PTSD and DNA Methylation in Select Immune Function Gene Promoter Regions: A Repeated Measures Case-Control Study of U.S. Military Service Members

Background: The underlying molecular mechanisms of PTSD are largely unknown. Distinct expression signatures for PTSD have been found, in particular for immune activation transcripts. DNA methylation may be significant in the pathophysiology of PTSD, since the process is intrinsically linked to gene expression. We evaluated temporal changes in DNA methylation in select promoter regions of immune system-related genes in U.S. military service members with a PTSD diagnosis, pre- and post-diagnosis, and in controls. Methods: Cases (n = 75) had a post-deployment diagnosis of PTSD in their medical record. Controls (n = 75) were randomly selected service members with no PTSD diagnosis. DNA was extracted from pre- and post-deployment sera. DNA methylation (%5-mC) was quantified at specific CpG sites in promoter regions of insulin-like growth factor 2 (IGF2), long non-coding RNA transcript H19, interleukin-8 (IL8), IL16, and IL18 via pyrosequencing. We used multivariate analysis of variance and generalized linear models to calculate adjusted means (adjusted for age, gender, and race) to make temporal comparisons of %5-mC for cases (pre- to post-deployment) versus controls (pre- to post-deployment). Results: There were significant differences in the change of %5-mC pre- to post-deployment between cases and controls for H19 (cases: +0.57%, controls: −1.97%; p = 0.04) and IL18 (cases: +1.39%, controls: −3.83%; p = 0.01). For H19 the difference was driven by a significant reduction in %5-mC among controls; for IL18 the difference was driven by both a reduction in %5-mC among controls and an increase in %5-mC among cases. Stratified analyses revealed more pronounced differences in the adjusted means of pre-post H19 and IL18 methylation differences for cases versus controls among older service members, males, service members of white race, and those with shorter deployments (6–12 months). Conclusion: In the study of deployed personnel, those who did not develop PTSD had reduced %5-mC levels of H19 and IL18 after deployment, while those who did develop PTSD had increased levels of IL18. Additionally, pre-deployment the people who later became cases had lower levels of IL18 %5-mC compared with controls. These findings are preliminary and should be investigated in larger studies

Robust artificial neural networks and outlier detection. Technical report

Large outliers break down linear and nonlinear regression models. Robust regression methods allow one to filter out the outliers when building a model. By replacing the traditional least squares criterion with the least trimmed squares criterion, in which half of data is treated as potential outliers, one can fit accurate regression models to strongly contaminated data. High-breakdown methods have become very well established in linear regression, but have started being applied for non-linear regression only recently. In this work, we examine the problem of fitting artificial neural networks to contaminated data using least trimmed squares criterion. We introduce a penalized least trimmed squares criterion which prevents unnecessary removal of valid data. Training of ANNs leads to a challenging non-smooth global optimization problem. We compare the efficiency of several derivative-free optimization methods in solving it, and show that our approach identifies the outliers correctly when ANNs are used for nonlinear regression

Under-five mortality: spatial-temporal clusters in Ifakara HDSS in South-eastern Tanzania.

BACKGROUND\ud \ud Childhood mortality remains an important subject, particularly in sub-Saharan Africa where levels are still unacceptably high. To achieve the set Millennium Development Goals 4, calls for comprehensive application of the proven cost-effective interventions. Understanding spatial clustering of childhood mortality can provide a guide in targeting the interventions in a more strategic approach to the population where mortality is highest and the interventions are most likely to make an impact.\ud \ud METHODS\ud \ud Annual child mortality rates were calculated for each village, using person-years observed as the denominator. Kulldorff's spatial scan statistic was used for the identification and testing of childhood mortality clusters. All under-five deaths that occurred within a 10-year period from 1997 to 2006 were included in the analysis. Villages were used as units of clusters; all 25 health and demographic surveillance sites (HDSS) villages in the Ifakara health and demographic surveillance area were included.\ud \ud RESULTS\ud \ud Of the 10 years of analysis, statistically significant spatial clustering was identified in only 2 years (1998 and 2001). In 1998, the statistically significant cluster (p < 0.01) was composed of nine villages. A total of 106 childhood deaths were observed against an expected 77.3. The other statistically significant cluster (p < 0.05) identified in 2001 was composed of only one village. In this cluster, 36 childhood deaths were observed compared to 20.3 expected. Purely temporal analysis indicated that the year 2003 was a significant cluster (p < 0.05). Total deaths were 393 and expected were 335.8. Spatial-temporal analysis showed that nine villages were identified as statistically significant clusters (p < 0.05) for the period covering January 1997-December 1998. Total observed deaths in this cluster were 205 while 150.7 were expected.\ud \ud CONCLUSION\ud \ud There is evidence of spatial clustering in childhood mortality within the Ifakara HDSS. Further investigations are needed to explore the source of clustering and identify strategies of reaching the cluster population with the existing effective interventions. However, that should happen alongside delivery of interventions to the broader population

Stress related epigenetic changes may explain opportunistic success in biological invasions in Antipode mussels

Different environmental factors could induce epigenetic changes, which are likely involved in the biological invasion process. Some of these factors are driven by humans as, for example, the pollution and deliberate or accidental introductions and others are due to natural conditions such as salinity. In this study, we have analysed the relationship between different stress factors: time in the new location, pollution and salinity with the methylation changes that could be involved in the invasive species tolerance to new environments. For this purpose, we have analysed two different mussels’ species, reciprocally introduced in antipode areas: the Mediterranean blue mussel Mytilus galloprovincialis and the New Zealand pygmy mussel Xenostrobus securis, widely recognized invaders outside their native distribution ranges. The demetylathion was higher in more stressed population, supporting the idea of epigenetic is involved in plasticity process. These results can open a new management protocols, using the epigenetic signals as potential pollution monitoring tool. We could use these epigenetic marks to recognise the invasive status in a population and determine potential biopollutants

Atrazine and cancer incidence among pesticide applicators in the agricultural health study (1994-2007).

Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association

Internal Stirring: An Approach to Approximate Evaluation of Shielding Effectiveness of Small Slotted Enclosures

The research for this paper was a collaboration between: 1 Plum Ltd., Wspolna 19, Ignatki, 16-001 Kleosin, Poland 2 Bialystok University of Technology, Wiejska 45D, 15-351 Bialystok, Poland 3 De Montfort University, The Gateway, Leicester, LE1 9BH, UK 4 University of L’Aquila, UAq EMC Laboratory, I-67100, L’Aquila, ItalyA new technique for approximate evaluation of a small slotted enclosure shielding effectiveness (SE) is proposed. The enclosure under test is equipped with a built-in, rotating, conductive stirrer, and the SE is determined for discrete angles of the stirrer position. The SE characteristics computed in the frequency domain for the enclosure with the stirrer are compared to those of the enclosure containing different arrangements of printed circuit boards. The paper concludes that the inclusion of an internal stirrer is a potentially beneficial approach to shielding effectiveness testing

Mammographic density and risk of breast cancer by age and tumor characteristics

Introduction: Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models. Methods: Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (51%) versus average density (11-25%). Women ages 2.1 cm) versus small tumors and positive versus negative lymph node status (P’s < 0.01). For women ages <55 years, there was a stronger association of MD with ER-negative breast cancer than ER-positive tumors compared to women ages 55–64 and ≥65 years (Page-interaction = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group. Conclusion: MD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women

Environmental chemical stressors as epigenome modifiers:a new horizon in assessment of toxicological effects

In eukaryotic cells, chromatin transformation from euchromatin into heterochromatin as a means of controlling gene expression and replication has been known as the ?accessibility hypothesis?. The interplay of epigenetic changes including histone modifications, DNA methylation, RNA interference (RNAi) and other functional epigenetic components are intricate. It is believed that these changes are well-programmed, inherited and can be modified by environmental contaminant stressors. Environmentally-driven epigenetic alterations during development, e.g. embryonic, foetal or neonatal stage, may influence disease susceptibility in adulthood. Therefore, understanding how epigenome modifications develop in response to environmental chemicals and, how epigenetic-xenobiotic interactions influence human health will shed new insights into gene-environment interactions in the epidemiology of several diseases including cancer. In this review, we consider studies of chemical modifiers including nutritional and xenobiotic effects on epigenetic components in vitro or in vivo. By examining the most-studied epigenome modifications and how their respective roles are interlinked, we highlight the central role of xenbiotic-modified epigenetic mechanisms. A major requirement will be to study and understand effects following environmentally-relevant exposures. We suggest that the study of epigenetic toxicology will open up new opportunities to devise strategies for the prevention or treatment of at-risk populations

Mortality among Pesticide Applicators Exposed to Chlorpyrifos in the Agricultural Health Study

BACKGROUND: Chlorpyrifos is one of the most widely used organophosphate insecticides in the United States. Although the toxicity of chlorpyrifos has been extensively studied in animals, the epidemiologic data are limited. OBJECTIVE: To evaluate whether agricultural chlorpyrifos exposure was associated with mortality, we examined deaths among pesticide applicators in the Agricultural Health Study, a prospective study of licensed pesticide applicators in Iowa and North Carolina. METHODS: A total of 55,071 pesticide applicators were included in this analysis. Detailed pesticide exposure data and other information were obtained from self-administered questionnaires completed at the time of enrollment (1993–1997). Lifetime chlorpyrifos use was divided into tertiles. Poisson regression analysis was used to evaluate the exposure–response relationships between chlorpyrifos use and causes of death after adjustment for potential confounders. RESULTS: A total of 1,851 deaths (588 among chlorpyrifos users) were observed during the study period, 1993–2001. The relative risk (RR) of death from all causes combined among applicators exposed to chlorpyrifos was slightly lower than that for nonexposed applicators (RR = 0.90; 95% confidence interval, 0.81–1.01). For most causes of death analyzed, there was no evidence of an exposure–response relationship. However, the relative risks for mortality from suicide and non-motor-vehicle accidents were increased 2-fold in the highest category of chlorpyrifos exposure days. CONCLUSIONS: Our findings of a possible association between chlorpyrifos use and external causes of death were based on small numbers. However, the findings may reflect a link between chlorpyrifos and depression or other neurobehavioral symptoms that deserves further evaluation