Bayesian modeling of time-varying and waning exposure effects

In epidemiologic studies, there is often interest in assessing the association between exposure history and disease incidence. For many diseases, incidence may depend not only on cumulative exposure, but also on the ages at which exposure occurred. This article proposes a flexible Bayesian approach for modeling age-varying and waning exposure effects. The Cox model is generalized to allow the hazard of disease to depend on an integral, across the exposed ages, of a piecewise polynomial function of age, multiplied by an exponential decay term. Linearity properties of the model facilitate posterior computation via a Gibbs sampler, which generalizes previous algorithms for Cox regression with time-dependent covariates. The approach is illustrated by an application to the study of protective effects of breastfeeding on incidence of childhood asthma.     

Effects of 50 Hz electromagnetic field exposure on apoptosis and differentiation in a neuroblastoma cell line

Experiments were carried out to assess whether a magnetic field of 50 Hz and 1 mT can influence apoptosis and proliferation in the human neuroblastoma cell line LAN-5. TUNEL assays and poly-ADP ribose polymerase (PARP) expression analysis were performed to test apoptosis induction, and the WST-1 assay was used to calculate the proliferation index in a long term exposure. No alterations were found in cellular ability to undergo programmed cell death, but a small increase in the proliferation index was evidenced after 7 days of continuous exposure. Also, a slight and transient increase of B-myb oncogene expression was detected after 5 days of exposure. Combined exposures of cells to EMF and to chemical agents which interfere with proliferation, such as the differentiative agent retinoic acid and the apoptotic inducer camptothecin, showed an antagonistic effect of magnetic fields against the differentiation of the LAN-5 cells and a protective effect towards apoptosis.     

Qualitative and quantitative procedures for health risk assessment.

Numerous reactive mutagenic electrophiles are present in the environment or are formed in the human body through metabolizing processes. Those electrophiles can directly react with DNA and are considered to be ultimate carcinogens. In the past decades more than 200 in vitro and in vivo genotoxic tests have been described to identify, monitor and characterize the exposure of humans to such agents. When the responses of such genotoxic tests are quantified by a weight-of-evidence analysis, it is found that the intrinsic potency of electrophiles being mutagens does not differ much for the majority of the agents studied. Considering the fact that under normal environmental circumstances human are exposed to low concentration of about a million electrophiles, the relation between exposure to such agents and adverse health effects (e.g., cancer) will become a 'Pandora's box'. For quantitative risk assessment it will be necessary not only to detect whether the agent is genotoxic, but also understand the mechanism of interaction of the agent with the DNA in target cells needs to be taken into account. Examples are given for a limited group of important environmental and carcinogenic agents for which such an approach is feasible. The groups identified are agents that form cross-links with DNA or are mono-alkylating agents that react with base-moieties in the DNA strands. Quantitative hazard ranking of the mutagenic potency of these groups of chemical can be performed and there is ample evidence that such a ranking corresponds with the individual carcinogenic potency of those agents in rodents. Still, in practice, with the exception of certain occupational or accidental exposure situations, these approaches have not be successful in preventing cancer death in the human population. However, this is not only due to the described 'Pandora's box' situation. At least three other factors are described. Firstly, in the industrial world the medical treatment of cancer in patients occurs with high levels of extremely mutagenic agents. Actually, both in number of persons and in exposure levels such medical treatment is the single largest exposure of humans to known carcinogens. Although such treatments are very effective in curing the tumor as present in the patient, the recurrence of cancer in those patients later in life is very high. In other words: "curing cancer is not the same as preventing cancer death in the human population". Secondly, the rate of cancer death in the human population is also determined by the efficacy in which other major causes of death are prevented. For instance, cardiovascular diseases are the major cause of death in humans in the industrialized world. There is evidence that the treatment of cardiovascular diseases is more successful than that of cancer. On a population level this will result in increase of cancer being the ultimate death cause. Finally, the improvement of medical treatment of diseases together with an improved quality of life will lead to increase average age of the population. Because the onset of most cancer is long after the exposure to carcinogens-in human often more than 30 years-cancer is predominantly a disease of the old age. This means that if the average age of human increases, there will be a selective preference of cancer becoming an even more important cause of death. This especially will be pronounced in those countries were the age distribution in a population is abnormal.     

Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis

Much data support a role for central nervous system antigen-specific antibodies in the pathogenesis of multiple sclerosis (MS). The effects of inducing a decrease in (auto)antibody levels on MS or experimental autoimmune encephalomyelitis (EAE) through specific blockade of FcRn, however, remain unexplored. We recently developed engineered antibodies that lower endogenous IgG levels by competing for binding to FcRn. These Abdegs (“antibodies that enhance IgG degradation”) can be used to directly assess the effect of decreased antibody levels in inflammatory diseases. In the current study, we show that Abdeg delivery ameliorates disease in an EAE model that is antibody dependent. Abdegs could therefore have promise as therapeutic agents for MS.     

Rate of resistance evolution and polymorphism in long‐ and short‐lived hosts

Recent theoretical work has shown that long‐lived hosts are expected to evolve higher equilibrium levels of disease resistance than shorter‐lived hosts, but questions of how longevity affects the rate of resistance evolution and the maintenance of polymorphism remain unanswered. Conventional wisdom suggests that adaptive evolution should occur more slowly in long‐lived organisms than in short‐lived organisms. However, the opposite may be true for the evolution of disease‐resistance traits where exposure to disease, and therefore the strength of selection for resistance increases with longevity. In a single locus model of innate resistance to a frequency‐dependent, sterilizing disease, longer lived hosts evolved resistance more rapidly than short‐lived hosts. Moreover, resistance in long‐lived hosts could only be polymorphic for more costly and more extreme resistance levels than short‐lived hosts. The increased rate of evolution occurred in spite of longer generation times because longer‐lived hosts had both a longer period of exposure to disease as well as higher disease prevalence. Qualitatively similar results were found when the model was extended to mortality‐inducing diseases, or to density‐dependent transmission modes. Our study shows that the evolutionary dynamics of host resistance is determined by more than just levels of resistance and cost, but is highly sensitive to the life‐history traits of the host.     

Impact of myxomatosis in relation to local persistence in wild rabbit populations: the role of waning immunity and the reproductive period

Many diseases are less severe when they are contracted in early life. For highly lethal diseases, such as myxomatosis in rabbits, getting infected early in life can represent the best chance for an individual to survive the disease. For myxomatosis, early infections are attenuated by maternal antibodies. This may lead to the immunisation of the host, preventing the subsequent development of the lethal form of the disease. But early infection of young individuals requires specific demographic and epidemiological contexts, such as a high transmission rate of the pathogen agent. To investigate other factors involved in the impact of such diseases, we have built a stochastic model of a rabbit metapopulation infected by myxomatosis. We show that the impact of the pathogen agent can be reduced by early infections only when the agent has a long local persistence time and/or when the host subpopulations are highly connected. The length of the reproductive period and the duration of acquired immunity are also important factors influencing the persistence of the pathogen and thus, the impact of the disease. Besides confirming the role of classical factors in the persistence of a pathogen agent, such as the size of the subpopulation or the degree of connectivity, our results highlight novel factors that can modulate the impact of diseases whose severity increase with age.     

Statins Do Not Alter the Incidence of Mesothelioma in Asbestos Exposed Mice or Humans

Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44–2.29, p = 0.99). Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61–1.67, p = 0.97). We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos.     

Caloric restriction prevents oxidative damage induced by the carcinogen clofibrate in mouse liver

Long-term caloric restriction in rodents is known to decrease levels of oxidative damage, which may contribute to an 'anti-ageing' effect. We show here that a shorter period (10 months) of caloric restriction had only small effects on levels of oxidative DNA and protein damage in the livers of mice, but completely attenuated increased oxidative damage caused by the carcinogen clofibrate. Since clofibrate is thought to exert its actions by increasing oxidative damage, our data suggest that 10 months of caloric restriction can increase the resistance of tissues to agents inducing oxidative stress. This may be an important factor in explaining how caloric restriction decreases cancer incidence.     

Induction of the cytoplasmic 'petite' mutation by chemical and physical agents in Saccharomyces cerevisiae.

A range of physical and chemical agents induce the mitochondrial 'petite' mutation in the yeast Saccharomyces cerevisiae. DNA intercalating agents as well as chemicals which can interfere with DNA synthesis induce this mutation, but only in growing cells. Many chemical or physical agents that produce a DNA lesion which is not simply reversed can induce various levels of the petite mutation, and may be more effective in non-growing cells. A limited number of chemicals act like ethidium bromide, inducing a high frequency of petites which is partially reversible with increasing concentration or time. The ability of a specific compound to be transported into mitochondria or its affinity for AT base pairs in DNA may determine whether it acts primarily as a nuclear or mitochondrial mutagen. In mammalian cells, some neoplastic changes occur at the mitochondrial level. Analogies between yeast and mammalian mitochondria suggest that agents which increase petite mutagenesis in yeast may have some carcinogenic potential. Although some types of petite inducer may have potential as antitumour drugs, those which are very effective antimitochondrial agents appear to be too toxic for therapeutic use. A process comparable to early stages in petite mutagensis occurs in human degenerative diseases and it seems possible that a consequence of exposure to petite mutagens could be an increase in the rate of degenerative diseases or of the aging process.     

Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence

Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The optimal level of vitamin D intake required to support optimal immune function is not known but is likely to be at least that required for healthy bones. Experimentally, vitamin D deficiency results in the increased incidence of autoimmune disease. Mechanistically, the data point to a role for vitamin D in the development of self-tolerance. The vitamin D hormone (1,25-dihydroxy vitamin D(3)) regulates T helper cell (Th1) and dendritic cell function while inducing regulatory T-cell function. The net result is a decrease in the Th1-driven autoimmune response and decreased severity of symptoms. This review discusses the accumulating evidence pointing to a link between vitamin D and autoimmunity. Increased vitamin D intakes might decrease the incidence and severity of autoimmune diseases and the rate of bone fracture.     

Restoration of the immune balance by autologous bone marrow transplantation in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is one of the most frequent autoimmune diseases in childhood and is characterized by chronic inflammation of the synovial fluid in joints. Several drugs are available for the treatment of JIA, including various biological agents that interfere with critical cytokine pathways. Though very effective in suppressing disease activity, none of these drugs can cure the disease and induce a lasting medication free remission. A small proportion of JIA patients will become or are unresponsive to any form of medical treatment. For these severely ill patients autologous bone marrow transplantation (aBMT) is a last resort treatment. aBMT is remarkably effective in suppressing disease activity, with beneficial outcome reported in around 70% of these previously refractory patients. Moreover aBMT is the only treatment that can induce a lasting medication-free-disease remission in these patients. In the very long term (after 7 years of remission) however, some disease relapses are observed, with the disease returning in a less severe form compared to prior aBMT. The exact mechanism of how aBMT is inducing this lasting disease remission is still largely unknown, but data from both animal models and humans suggest a prominent role for regulatory T cells. In this review we reviewed the current views of the cellular mechanisms that lay beneath disease induction of JIA and the disease remission caused by aBMT therapy.     

The effect of combat exposure on sexually transmitted diseases

Traumatic exposures can affect beliefs and behaviors related to the spread of sexually transmitted diseases (STDs), a persistent public health problem. I leverage a natural experiment created by variation in US military deployment location assignments to estimate how combat exposure changes a surviving deployed male veteran’s probability of acquiring a sexually transmitted disease. I analyze longitudinal data from 1994 to 2008 on 485 deployed veterans with information theoretic methods to reduce the sensitivity of estimates to small samples, an infrequently observed outcome, and highly correlated covariates. For veterans assigned to a combat zone, I estimate combat exposure results in a 5.4 percentage point increase in the probability of acquiring an STD. Additional estimations provide evidence suggesting risky behaviors involving substance use or multiple sexual partners may serve as pathways from combat exposure to STDs. My results are relevant to discussions regarding STD screening and care needs for trauma exposed individuals.     

Enhanced tolerance to autoimmune uveitis in CD200-deficient mice correlates with a pronounced Th2 switch in response to antigen challenge

A single exposure to inhaled Ag 10 days before immunization leads to long term, Ag-specific tolerance. Respiratory tract myeloid APCs are implicated, but how regulation is invoked, and how tolerance is sustained are unclear. This study examines the in vivo function of the myeloid regulatory molecule CD200 in the process of tolerance induction. Despite earlier onset of experimental autoimmune uveitis in sham-tolerized, CD200-deficient mice, disease incidence and subsequent severity were actually reduced compared with those in wild-type mice. Protection was more effective and long term, lasting at least 28 days. Halting disease progression and tolerance in CD200(-/-) mice correlated with a marked increase in Th2-associated cytokine production by Ag-challenged splenocytes. Reduced overall disease and enhanced tolerance in the CD200-deficient mice in this model system were unexpected and may be related to altered populations of MHC class II(low) APC in the respiratory tract compared with wild-type mice together with associated activation of STAT6 in draining lymph nodes of tolerized mice. These data indicate that in the absence of default inhibitory CD200 receptor signaling, alternative, powerful regulatory mechanisms are invoked. This may represent either permissive dominant Th2 activation or an altered hierarchy of negative signaling by other myeloid cell-expressed regulatory molecules.     

Site specific effects of zoledronic acid during tibial and mandibular fracture repair

Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading, inflammation and exogenous molecules. Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of metabolic bone diseases. Zoledronate (ZA), a nitrogen-containing bisphosphonate (N-BP), is the most potent bisphosphonate among the clinically approved bisphosphonates. Cases of bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet, osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized tibial fractures and a new model of mandibular fracture repair. Contrary to tibial fractures, which heal mainly through endochondral ossification, mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones.     

Determinants of emerging and re-emerging infectious diseases.

In the 1960s and 1970s, many public health experts assumed that infectious diseases could at long last be conquered as had occurred with smallpox. In the last two decades, reports warned that infectious diseases were clearly not a problem of the past. They could not be considered as a unique or isolated event of wild and faraway regions, but penetrated every corner of the globe. Emerging infectious diseases have been recently described as clinically distinct conditions whose incidence in humans has increased regionally or worldwide within the past two decades. Emergence may be due to the introduction of new agents to or the recognition of an existing disease that has gone undetected, and re-emergence may describe the re-appearance of known diseases after a decline in incidence. In this article a global, multidisciplinary and integrated approach in different fields of demography, epidemiology, economy, ecology, anthropology and environment at science has been considered to describe the different determinants responsible for the emergence and re-emergence of infectious diseases.     

Mathematical modelling of arsenic transport,distribution and detoxification processes in yeast

Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed experimentally by dedicated experiments. Specifically, our analyses suggest that: (i) arsenic is mainly protein‐bound during short‐term (acute) exposure, whereas glutathione‐conjugated arsenic dominates during long‐term (chronic) exposure, (ii) arsenic is not stably retained, but can leave the vacuole via an export mechanism, and (iii) Fps1 is controlled by Hog1‐dependent and Hog1‐independent mechanisms during arsenite stress. Our results challenge glutathione depletion as a key mechanism for arsenic toxicity and instead suggest that (iv) increased glutathione biosynthesis protects the proteome against the damaging effects of arsenic and that (v) widespread protein inactivation contributes to the toxicity of this metalloid. Our work in yeast may prove useful to elucidate similar mechanisms in higher eukaryotes and have implications for the use of arsenic in medical therapy.     

INTERFERENTIAL ELECTRIC FIELDS REVEAL NONUNIFORM EFFECTS ON PROLIFERATION AND hCG SECRETION IN JAr CELLS

The effect of low frequency electromagnetic fields on changes in intracellular cAMP concentrations was investigated in the frequency range 10–100 Hz using a choriocarcinoma cell line. JAr cells significantly reduce proliferation and increase β-hCG secretion upon dibutyryl cAMP and forskolin treatment after 10 days of culturing. Choriocarcinoma cells exposed to a modulation frequency of 10 Hz for 5 min change their intracellular cAMP level significantly to higher as well as to lower concentrations in half of the experimental series, respectively. At frequencies of 70 and 100 Hz levels, half of the experimental series revealed a significant decrease in cAMP levels. Long term exposure at 100 Hz for 10 days leads to a significant reduction in proliferation but not in β-hCG secretion. These results point to a modulatory effect of low frequency electromagnetic fields on intracellular cAMP levels which are dependent on the frequency window. The reduced proliferation after long term exposure at the frequency of 100 Hz, which lowers cAMP levels, is discussed.     

Biological control of <Emphasis Type="Italic">Septoria tritici</Emphasis> blotch on wheat by <Emphasis Type="Italic">Trichoderma</Emphasis> spp. under field conditions in Argentina

Biological control is an additional tool available for the design of more sustainable control strategies of wheat diseases. Trichoderma spp. have previously been used as biocontrol agents to protect wheat plants against leaf spots diseases in Argentina, but the information from field assays is scarce. The effectiveness of four Trichoderma harzianum strains and one T. koningii strain in reducing the incidence and severity of the leaf blotching of wheat caused by Septoria tritici blotch (STB) under two formulation conditions, spore suspension and the coated-seed technique, was studied under field conditions. Significant differences between wheat cultivars, formulation types and growth stages were found. In 2003, at the tillering stage, all of the treatments tested (except SST1 for incidence) effectively reduced the incidence or the severity of the disease compared to the control. Similarly, in 2004, ten of the treatments reduced the severity at tillering. At the heading stage, none of the treatments tested caused a significant decrease of the disease. These results indicated, therefore, that the antagonism was effective at an early stage of the disease only. Comparing both formulations, spraying spore suspension onto leaves and the coated-seed application technique, both were effective in decreasing the disease. Some isolates, such as CST4 and CST2, reduced the incidence value of STB to 40% and the severity value to 70% of the control values applied as coated-seed formulation. On the other hand, isolates T4 and T2 showed the greatest effectiveness for controlling STB, with similar reduction values to that shown by the fungicide (Folicur^®) application treatment. The results of this study indicated that, although the immediate impact of Trichoderma isolates may be seen as reduced incidence and severity on the first stages of STB, in the long term, the same disease levels as found in untreated sites may be attained. This study also demonstrated that the incorporation of Trichoderma as a biocontrol preparation may be a promising step towards reducing STB disease in the field and the levels of fungicide residues in the context of a more integrated approach to the problem.     

Modelling the effect of treatment and behavioral change in HIV transmission dynamics

In this paper we analyze a model for the HIV-infection transmission in a male homosexual population. In the model we consider two types of infected individuals. Those that are infected but do not know their serological status and/or are not under any sort of clinical /therapeutical treatment, and those who are. The two groups of infectives differ in their incubation time, contact rate with susceptible individuals, and probability of disease transmission. The aim of this article is to study the roles played by detection and changes in sexual behavior in the incidence and prevalence of HIV. The analytical results show that there exists a unique endemic equilibrium which is globally asymptotically stable under a range of parameter values whenever a detection /treatment rate and an indirect measure of the level of infection risk are sufficiently large. However, any level of detection/ treatment rate coupled with a decrease of the transmission probability lowers the incidence rate and prevalence level in the population. In general, only significant reductions in the transmission probability (achieved through, for example, the adoption of safe sexual practices) can contain effectively the spread of the disease.     

cAMP has distinct acute and chronic effects on aquaporin-5 in lung epithelial cells

Aquaporin-5 (AQP5) is present on the apical membrane of epithelial cells in various secretory glands as well as on the apical membrane of the airway epithelium, airway submucosal glands, and type 1 pneumocytes, where it can participate in respiratory tract water homeostasis. We examined the effects of cAMP on AQP5 distribution and abundance. When AQP5-expressing mouse lung epithelial cells were treated with cAMP or the beta-adrenergic agonist terbutaline, a biphasic AQP5 response was observed. Short term (minutes) exposure to cAMP produced internalization of AQP5 off of the membrane and a decrease in protein abundance. Both of these responses were blocked by inhibition of protein kinase A and the decrease in abundance was blocked by chloroquine, indicating lysosome-mediated degradation. Sustained cAMP exposure (hours) produced an increase in membrane localization and increased abundance; these effects were also blocked by protein kinase A inhibition. The beta-adrenergic agonist terbutaline produced changes in AQP5 abundance in mouse trachea and lung, consistent with our findings in cultured epithelial cells. Purified AQP5 protein was phosphorylated by protein kinase A but not protein kinase C or casein kinase II, and aquaporin-5 was phosphorylated in cultured cells after long term (but not short term) exposure to cAMP. These studies indicate that cAMP and beta-adrenergic agonists produce distinct short and long term effects on AQP5 distribution and abundance that may contribute to regulation of lung water homeostasis.