Advances in the development of a screening test for variant Creutzfeldt–Jakob disease
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Variant Creutzfeldt-Jakob disease (vCJD) is a transmissible neurodegenerative prion disease that continues to present a unique problem for medical diagnostics. Uncertainties remain over the prevalence of vCJD in the UK population and its incubation period in individuals of different genotypes. Although the infectious agent that causes vCJD is widely distributed in the peripheral tissues of patients and those carrying the disease, it does not provoke any host immune response that would be amenable to detection. The recent realisation that it can be transmitted by blood transfusion, and that individuals are infectious long before the appearance of symptoms, have increased the need for a blood-screening assay. This paper reviews progress that has been made in the development of potential tests and the protocols that have been devised for their evaluation.Keywords:
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To explore the effects of combined CYP1A1 Msp1 genotypes with Ile/Val genotypes on susceptibility to lung cancer. Msp1 and Ile/Val genotypes of CYP1A1 gene were detected with the methods of PCR RFLP and allele specific amplification(ASA) in a case control study,including 92 cases of lung cancer and 98 hospital controls. Msp1 polymorphism site:The risk of lung cancer with the individuals of genotype B or genotype C was 1 85 times greater than that with the individual of genotype A ( χ 2=4 36,P0 05,OR=1 85,95% CI 1 04～3 30 ).Ile/Val polymorphism site:The risk of lung cancer of the individuals with genotype Val/Val was 3 3 times greater than the individual with genotype Ile/Ile ( χ 2=4 12,P0 05,OR=3 3,95% CI 1 02～10 72 ).The lung cancer risks of individuals with combined Ile/Ile genotype and A genotype were compared with these of individuals combined Ile/Val genotype and B ( χ 2=5 81,P0 05,95% CI 1 7～9 96 ),the individuals combined Ile/Val genotype and C genotype ( χ 2=4 74,P0 05,95% CI 1 11～20 9 ) and the individuals combined Val/Val genotype and C genotype ( χ 2=4 42,P0 05,95% CI 1 27～23 6 ). [Conclusion] The genotype C and genotype Val/Val of CYP1A1 gene may be susceptible to lung cancer,the individuals with two susceptible genotypes were more susceptible to lung cancer.
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Feeding of stool supernates to volunteers has demonstrated that there are at least two different types—afebrile and febrile—of acute infectious non-bacterial gastroenteritis. The afebrile illness, produced by the Marcy agent previously described, has an average incubation period of 60 hours and is characterized by watery diarrhea. The agent (FS) responsible for the febrile illness has been carried through 3 human passages. The febrile disease has an average incubation period of 27 hours and is characterized by constitutional symptoms. It is believed that the two agents are not the same because of the differences in incubation period, the clinical picture, and the absence of cross-immunity. Intranasal instillation of throat washings obtained from 2 persons with gastroenteritis failed to produce illness in 2 groups of volunteers.
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Prion diseases continue to fascinate scientists from different disciplines since the discovery that a misfolded prion protein can act as an infectious agent. Infectious prions have caused epidemics, including kuru in humans, cervid chronic wasting disease, bovine spongiform encephalopathy (BSE) or "mad cow disease," and most recently, camel prion disease, which was identified in 2018 1. In Kuru, spread of the disease occurred from the ingestion of prion-infected, dead relatives as part of mourning practices, whereas in chronic wasting disease, prions may be transmitted not only through ingesting prion-contaminated food, but also by exposure to a prion-contaminated environment 12, 13. In all instances, prions hold structural properties that cause different disease presentations, which can be passed on to another individuals 21. However, the most common form of human prion disease, sporadic Creutzfeldt-Jakob disease, is not caused by exposure to infectious prions but occurs as a rare disease from unknown causes 23. In all instances, prions cause a neurodegenerative disease with neuropathological and mechanistic overlap with other protein misfolding disorders, such as Alzheimer's or Parkinson's disease 9. Interestingly, a great number of neurodegenerative diseases spread through the brain as prions do, yet some obvious differences in disease characteristics have to considered (Table 1). Although our understanding of prion disease has experienced a boost in the last 10 years, there are gaps in our understanding of the molecular basis of this complex disease 18. An incomplete list of these unchartered territories include (i) the structure of the prion aggregate and how this relates to the spread of prions within a host and also from host to host, (ii) the need to detect prions or disease biomarkers ante-mortem in order to establish and test therapies and (iii) an integrated view of the mechanisms underlying prion neurotoxicity. In this issue of Brain Pathology, we have assembled experts in the field to report on the state of the art developments in human prion diseases, animal prion diseases and on the mechanisms of prion neurotoxicity. The mini-symposium is further completed by one original article reporting on the influence of microRNAs in regulating the prion protein 17 and by one original article proposing a molecular mechanism to explain the extraordinary susceptibility of bank voles to prion infection 8. One thing prion scientists, especially the ones involved in neuropathological characterization of the disease, are particularly proud of, is the categorization of disease subtypes based on histological, genetic and biochemical criteria. In the review by Piero Parchi and colleagues, this categorization-system is introduced, and novel aspects relevant not only to prion scientists but also to the wider neuropathological community concerning co-pathology or cross-seeding phenomena are elucidated 2. Animal prion diseases continue to emerge, recently with variants of scrapie and BSE, a camel prion disease in Algeria 1 and chronic wasting disease in Scandinavian wild reindeer 3 and moose 19. What are the risks for animal prions infecting humans? Houston and Andreoletti summarize the history, epidemiology and pathogenesis of the animal prion diseases, and review research designed to estimate the risk of human infection 7. The authors also highlight the limitations of experimental models and consider the uncertainties for zoonotic transmission that still remain, ultimately emphasizing the importance of preventing human exposure to prions. The pathologic hallmarks of prion disease include spongiform degeneration, gliosis, aggregated prion protein and neuronal loss, yet we are only beginning to understand how toxic signaling through the prion protein can induce neuronal death. David Harris and colleagues note the obstacles that have hampered investigations of neurotoxicity, most notably the lack of an in vitro model system that recapitulates features of neuronal degeneration. They review new experimental systems used in recent years to model prion neurotoxicity in order to define the signaling pathways activated by prion aggregates 10. They also consider structural modifications in the prion protein that can trigger neurotoxic sequelae. Finally, the authors discuss missing links in the neurotoxic signaling pathway and note opportunities to identify novel drug targets to mitigate toxic signaling, which may also have relevance for other neurodegenerative diseases. In summary, this mini-symposium is as interesting and diverse as prion diseases, and we hope the readers enjoy reading the articles as much as we have.
Chronic wasting disease
Kuru
Bovine spongiform encephalopathy
Fatal familial insomnia
Transmissible spongiform encephalopathy
Creutzfeldt-Jakob Syndrome
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Abstract The incubation period is the time interval between exposure to a disease‐causing agent and the onset of symptomatic disease. For example, the incubation period of an infectious disease refers to the time interval between infection or exposure to a viral or bacterial agent and the onset of symptomatic (clinical) disease. The incubation period is also called the clinical latency period. The focus of this article is on modeling and estimating the incubation period of infectious diseases. However, some of the ideas may also be applicable to the incubation period of noninfectious disease, for example, the incubation period of radiation‐induced cancer that refers to the time interval from radiation exposure to cancer diagnosis. Alternative designs for the estimation of an incubation period are reviewed, and methods to synthesize studies on incubation periods are mentioned.
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Both small and large variant Creutzfeldt Jakob disease (vCJD) epidemics are consistent with the current observed incidence. Uncertainty in vCJD projections could potentially be reduced by incorporating information on the prevalence of the infectious agent in persons incubating vCJD. The prospect of vCJD prevalence studies has been raised by detection of abnormal prion protein, thought to be the infectious agent, in appendices and tonsils removed from vCJD patients. Although unlinked anonymous testing of stored operative tissues for abnormal prion protein is very appealing, the design and interpretation of such prevalence studies is complicated by the lack of information on how early in the incubation period of vCJD the abnormal prion protein becomes detectable.We simulate a range of vCJD epidemics, consistent with the limited available information on the incidence of vCJD, to illustrate some of the potential problems encountered when interpreting the results from prevalence studies of detectable abnormal prion protein. We assume plausible incubation period distributions and dietary exposure patterns.We demonstrate, in the context of our simulated epidemics, that prevalence studies of detectable abnormal prion protein would require the testing of tens of thousands of operative specimens and, even then, that unlinked anonymous testing positives would be unexpected.
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Infectious hepatitis and serum hepatitis have been distinguished in the past largely on epidemiologic grounds, the former being characterized by a shorter incubation period, high rate of contact transmission and presence of the infectious agent in the stool, and the latter by a longer incubation period and dissemination of the agent by parenteral means. Krugman and his associates1 have identified two infectious agents capable of producing hepatitis: MS-1, which causes a highly contagious short-incubation disease; and MS-2, which produces a long-incubation disease having a low rate of contact transmission. In the article appearing in the current issue of the Journal . . .
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Abstract The incubation period is the time interval between exposure to a disease‐causing agent and the onset of symptomatic disease. For example, the incubation period of an infectious disease refers to the time interval between infection or exposure to a viral or bacterial agent and the onset of symptomatic (clinical) disease. The incubation period is also called the clinical latency period. The focus of this article is on modeling and estimating the incubation period of infectious diseases. However, some of the ideas may also be applicable to the incubation period of noninfectious disease, for example, the incubation period of radiation‐induced cancer that refers to the time interval from radiation exposure to cancer diagnosis. Alternative designs for the estimation of an incubation period are reviewed, and methods to synthesize studies on incubation periods are mentioned.
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Parvovirus B19 comprises three distinct genotypes (1, 2, and 3). The distribution of B19 genotypes has not before been examined in South Africa. Two hundred thirty-nine laboratory samples submitted to a diagnostic virology laboratory for parvovirus DNA detection were analyzed retrospectively. Of the 53 PCR-positive samples investigated, 40 (75.4%) were identified as genotype 1 by genotype-specific PCR or consensus NS1 PCR and sequencing and 3 (5.7%) as genotype 2 and 10 (18.9%) as genotype 3 by analysis of NS1 sequences. Furthermore, phylogenetic analysis identified two genotype 1 sequences which were distinct from the previously described genotypes 1A and 1B. Interestingly, a genotype 2 virus was detected in the serum of an 11-year-old child, providing evidence for its recent circulation. This is the first study to demonstrate the concurrent circulation of all three genotypes of B19 in South Africa and the provisional identification of a novel subtype of genotype 1. The implications of parvovirus B19 variation are discussed.
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Incubation period
Bovine spongiform encephalopathy
Infectious agent
Creutzfeldt-Jakob Syndrome
Transmissible spongiform encephalopathy
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