On the issue of transmissibility of Alzheimer disease

Results from recent experiments with rodents imply that Alzheimer disease might be inducible by seeding Aβ peptides into recipient animals. In respect to this new experimental data, public health aspects as well as epidemiological data have to be reevaluated. In this article, the available experimental and epidemiological data are reviewed.     

UV-induced skin cancer in a hairless mouse model

Ultraviolet (UV) radiation is a very common carcinogen in our environment, but epidemiological data on the relationship between skin cancers and ambient solar UV radiation are very restricted. In hairless mice the process of UV carcinogenesis can be studied in depth. Experiments with this animal model have yielded quantitative data on how tumor development depends on dose, time and wavelength of the UV radiation. In combination with epidemiological data, these experimental results can be transposed to humans. Comparative studies on molecular, cellular and physiological changes in mouse and man can further our fundamental understanding of UV carcinogenesis in man. This is likely to improve risk assessments such as those related to a stratospheric ozone depletion, and to yield well-targeted intervention schemes, e.g. prescribing a specific drug or diet, for high-risk individuals.     

Topical problems in the study of remote effects of chemical compounds on the cardiovascular system

The main tasks in epidemiological and experimental study of remote effects on the cardiovascular system of exposure to chemical compounds were formulated. In the epidemiological respect, the most important points are development of methods for integral evaluation of the effect of the environment, including the industrial environment, and improvement of the methods of detecting early signs of cardiovascular pathology closely correlating with the structure of cardiovascular morbidity and mortality. The most topical experimental problem is to refine the criteria and methods of assessing the state of the heart and vessels of experimental animals so as to make possible a substantiated and adequate extrapolation of experimental data to man.     

Cell population-based framework of genetic epidemiology in the single-cell omics era

Genetic epidemiology is a rapidly advancing field due to the recent availability of large amounts of omics data. In recent years, it has become possible to obtain omics information at the single-cell level, so genetic epidemiological models need to be updated to integrate with single-cell expression data. In this perspective paper, we propose a cell population-based framework for genetic epidemiology in the single-cell era. In this framework, genetic diversity influences phenotypic diversity through the diversity of cell population profiles, which are defined as high-dimensional probability distributions of the state spaces of biomolecules of each omics layer. We discuss how biomolecular experimental measurement data can capture the different properties of this distribution. In particular, single-cell data constitute a sample from this population distribution where only some coordinate values are observable. From a data analysis standpoint, we introduce methodology for feature extraction from cell population profiles. Finally, we discuss how this framework can be applied not only to genetic epidemiology but also to systems biology.     

Transgenerational inheritance of longevity: Theoretical framework and empirical evidence

A number of experimental and epidemiological investigations have provided evidence that the health status and aging rate may largely depend on the conditions of early development. Several recent studies provided data suggesting that effects of stresses in early development can be inherited transgenerationally, causing changes of various characteristics in subsequent generations. It has been shown that epigenetic factors associated with regulation of genetic expression, including DNA methylation and modifications of histones and microRNAs, can play a key role in transgenerational inheritance. Until now, it has been generally accepted that the complete erasure of epigenetic marks takes place during gametogenesis and early embryogenesis. In recent years, however, several papers obtained data demonstrating that, in certain cases, epigenetic modifications induced during early ontogenesis could not be erased completely and be transmitted to descendants, affecting their phenotype over several generations. This review provides data of epidemiological and experimental studies showing the possibility of transgenerational inheritance of life expectancy and longevity-associated traits in several generations.     

Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms

Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.     

Cellular and molecular mechanisms of aging: a review]

Since the beginning of this century, a large body of experimental data and observations accumulated concerning experimental and clinical gerontology. These data can be classified and analyzed according to the level of experimentation or observation as concerning aging at the molecular, cellular level or at higher levels of hierarchical organisation such as tissues, organs or the whole organism. Observations of these higher levels are mostly derived from epidemiological studies of human aging, horizontal studies or preferably vertical studies. The relative coherence of data collected at the molecular and cellular levels renders plausible a tentative of interpretation of aging phenomena at higher levels or hierarchical organisations from the tissues to the whole organism by using the data obtained at the molecular and cellular levels. The present article is a tentative for this kind or integrative interpretation of aging.     

An evolutionary epidemiological mechanism, with applications to type a influenza

In this paper I develop a model that describes an evolutionary epidemiological mechanism and apply this model to the epidemiology of type A influenza. This evolutionary epidemiological model differs from the classical nonevolutionary epidemiological model which has been applied to diseases like measles, rubella, and whooping cough in having a novel mechanism which causes susceptible individuals to be introduced into the host population. In the nonevolutionary model, susceptibles are continually introduced into the host population by demographic processes: most hosts that die are immune, while newborn hosts are susceptible. In this evolutionary model, the susceptible class is continually replenished because the pathogen changes genetically, and hence immunologically, from one epidemic to the next, causing previously immune hosts to become susceptible. I derive formulae which describe how the equilibrium number of infected hosts, the interepidemic period, and the probability that a host will become reinfected depend on the rate of amino acid substitution in the pathogen, m, a parameter describing the effect of these substitutions on host immunity, gamma, as well as the host population size, N, and the recovery rate, r. To apply the model to influenza, I show how the nondimensional parameter epsilon = m gamma N/r2 may be estimated from four types of data. The methods are applied to several data sets, and I conclude that epsilon much less than 1; sampling variation and inconsistencies between the various data sets do not permit epsilon to be estimated more precisely. The evolutionary epidemiological model has no threshold host population size, in contrast to the nonevolutionary model.     

Fundamental Identifiability Limits in Molecular Epidemiology

Viral phylogenies provide crucial information on the spread of infectious diseases, and many studies fit mathematical models to phylogenetic data to estimate epidemiological parameters such as the effective reproduction ratio (R_e) over time. Such phylodynamic inferences often complement or even substitute for conventional surveillance data, particularly when sampling is poor or delayed. It remains generally unknown, however, how robust phylodynamic epidemiological inferences are, especially when there is uncertainty regarding pathogen prevalence and sampling intensity. Here, we use recently developed mathematical techniques to fully characterize the information that can possibly be extracted from serially collected viral phylogenetic data, in the context of the commonly used birth-death-sampling model. We show that for any candidate epidemiological scenario, there exists a myriad of alternative, markedly different, and yet plausible “congruent” scenarios that cannot be distinguished using phylogenetic data alone, no matter how large the data set. In the absence of strong constraints or rate priors across the entire study period, neither maximum-likelihood fitting nor Bayesian inference can reliably reconstruct the true epidemiological dynamics from phylogenetic data alone; rather, estimators can only converge to the “congruence class” of the true dynamics. We propose concrete and feasible strategies for making more robust epidemiological inferences from viral phylogenetic data.     

Genomic stability over 9 years of an isoniazid resistant Mycobacterium tuberculosis outbreak strain in Sweden

In molecular epidemiological studies of drug resistant Mycobacterium tuberculosis (TB) in Sweden a large outbreak of an isoniazid resistant strain was identified, involving 115 patients, mainly from the Horn of Africa. During the outbreak period, the genomic pattern of the outbreak strain has stayed virtually unchanged with regard to drug resistance, IS6110 restriction fragment length polymorphism and spoligotyping patterns. Here we present the complete genome sequence analyses of the index isolate and two isolates sampled nine years after the index case as well as experimental data on the virulence of this outbreak strain. Even though the strain has been present in the community for nine years and passaged between patients at least five times in-between the isolates, we only found four single nucleotide polymorphisms in one of the later isolates and a small (4 amino acids) deletion in the other compared to the index isolate. In contrast to many other evolutionarily successful outbreak lineages (e.g. the Beijing lineage) this outbreak strain appears to be genetically very stable yet evolutionarily successful in a low endemic country such as Sweden. These findings further illustrate that the rate of genomic variation in TB can be highly strain dependent, something that can have important implications for epidemiological studies as well as development of resistance.     

Appropriate use of animal models in the assessment of risk during prenatal development: an illustration using inorganic arsenic

BACKGROUND: Assessing risks to human development from chemical exposure typically requires integrating findings from laboratory animal and human studies. METHODS: Using a case study approach, we present a program designed to assess the risk of the occurrence of malformations from inorganic arsenic exposure. We discuss how epidemiological data should be evaluated for quality and criteria for determining whether an association is causal. In this case study, adequate epidemiological data were not available for evaluating the potential effect of arsenic on development. Consequently, results from appropriately designed, conducted, and interpreted developmental toxicity studies, which have been shown to be predictive of human risk under numerous scenarios, were used. In our case study, the existing animal data were not designed appropriately to assess risk from environmental exposures, although such studies may be useful for hazard identification. Because the human and animal databases were deficient, a research program comprising modern guideline toxicological studies was designed and conducted. RESULTS: The results of those studies in rats, mice, and rabbits indicate that oral and inhalational exposures to inorganic arsenic do not cause structural malformations, and inhalational exposures produced no developmental effects at all. The new study results are discussed in conjunction with considerations of metabolism, toxicokinetics, and maternal toxicity. CONCLUSIONS: Based on the available experimental data, and absent contrary findings from adequately conducted epidemiological studies, we conclude that exposure to inorganic arsenic by environmentally relevant routes poses no risk of the occurrence of malformations and little risk of other prenatal developmental toxicity in developing humans without concomitant and near-lethal toxicological effects in mothers.     

Combining mathematics and empirical data to predict emergence of RNA viruses that differ in reservoir use

RNA viruses may be particularly capable of contributing to the increasing biomedical problem of infectious disease emergence. Empirical studies and epidemiological models are informative for the understanding of evolutionary processes that promote pathogen emergence, but rarely are these approaches combined in the same study. Here, we used an epidemiology model containing observations of pathogen productivity in reservoirs, as a means to predict which pathogens should be most prone to emerge in a primary host such as humans. We employed as a model system a collection of vesicular stomatitis virus populations that had previously diverged in host-use strategy: specialists, directly selected generalists and indirectly selected (fortuitous) generalists. Using data from experiments where these viral strategists were challenged to grow on unencountered novel hosts in vitro, logistic growth models determined that the directly selected generalist viruses tended to grow best on model reservoirs. Furthermore, when we used the growth data to estimate average reproductive rate across secondary reservoirs, we showed that the combined approach could be used to estimate relative success of the differing virus strategists when encountering a primary host. Our study suggests that synergistic approaches combining epidemiological modelling with empirical data from experimental evolution may be useful for developing efforts to predict which types of pathogens pose the greatest probability of emerging in the future.     

The Perplexing Paradox of Paraquat: The Case for Host‐Based Susceptibility and Postulated Neurodegenerative Effects

Paraquat is an herbicide used extensively in agriculture and has also been proposed to be a risk factor for Parkinson's disease. To date, experimental, clinical, and epidemiological data on paraquat neurotoxicity have been equivocal. In this short review, we discuss some technical and biological mechanisms that contribute to inconsistencies regarding paraquat neurotoxicity. We hypothesize that individual genetic variations in susceptibility generate major differences in neurotoxic risk and functional outcome. Identifying these heritable sources of variation in host susceptibility, and their role in complex gene–environment interactions, is crucial to identify risk biomarkers and to devise better prevention and treatment for those exposed to paraquat and other potential neurotoxicants.     

Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential

Nitrosamines form a large group of genotoxic chemical carcinogens which occur in the human diet and other environmental media, and can be formed endogenously in the human body. N-Nitroso compounds can induce cancer in experimental animals. Some representative compounds of this class induce cancer in at least 40 different animal species including higher primates. Tumours induced in experimental animals resemble their human counterparts with respect to both morphological and biochemical properties. Extensive experimental, and some epidemiological data suggest that humans are susceptible to carcinogenesis by N-nitroso compounds and that the presence of these compounds in some foods may be regarded as an aetiological risk factor for certain human cancers including cancers of the oesophagus, stomach and nasopharynx.     

Experimental design and quantitative analysis of microbial community multiomics

Studies of the microbiome have become increasingly sophisticated, and multiple sequence-based, molecular methods as well as culture-based methods exist for population-scale microbiome profiles. To link the resulting host and microbial data types to human health, several experimental design considerations, data analysis challenges, and statistical epidemiological approaches must be addressed. Here, we survey current best practices for experimental design in microbiome molecular epidemiology, including technologies for generating, analyzing, and integrating microbiome multiomics data. We highlight studies that have identified molecular bioactives that influence human health, and we suggest steps for scaling translational microbiome research to high-throughput target discovery across large populations.     

A new phylodynamic model of Mycobacterium bovis transmission in a multi-host system uncovers the role of the unobserved reservoir

Multi-host pathogens are particularly difficult to control, especially when at least one of the hosts acts as a hidden reservoir. Deep sequencing of densely sampled pathogens has the potential to transform this understanding, but requires analytical approaches that jointly consider epidemiological and genetic data to best address this problem. While there has been considerable success in analyses of single species systems, the hidden reservoir problem is relatively under-studied. A well-known exemplar of this problem is bovine Tuberculosis, a disease found in British and Irish cattle caused by Mycobacterium bovis, where the Eurasian badger has long been believed to act as a reservoir but remains of poorly quantified importance except in very specific locations. As a result, the effort that should be directed at controlling disease in badgers is unclear. Here, we analyse densely collected epidemiological and genetic data from a cattle population but do not explicitly consider any data from badgers. We use a simulation modelling approach to show that, in our system, a model that exploits available cattle demographic and herd-to-herd movement data, but only considers the ability of a hidden reservoir to generate pathogen diversity, can be used to choose between different epidemiological scenarios. In our analysis, a model where the reservoir does not generate any diversity but contributes to new infections at a local farm scale are significantly preferred over models which generate diversity and/or spread disease at broader spatial scales. While we cannot directly attribute the role of the reservoir to badgers based on this analysis alone, the result supports the hypothesis that under current cattle control regimes, infected cattle alone cannot sustain M. bovis circulation. Given the observed close phylogenetic relationship for the bacteria taken from cattle and badgers sampled near to each other, the most parsimonious hypothesis is that the reservoir is the infected badger population. More broadly, our approach demonstrates that carefully constructed bespoke models can exploit the combination of genetic and epidemiological data to overcome issues of extreme data bias, and uncover important general characteristics of transmission in multi-host pathogen systems.     

Bridging scales in the evolution of infectious disease life histories: application

Within- and between-host disease processes occur on the same timescales, therefore changes in the within-host dynamics of parasites, resources, and immunity can interact with changes in the epidemiological dynamics to affect evolutionary outcomes. Consequently, studies of the evolution of disease life histories, that is, infection-age-specific patterns of transmission and virulence, have been constrained by the need for a mechanistic understanding of within-host disease dynamics. In a companion paper (Day et al. 2011), we develop a novel approach that quantifies the relevant within-host aspects of disease through genetic covariance functions. Here, we demonstrate how to apply this theory to data. Using two previously published datasets from rodent malaria infections, we show how to translate experimental measures into disease life-history traits, and how to quantify the covariance in these traits. Our results show how patterns of covariance can interact with epidemiological dynamics to affect evolutionary predictions for disease life history. We also find that the selective constraints on disease life-history evolution can vary qualitatively, and that "simple" virulence-transmission trade-offs that are often the subject of experimental investigation can be obscured by trade-offs within one trait alone. Finally, we highlight the type and quality of data required for future applications.     

Evaluating the Adequacy of Gravity Models as a Description of Human Mobility for Epidemic Modelling

Gravity models have a long history of use in describing and forecasting the movements of people as well as goods and services, making them a natural basis for disease transmission rates over distance. In agent-based micro-simulations, gravity models can be directly used to represent movement of individuals and hence disease. In this paper, we consider a range of gravity models as fits to movement data from the UK and the US. We examine the ability of synthetic networks generated from fitted models to match those from the data in terms of epidemic behaviour; in particular, times to first infection. For both datasets, best fits are obtained with a two-piece ‘matched’ power law distance distribution. Epidemics on synthetic UK networks match well those on data networks across all but the smallest nodes for a range of aggregation levels. We derive an expression for time to infection between nodes in terms of epidemiological and network parameters which illuminates the influence of network clustering in spread across networks and suggests an approximate relationship between the log-likelihood deviance of model fit and the match times to infection between synthetic and data networks. On synthetic US networks, the match in epidemic behaviour is initially poor and sensitive to the initially infected node. Analysis of times to infection indicates a failure of models to capture infrequent long-range contact between large nodes. An assortative model based on node population size captures this heterogeneity, considerably improving the epidemiological match between synthetic and data networks.     

Altérations environnementales du développement du testicule foetal: zoom sur les phtalates

There are great concerns about the increasing incidence of abnormalities in male reproductive function. Human sperm counts have markedly dropped, and the rate of testicular cancer has clearly increased over the past four decades. Moreover, the prevalence rates of cryptorchidism and hypospadias are also probably increasing. It has been hypothesized that all these adverse trends in male reproduction result from abnormalities in the development of the testis during foetal and neonatal life. Furthermore, many recent epidemiological, clinical and experimental data suggest that these male reproductive disorders could be due to xenobiotics termed endocrine disruptors, which are becoming more and more concentrated and prevalent in our environment. Among these endocrine disruptors, we chose to focus this review on phthalates for different reasons: 1) they are widespread in the environment; 2) their concentrations in many human biological fluids have been measured; 3) the experimental data using rodent models suggesting a reprotoxicity are numerous and are the most convincing; 4) their deleterious effects on the development and function of the rat foetal testis have been largely studied; 5) some epidemiological data in humans suggest a reprotoxic effect at environmental concentrations at least during neonatal life. However, the direct effects of phthalates on human foetal testis have never been explored. Thus, as we did for the rat in the 1990s, we recently developed and validated an organotypic culture system, which allows maintenance of the development of the different cell types of human foetal testis. In this system, the addition of 10^?4 M MEHP (mono-2-ethylhexyl phthalate), the most produced phthalate, had no effect on basal or LH-stimulated production of testosterone, but it reduced the number of germ cells by increasing their apoptosis, without modifying their proliferation. This is the first experimental demonstration that phthalates alter the development of the foetal testis in humans. Using our organotypic culture system, it is interesting to compare these results obtained in humans with the response to MEHP in the mouse and the rat testes to analyse the relevance of toxicological tests based on rodent models.