Spatial analysis of BSE cases in the Netherlands

Background

In many of the European countries affected by Bovine Spongiform Encephalopathy (BSE), case clustering patterns have been observed. Most of these patterns have been interpreted in terms of heterogeneities in exposure of cattle to the BSE agent. Here we investigate whether spatial clustering is present in the Dutch BSE case data.

Results

We have found three spatial case clusters in the Dutch BSE epidemic. The clusters are geographically distinct and each cluster appears in a different birth cohort. When testing all birth cohorts together, only one significant cluster was detected. The fact that we found stronger spatial clustering when using a cohort-based analysis, is consistent with the evidence that most BSE infections occur in animals less than 12 or 18 months old.

Conclusion

Significant spatial case clustering is present in the Dutch BSE epidemic. The spatial clusters of BSE cases are most likely due to time-dependent heterogeneities in exposure related to feed production.

     

No H- and L-type cases in Belgium in cattle diagnosed with bovine spongiform encephalopathy (1999-2008) aging seven years and older

Background  

The bovine spongiform encephalopathy (BSE) epidemic presented homogeneity of the phenotype. This classical BSE (called C-type) was probably due to the contamination of the food chain by a single prion strain. However, due to the active surveillance and better techniques, two rare variants of BSE have been recently reported in different continents without a clear correlation to the BSE epidemic. These emerging types behave as different strains of BSE and were named H-type and L-type according to the high and low molecular mass of the unglycosylated fragment of their proteinase K resistant prion protein (PrP^res). In these types, the proportion of the un-, mono- and di-glycosylated fragments of PrP (glycoprofile) is also atypical and represents an effective diagnostic parameter. This study evaluated the presence of such types in bovine of 7 years and older in Belgium.     

Spatiotemporal Scan and Age-Period-Cohort Analysis of Hepatitis C Virus in Henan,China: 2005–2012

Background

Studies have shown that hepatitis C virus (HCV) infection increased during the past decades in China. However, little evidence is available on when, where, and who were infected with HCV. There are gaps in knowledge on the epidemiological burden and evolution of the HCV epidemic in China.

Methods

Data on HCV cases were collected by the disease surveillance system from 2005 to 2012 to explore the epidemic in Henan province. Spatiotemporal scan statistics and age-period-cohort (APC) model were used to examine the effects of age, period, birth cohort, and spatiotemporal clustering.

Results

177,171 HCV cases were reported in Henan province between 2005 and 2012. APC modelling showed that the HCV reported rates significantly increased in people aged > 50 years. A moderate increase in HCV reported rates was observed for females aged about 25 years. HCV reported rates increased over the study period. Infection rates were greatest among people born between 1960 and 1980. People born around 1970 had the highest relative risk of HCV infection. Women born between 1960 and 1980 had a five-fold increase in HCV infection rates compared to men, for the same birth cohort. Spatiotemporal mapping showed major clustering of cases in northern Henan, which probably evolved much earlier than other areas in the province.

Conclusions

Spatiotemporal mapping and APC methods are useful to help delineate the evolution of the HCV epidemic. Birth cohort should be part of the criteria screening programmes for HCV in order to identify those at highest risk of infection and unaware of their status. As Henan is unique in the transmission route for HCV, these methods should be used in other high burden provinces to help identify subpopulations at risk.     

The identification of disease-induced biomarkers in the urine of BSE infected cattle

Background  

The bovine spongiform encephalopathy (BSE) epidemic and the emergence of a new human variant of Creutzfeldt-Jakob Disease (vCJD) have led to profound changes in the production and trade of agricultural goods. The rapid tests currently approved for BSE monitoring in slaughtered cattle are all based on the detection of the disease related isoform of the prion protein, PrP^d, in brain tissue and consequently are only suitable for post-mortem diagnosis. Objectives: In instances such as assessing the health of breeding stock for export purposes where post-mortem testing is not an option, there is a demand for an ante-mortem test based on a matrix or body fluid that would permit easy access and repeated sampling. Urine and urine based analyses would meet these requirements.     

Factors affecting the accuracy of urine-based biomarkers of BSE

Background  

Transmissible spongiform encephalopathy diseases are untreatable, uniformly fatal degenerative syndromes of the central nervous system that can be transmitted both within as well as between species. The bovine spongiform encephalopathy (BSE) epidemic and the emergence of a new human variant of Creutzfeldt-Jakob disease (vCJD), have profoundly influenced beef production processes as well as blood donation and surgical procedures. Simple, robust and cost effective diagnostic screening and surveillance tools are needed for both the preclinical and clinical stages of TSE disease in order to minimize both the economic costs and zoonotic risk of BSE and to further reduce the risk of secondary vCJD.     

Surveillance and simulation of bovine spongiform encephalopathy and scrapie in small ruminants in Switzerland

Background  

After bovine spongiform encephalopathy (BSE) emerged in European cattle livestock in 1986 a fundamental question was whether the agent established also in the small ruminants' population. In Switzerland transmissible spongiform encephalopathies (TSEs) in small ruminants have been monitored since 1990. While in the most recent TSE cases a BSE infection could be excluded, for historical cases techniques to discriminate scrapie from BSE had not been available at the time of diagnosis and thus their status remained unclear. We herein applied state-of-the-art techniques to retrospectively classify these animals and to re-analyze the affected flocks for secondary cases. These results were the basis for models, simulating the course of TSEs over a period of 70 years. The aim was to come to a statistically based overall assessment of the TSE situation in the domestic small ruminant population in Switzerland.     

A heuristic solution of the identifiability problem of the age-period-cohort analysis of cancer occurrence: lung cancer example

Background

The Age–Period–Cohort (APC) analysis is aimed at estimating the following effects on disease incidence: (i) the age of the subject at the time of disease diagnosis; (ii) the time period, when the disease occurred; and (iii) the date of birth of the subject. These effects can help in evaluating the biological events leading to the disease, in estimating the influence of distinct risk factors on disease occurrence, and in the development of new strategies for disease prevention and treatment.

Methodology/Principal Findings

We developed a novel approach for estimating the APC effects on disease incidence rates in the frame of the Log-Linear Age-Period-Cohort (LLAPC) model. Since the APC effects are linearly interdependent and cannot be uniquely estimated, solving this identifiability problem requires setting four redundant parameters within a set of unknown parameters. By setting three parameters (one of the time-period and the birth-cohort effects and the corresponding age effect) to zero, we reduced this problem to the problem of determining one redundant parameter and, used as such, the effect of the time-period adjacent to the anchored time period. By varying this identification parameter, a family of estimates of the APC effects can be obtained. Using a heuristic assumption that the differences between the adjacent birth-cohort effects are small, we developed a numerical method for determining the optimal value of the identification parameter, by which a unique set of all APC effects is determined and the identifiability problem is solved.

Conclusions/Significance

We tested this approach while estimating the APC effects on lung cancer occurrence in white men and women using the SEER data, collected during 1975–2004. We showed that the LLAPC models with the corresponding unique sets of the APC effects estimated by the proposed approach fit very well with the observational data.     

The new school absentees reporting system for pandemic influenza A/H1N1 2009 infection in Japan

Objective

To evaluate the new Japanese School Absentees Reporting System for Infectious Disease (SARSID) for pandemic influenza A/H1N1 2009 infection in comparison with the National epidemiological Surveillance of Infectious Disease (NESID).

Methods

We used data of 53,223 students (97.7%) in Takamatsu city Japan. Data regarding school absentees in SARSID was compared with that in NESID from Oct 13, 2009 to Jan 12, 2010.

Results

Similar trends were observed both in SARSID and NESID. However, the epidemic trend for influenza in SARSID was thought to be more sensitive than that in NESID.

Conclusion

The epidemic trend for influenza among school-aged children could be easily and rapidly assessed by SARSID compared to NESID. SARSID might be useful for detecting the epidemic trend of influenza.     

Estimating incidence of the French BSE infection using a joint analysis of both asymptomatic and clinical BSE surveillance data

Bovine Spongiform Encephalopathy (BSE) clinical surveillance data were the main source of information to perform back-calculation of BSE infection incidence. Since 2001, systematic BSE screening tests enhanced the clinical surveillance and allowed to detect some preclinical, i.e. asymptomatic, cases of BSE. We propose a method to incorporate additional information provided by screening tests. It was the first time that a back-calculation model was developed for a full BSE clinical surveillance. In the spirit, our approach resembles what it was done in the Acquired Immune Deficiency Syndrome (AIDS) epidemic to incorporate the Human Immunodeficiency Virus (HIV) diagnosis. Nevertheless, in the BSE epidemic, we had to consider different surveillance systems, their peculiarity, and the phenomenon of communicating vessels between these surveillance systems. In addition, both the preclinical sensitivity of tests and the status of BSE cases, asymptomatic or clinical, were not precisely known. We applied the model to the French BSE epidemic in order to obtain an updated estimate of the incidence of BSE infection. Our back-calculation model fitted very well the observed data of each surveillance system. We detected a lengthening of the incubation period and estimated that the number of infections was very small in the late 1990s and zero in July 2001.     

Reconstructing the ups and downs of primate brain evolution: implications for adaptive hypotheses and <Emphasis Type="Italic">Homo floresiensis</Emphasis>

Background  

Brain size is a key adaptive trait. It is often assumed that increasing brain size was a general evolutionary trend in primates, yet recent fossil discoveries have documented brain size decreases in some lineages, raising the question of how general a trend there was for brains to increase in mass over evolutionary time. We present the first systematic phylogenetic analysis designed to answer this question.     

Examination of actin and microtubule dependent APC localisations in living mammalian cells

Background  

The trafficking of the adenomatous polyposis coli (APC) tumour suppressor protein in mammalian cells is a perennially controversial topic. Immunostaining evidence for an actin-associated APC localisation at intercellular junctions has been previously presented, though live imaging of mammalian junctional APC has not been documented.     

Long-Term Outcome of Healthy Participants with Atrial Premature Complex: A 15-Year Follow-Up of the NIPPON DATA 90 Cohort

Background

Atrial premature complexes (APC) are among the most frequently encountered electrocardiographic abnormalities. However, their prognostic value among healthy individuals is unclear. This study aimed to clarify the role of APC in predicting cardiovascular events in a large Japanese community cohort using long-term follow-up data.

Methods

National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1990-2005, (NIPPON DATA 90) was a large cohort study of cardiovascular disease (CVD) in Japan. A total of 7692 otherwise healthy participants with no history of myocardial infarction, stroke, atrial fibrillation, or atrial flutter were enrolled (men, 41.5%; mean age, 52.5 ± 13.7 years).

Results

A total of 64 (0.8%) participants had at least one beat of APC on screening 12-lead electrocardiogram. During the follow-up of 14.0 ± 2.9 years (total, 107,474 patient-years), 338 deaths occurred due to CVD. The association between APC and CVD outcome was assessed using Cox proportional hazard models. Cox regression analysis revealed that the presence of APC was an independent predictor for CVD deaths (HR: 2.03, 95% CI: 1.12–3.66, P = 0.019). The association of APC on CVD death was more evident in participants with hypertension (P-value for interaction, 0.03).

Conclusions

APC recorded during the screening electrocardiogram are significantly associated with an increased risk of CVD deaths in a Japanese community-dwelling population and are a strong prognostic factor for hypertensive participants.     

Evaluating the influence of epidemiological parameters and host ecology on the spread of phocine distemper virus through populations of harbour seals

Background

Outbreaks of phocine distemper virus (PDV) in Europe during 1988 and 2002 were responsible for the death of around 23,000 and 30,000 harbour seals, respectively. These epidemics, particularly the one in 2002, provided an unusual opportunity to estimate epidemic parameters for a wildlife disease. There were marked regional differences in the values of some parameters both within and between epidemics.

Methodology and Principal Findings

We used an individual-based model of seal movement that allowed us to incorporate realistic representations of space, time and animal behaviour into a traditional epidemiological modelling framework. We explored the potential influence of a range of ecological (foraging trip duration, time of epidemic onset, population size) and epidemiological (length of infectious period, contact rate between infectious and susceptible individuals, case mortality) parameters on four readily-measurable epidemic characteristics (number of dead individuals, duration of epidemic, peak mortality date and prevalence) and on the probability that an epidemic would occur in a particular region. We analysed the outputs as if they were the results of a series of virtual experiments, using Generalised Linear Modelling. All six variables had a significant effect on the probability that an epidemic would be recognised as an unusual mortality event by human observers.

Conclusions

Regional and temporal variation in contact rate was the most likely cause of the observed differences between the two epidemics. This variation could be a consequence of differences in the way individuals divide their time between land and sea at different times of the year.     

Monitoring of clinical signs in goats with transmissible spongiform encephalopathies

Background  

As there is limited information about the clinical signs of BSE and scrapie in goats, studies were conducted to describe the clinical progression of scrapie and BSE in goats and to evaluate a short clinical protocol for its use in detecting scrapie-affected goats in two herds with previously confirmed scrapie cases. Clinical assessments were carried out in five goats intracerebrally infected with the BSE agent as well as five reported scrapie suspects and 346 goats subject to cull from the two herds, 24 of which were retained for further monitoring. The brain and selected lymphoid tissue were examined by postmortem tests for disease confirmation.     

Recent HIV-1 infection contributes to the viral diffusion over the French territory with a recent increasing frequency

Objective

To analyse the contribution of primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) to the French viral epidemic.

Methods

HIV-1 pol sequences included 987 PHI from the French ANRS PRIMO cohort between 1999 and 2010 and were analysed using a population-based phylogenetic approach. Clinical features, risk factors, sexual behaviour and drug resistance for clustered and nonclustered transmission events were ascertained.

Results

Viruses from 125 (12.7%) of PHI cosegregated into 56 transmission chains, with increasing frequency during the last years (10.2% before 2006 versus 15.2% of clusters in 2006–2010, p = 0.02). The mean number of patients per cluster was 2.44. Compared to unique PHI, clusters involved more often men, infected through homosexual intercourse, of young age, with a high number of casual sexual partnerships and frequent previous HIV serological tests. Resistant strains were found in 16.0% and 11.1% of clusters and unique PHI, respectively (p = 0.11). Overall, 34% (n = 19) clusters included patients followed in French regions far apart, involving 13 clusters with at least one Parisian patient.

Conclusions

PHIs are a significant source of onward transmission, especially in the MSM population. Recently infected people contribute to the spread of the viral epidemic throughout the French territory. Survey of transmitted drug resistance and behavioural characteristics of patients involved into clustered PHI may help to guide prevention and treatment interventions.     

Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain

Background

Given the theoretical proposal that bovine spongiform encephalopathy (BSE) could have originated from sheep scrapie, this study investigated the pathogenicity for cattle, by intracerebral (i.c.) inoculation, of two pools of scrapie agents sourced in Great Britain before and during the BSE epidemic. Two groups of ten cattle were each inoculated with pools of brain material from sheep scrapie cases collected prior to 1975 and after 1990. Control groups comprised five cattle inoculated with sheep brain free from scrapie, five cattle inoculated with saline, and for comparison with BSE, naturally infected cattle and cattle i.c. inoculated with BSE brainstem homogenate from a parallel study. Phenotypic characterisation of the disease forms transmitted to cattle was conducted by morphological, immunohistochemical, biochemical and biological methods.

Results

Disease occurred in 16 cattle, nine inoculated with the pre-1975 inoculum and seven inoculated with the post-1990 inoculum, with four cattle still alive at 83 months post challenge (as at June 2006). The different inocula produced predominantly two different disease phenotypes as determined by histopathological, immunohistochemical and Western immunoblotting methods and biological characterisation on transmission to mice, neither of which was identical to BSE. Whilst the disease presentation was uniform in all scrapie-affected cattle of the pre-1975 group, the post-1990 inoculum produced a more variable disease, with two animals sharing immunohistochemical and molecular profile characteristics with animals in the pre-1975 group.

Conclusion

The study has demonstrated that cattle inoculated with different pooled scrapie sources can develop different prion disease phenotypes, which were not consistent with the phenotype of BSE of cattle and whose isolates did not have the strain typing characteristics of the BSE agent on transmission to mice.     

Identification of a heritable polymorphism in bovine PRNP associated with genetic transmissible spongiform encephalopathy: evidence of heritable BSE

Background

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle. Classical BSE is associated with ingestion of BSE-contaminated feedstuffs. H- and L-type BSE, collectively known as atypical BSE, differ from classical BSE by displaying a different disease phenotype and they have not been linked to the consumption of contaminated feed. Interestingly, the 2006 US H-type atypical BSE animal had a polymorphism at codon 211 of the bovine prion gene resulting in a glutamic acid to lysine substitution (E211K). This substitution is analogous a human polymorphism associated with the most prevalent form of heritable TSE in humans, and it is considered to have caused BSE in the 2006 US atypical BSE animal. In order to determine if this amino acid change is a heritable trait in cattle, we sequenced the prion alleles of the only known offspring of this animal, a 2-year-old heifer.

Principal Findings

Sequence analysis revealed that both the 2006 US atypical BSE animal and its 2-year-old heifer were heterozygous at bovine prion gene nucleotides 631 through 633 for GAA (glutamic acid) and AAA (lysine). Both animals carry the E211K polymorphism, indicating that the allele is heritable and may persist within the cattle population.

Conclusions

This is the first evidence that the E211K polymorphism is a germline polymorphism, not a somatic mutation, suggesting BSE may be transmitted genetically in cattle. In the event that E211K proves to result in a genetic form of BSE, this would be the first indication that all 3 etiologic forms of TSEs (spontaneous, hereditary, and infectious) are present in a non-human species. Atypical BSE arising as both genetic and spontaneous disease, in the context of reports that at least some forms of atypical BSE can convert to classical BSE in mice, suggests a cattle origin for classical BSE.     

Atypical BSE (BASE) transmitted from asymptomatic aging cattle to a primate

Background

Human variant Creutzfeldt-Jakob Disease (vCJD) results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains.

Methodology/Principal Findings

Brain homogenates from cattle with classical BSE and atypical (BASE) infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis), a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres). The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine.

Conclusion/Significance

Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.