypertension are reviewed. The usual paradigm is to produce segregating populations derived from a hypertensive and normotensive strain and to seek linkage of blood pressure to genetic markers using recently developed statistical techniques for QTL analysis. This has yielded candidate QTL regions on almost every rat chromosome, and also some interactions between QTL have been defined. These statistically defined QTL regions are much too large to practice positional cloning to identify the genes involved. Most investigators are, therefore, fine mapping the QTL using congenic strains to substitute small segments of chromosome from one strain into another. Although impressive progress has been made, this process is slow due to the extensive breeding that is required. At this point, no blood pressure QTL have met stringent criteria for identification, but this should be an attainable goal given the recently developed genomic resources for the rat. Similar experiments are ongoing to look for genes that influence cardiac hypertrophy, stroke, and renal failure and that are independent of the genes for hypertension.
With the advent of RFLPs, genetic linkage maps are now being assembled for a number of organisms including both inbred experimental populations such as maize and outbred natural populations such as humans. Accurate construction of such genetic maps requires multipoint linkage analysis of particular types of pedigrees. We describe here a computer package, called MAPMAKER, designed specifically for this purpose. The program uses an efficient algorithm that allows simultaneous multipoint analysis of any number of loci. MAPMAKER also includes an interactive command language that makes it easy for a geneticist to explore linkage data. MAPMAKER has been applied to the construction of linkage maps in a number of organisms, including the human and several plants, and we outline the mapping strategies that have been used.
Fourteen cases of new-variant Creutzfeldt-Jakob disease have so far been
confirmed in the United Kingdom. Are they the start of an epidemic? If
so, how informative will cases in the next few years be in predicting
its course?