Genome-wide association study of Alzheimer's disease with psychotic symptoms

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.Molecular Psychiatry advance online publication, 18 October 2011; doi:10.1038/mp.2011.125.

A genome-wide association study provides evidence for association of chromosome 8p23 (MYP10) and 10q21.1 (MYP15) with high myopia in the French population.

PURPOSE. Myopia is a complex trait affected by both genetic and environmental factors. High myopia is associated with increased risk of sight-threatening eye disorders such as retinal detachment. The purpose of this genome-wide association study was to identify susceptibility genes contributing to high myopia in the French population. METHODS. High myopic cases were genotyped using Affymetrix SNP 6.0 chips and population controls were selected from the GABRIEL French dataset in which samples were genotyped by Illumina Human610 quad array. The association study was conducted using 152,234 single nucleotide polymorphisms that were present on both manufacturers' chips in 192 high myopic cases and 1064 controls to identify associated regions. Imputation was performed on peak regions. RESULTS. Associations were found at known myopia locus MYP10 on chromosome 8p23 and MYP15 on chromosome 10q21.1. Rs189798 (8p23) and rs10825992 (10q21.1) showed the strongest associations in these regions (P=6.32x10-7 and P=2.17x10-5, respectively). The imputed results at 8p23 showed 2 peaks of interest. The first spanned 30kb including rs189798 between MIR4660 and PPP1R3B with the most significant association at rs17155227 (P=1.07x10-10). The second novel peak was 4kb in length, encompassing MIR124-1 and the MSRA gene, with the strongest association at rs55864141 (P=1.30x10-7). The peak of imputed data at 10q21.1 was 70kb in length between ZWINT and MIR3924, with rs3107503 having the lowest P value (P=1.54x10-7). CONCLUSION. We provide evidence for the association of MYP10 at 8p23 and MYP15 at 10p21.1 with high myopia in the French population and refine these regions of association.

Breast Cancer Risk in Relation to Occupations with Exposure to Carcinogens and Endocrine Disruptors:a Canadian Case-Control Study

Background

Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours.

Methods

1005 breast cancer cases referred by a regional cancer center and 1147 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case?control design, exposure effects were estimated using conditional logistic regression.

Results

Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5).

Conclusions

These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.

Environmental and genetic control of arsenic accumulation and speciation in rice grain:comparing a range of common cultivars grown in contaminated sites across Bangladesh, China, and India

The concentration of arsenic (As) in rice grains has been identified as a risk to human health. The high proportion of inorganic species of As (As(i)) is of particular concern as it is a nonthreshold, class 1 human carcinogen. To be able to breed rice with low grain As, an understanding of genetic variation and the effect of different environments on genetic variation is needed. In this study, 13 cultivars grown at two field sites each in Bangladesh, India, and China are evaluated for grain As. There was a significant site, genotype, and site by genotype interaction for total grain As. Correlations were observed only between sites in Bangladesh and India, not between countries or within the Chinese sites. For seven cultivars the As was speciated which revealed significant effects of site, genotype, and site by genotype interaction for percentage As(i). Breeding low grain As cultivars that will have consistently low grain As and low As(i), over multiple environments using traditional breeding approaches may be difficult, although CT9993-5-10-1-M, Lemont, Azucena, and Te-qing in general had low grain As across the field sites.

The influence of evidence-based medicine training on decision-making in relation to over-the-counter medicines: a qualitative study

Objectives
To explore the role of evidence of effectiveness when making decisions about over-the-counter (OTC) medication and to ascertain whether evidence-based medicine training raised awareness in decision-making. Additionally, this work aimed to complement the findings of a previous study because all participants in this current study had received training in evidence-based medicine (unlike the previous participants).

Methods
Following ethical approval and an e-mailed invitation, face-to-face, semi-structured interviews were conducted with newly registered pharmacists (who had received training in evidence-based medicine as part of their MPharm degree) to discuss the role of evidence of effectiveness with OTC medicines. Interviews were recorded and transcribed verbatim. Following transcription, all data were entered into the NVivo software package (version 8). Data were coded and analysed using a constant comparison approach.

Key findings
Twenty-five pharmacists (7 males and 18 females; registered for less than 4 months) were recruited and all participated in the study. Their primary focus with OTC medicines was safety; sales of products (including those that lack evidence of effectiveness) were justified provided they did no harm. Meeting patient expectation was also an important consideration and often superseded evidence. Despite knowledge of the concept, and an awareness of ethical requirements, an evidence-based approach was not routinely implemented by these pharmacists. Pharmacists did not routinely utilize evidence-based resources when making decisions about OTC medicines and some felt uncomfortable discussing the evidence-base for OTC products with patients.

Conclusions
The evidence-based medicine training that these pharmacists received appeared to have limited influence on OTC decision-making. More work could be conducted to ensure that an evidence-based approach is routinely implemented in practice

Understanding the migratory orientation program of birds: extending laboratory studies to study free flying migrants in a natural setting

For many years, orientation in migratory birds has primarily been studied in the laboratory. Although a laboratory-based setting enables greater control over environmental cues, the laboratory-based findings must be confirmed in the wild in free-flying birds to be able to fully understand how birds orient during migration. Despite the difficulties associated with following free-flying birds over long distances, a number of possibilities currently exist for tracking the long distance, sometimes even globe-spanning, journeys undertaken by migrating birds. Birds fitted with radio transmitters can either be located from the ground or from aircraft (conventional tracking), or from space. Alternatively, positional information obtained by onboard equipment (e.g., GPS units) can be transmitted to receivers in space. Use of these tracking methods has provided a wealth of information on migratory behaviors that are otherwise very difficult to study. Here, we focus on the progress in understanding certain components of the migration-orientation system. Comparably exciting results can be expected in the future from tracking free-flying migrants in the wild. Use of orientation cues has been studied in migrating raptors (satellite telemetry) and thrushes (conventional telemetry), highlighting that findings in the natural setting may not always be as expected on the basis of cage-experiments. Furthermore, field tracking methods combined with experimental approaches have finally allowed for an extension of the paradigmatic displacement experiments performed by Perdeck in 1958 on the short-distance, social migrant, the starling, to long-distance migrating storks and long-distance, non-socially migrating passerines. Results from these studies provide fundamental insights into the nature of the migratory orientation system that enables experienced birds to navigate and guide inexperienced, young birds to their species-specific winter grounds.

Holocene environmental changes in northeast Thailand as reconstructed from a tropical wetland

Geochemical variables (TOC, C/N, TS, delta C-13) and diatom assemblages were analyzed in a lake sediment sequence from Nong (Lake) Han Kumphawapi in northeast Thailand to reconstruct regional climatic and environmental history during the Holocene. By around c. 10,000-9400 cal yr BP, a large shallow freshwater lake had formed in the Kumphawapi basin. Oxygenated bottom waters and a well-mixed water column were characteristic of this early lake stage, which was probably initiated by higher effective moisture and a stronger summer monsoon. Decreased run-off after c. 6700 cal yr BP favored increased aquatic productivity in the shallow lake. Multiple proxies indicate a marked lowering of the lake level around 5900 cal yr BP, the development of an extensive wetland around 5400 cal yr BP, and the subsequent transition to a peatland. The shift from shallow lake to wetland and later to a peatland is interpreted as a response to lower effective moisture. A hiatus at the transition from wetland to peatland suggests very low accumulation rates, which may result from very dry climatic conditions. A rise in groundwater and lake level around 3200 cal yr BP allowed the re-establishment of a wetland in the Kumphawapi basin. However, the sediments deposited between c. 3200 and 1600 cal yr BP provide evidence for at least two hiatuses at c. 2700-2500 cal yr BP, and at c. 1900-1600 cal yr BP, which would suggest surface dryness and consequently periods of low effective moisture. Around 1600 cal yr BP a new shallow lake became re-established in the basin. Although the underlying causes for this new lake phase remain unclear, we hypothesize that higher effective moisture was the main driving force. This shallow lake phase continued up to the present but was interrupted by higher nutrient fluxes to the lake around 1000-600 cal yr BP. Whether this was caused by intensified human impact in the catchment or, whether this signals a lowering of the lake level due to reduced effective moisture, needs to be corroborated by further studies in the region. The multi-proxy study of Kumphawapi's sediment core CP3A clearly shows that Kumphawapi is a sensitive archive for recording past shifts in effective moisture, and as such in the intensity of the Asian summer monsoon. Many more continental paleorecords, however, will be needed to fully understand the spatial and temporal patterns of past changes in Asian monsoon intensity and its ecosystem impacts. (C) 2012 Elsevier B.V. All rights reserved.

Postweaning exposure to aflatoxin results in impaired child growth: A longitudinal study in Benin, west Africa

Aflatoxins are dietary contaminants that are hepatocarcinogenic and immunotoxic and cause growth retardation in animals, but there is little evidence concerning the latter two parameters in exposed human populations. Aflatoxin exposure of West African children is known to be high, so we conducted a longitudinal study over an 8-month period in Benin to assess the effects of exposure on growth. Two hundred children 16-37 months of age were recruited from four villages, two with high and two with low aflatoxin exposure (50 children per village). Serum aflatoxin-albumin (AF-alb) adducts, anthropometric parameters, information on food consumption, and various demographic data were measured at recruitment (February) and at two subsequent time points (June and October). Plasma levels of vitamin A and zinc were also measured. AF-alb adducts increased markedly between February and October in three of the four villages, with the largest increases in the villages with higher exposures. Children who were fully weaned at recruitment had higher AF-alb than did those still partially breast-fed (p < 0.0001); the major weaning food was a maize-based porridge. There was no association between AF-alb and micronutrient levels, suggesting that aflatoxin exposure was not accompanied by a general nutritional deficiency. There was, however, a strong negative correlation (p < 0.0001) between AF-alb and height increase over the 8-month follow-up after adjustment for age, sex, height at recruitment, socioeconomic status, village, and weaning status; the highest quartile of AF-alb was associated with a mean 1.7 cm reduction in growth over 8 months compared with the lowest quartile. This study emphasizes the association between aflatoxin and stunting, although the underlying mechanisms remain unclear. Aflatoxin exposure during the weaning period may be critical in terms of adverse health effects in West African children, and intervention measures to reduce exposure merit investigation.

How standardised patients award global scores in OSCEs: a qualitative study

Standardized patients (SPs) are often asked to award global scores on the humanistic aspects of a candidate’s performance in an OSCE. However, little is known about the process by which SPs arrive at their mark.
Five focus groups of SPs, using a convenience sample, were used to collect data until saturation. Thematic analysis was carried out independently by three researchers using a grounded theory approach.

Four major themes contributed to their decision-making process: environment, relationships within the exam, preparedness for the task and expectations of the student’s performance. Environmental factors included the station itself, the rating scale and examiner fatigue. Relationship factors included first impressions, the sense of purpose derived from examining and a tendency to mirror the examiner’s reaction. Factors relating to preparedness for task involved experience as an SP and technical aspects, such as the need for calibration. Lastly, expectations of performance were related to preconceptions about what makes a ‘good’ student, including their level of studies, appearance and technical performance.

In assessing students, SPs drew on their wider attitudes and experiences. SPs did not limit their assessment to humanistic traits but often included technical performance. Thus, SPs to some extent assessed a similar construct to examiners and this may help to explain the increased reliability associated with using SP scores. SP global scores are a useful adjunct but the process by which SPs award marks is complex and provides a challenge for training and standardisation.

Chronic workplace stress and insufficient physical activity: a cohort study

Objectives To examine whether exposure to workplace stressors predicts changes in physical activity and the risk of insufficient physical activity.

Methods Prospective data from the Finnish Public Sector Study. Repeated exposure to low job control, high job demands, low effort, low rewards and compositions of these (job strain and effort-reward imbalance) were assessed at Time 1 (2000-2002) and Time 2 (2004). Insufficient physical activity (<14 metabolic equivalent task hours per week) was measured at Time 1 and Time 3 (2008). The effect of change in workplace stressors on change in physical activity was examined using fixed-effects (within-subject) logistic regression models (N=6665). In addition, logistic regression analysis was applied to examine the associations between repeated exposure to workplace stressors and insufficient physical activity (N=13 976). In these analyses, coworker assessed workplace stressor scores were used in addition to individual level scores.

Results The proportion of participants with insufficient physical activity was 24% at baseline and 26% at follow-up. 19% of the participants who were sufficiently active at baseline became insufficiently active at follow-up. In the fixed-effect analysis, an increase in workplace stress was weakly related to an increase in physical inactivity within an individual. In between-subjects analysis, employees with repeated exposure to low job control and low rewards were more likely to be insufficiently active at follow-up than those with no reports of these stressors; fully adjusted ORs ranged from 1.11 (95% CI 1.00 to 1.24) to 1.21 (95% CI 1.05 to 1.39).

Conclusions Workplace stress is associated with a slightly increased risk of physical inactivity.

The p-hub Model with Hub-catchment Areas, Existing Hubs, and Simulation: A Case Study of Serbian Intermodal Terminals

This paper addresses the problem of optimally locating intermodal freight terminals in Serbia. To solve this problem and determine the effects of the resulting scenarios, two modeling approaches were combined. The first approach is based on multiple-assignment hub-network design, and the second is based on simulation. The multiple-assignment p-hub network location model was used to determine the optimal location of intermodal terminals. Simulation was used as a tool to estimate intermodal transport flow volumes, due to the unreliability and unavailability of specific statistical data, and as a method for quantitatively analyzing the economic, time, and environmental effects of different scenarios of intermodal terminal development. The results presented here represent a summary, with some extension, of the research realized in the IMOD-X project (Intermodal Solutions for Competitive Transport in Serbia).

Vegetation changes and human settlement of Easter Island during the last millennia: a multiproxy study of the Lake Raraku sediments

Earlier palynological studies of lake sediments from Easter Island suggest that the island underwent a recent and abrupt replacement of palm-dominated forests by grasslands, interpreted as a deforestation by indigenous people. However, the available evidence is inconclusive due to the existence of extended hiatuses and ambiguous chronological frameworks in most of the sedimentary sequences studied. This has given rise to an ongoing debate about the timing and causes of the assumed ecological degradation and cultural breakdown. Our multiproxy study of a core recovered from Lake Raraku highlights the vegetation dynamics and environmental shifts in the catchment and its surroundings during the late Holocene. The sequence contains shorter hiatuses than in previously recovered cores and provides a more continuous history of environmental changes. The results show a long, gradual and stepped landscape shift from palm-dominated forests to grasslands. This change started c. 450 BC and lasted about two thousand years. The presence of Verbena litoralis, a common weed, which is associated with human activities in the pollen record, the significant correlation between shifts in charcoal influx, and the dominant pollen types suggest human disturbance of the vegetation. Therefore, human settlement on the island occurred c. 450 BC, some 1500 years earlier than is assumed. Climate variability also exerted a major influence on environmental changes. Two sedimentary gaps in the record are interpreted as periods of droughts that could have prevented peat growth and favoured its erosion during the Medieval Climate Anomaly and the Little Ice Age, respectively. At c. AD 1200, the water table rose and the former Raraku mire turned into a shallow lake, suggesting higher precipitation/evaporation rates coeval with a cooler and wetter Pan-Pacific AD 1300 event. Pollen and diatom records show large vegetation changes due to human activities c. AD 1200. Other recent vegetation changes also due to human activities entail the introduction of taxa (e.g. Psidium guajava, Eucalyptus sp.) and the disappearance of indigenous plants such as Sophora toromiro during the two last centuries. Although the evidence is not conclusive, the American origin of V. litoralis re-opens the debate about the possible role of Amerindians in the human colonisation of Easter Island.

Burnout and behavior-related health risk factors:results from the population-based Finnish Health 2000 study

To explore the relationship between burnout and behavior-related health risk factors.

Biomonitoring aquatic environmental quality in a marine protected area: A biomarker approach

The main aims of the present study, conducted in the framework of the MONIQUA-Egadi Scientific Project, were twofold: first, to make the first step in the development and validation of an ecotoxicological approach for the assessment of marine pollution in coastal environments on the basis of a set of biomarker responses in new sentinel species; and second, to obtain preliminary information on environmental quality in an Italian marine protected area, the Egadi Islands (Sicily). Several cytochrome P450-dependent mixed-function oxidase activities were measured in the following sentinel species: rainbow wrasse Coris julis, gastropod limpet Patella caerulea, and sea urchin Paracentrotus lividus. The results suggest that specimens from the Favignana Harbor may be exposed to P450 inducers, whereas most of the other sites seem to share similar environmental quality. The proposed approach has potential for assessment of environmental quality in marine protected areas.

An Examination of Transformation Techniques to Investigate and Interpret Multivariate Geochemical Data Analysis: Tellus Case Study

This research aims to use the multivariate geochemical dataset, generated by the Tellus project, to investigate the appropriate use of transformation methods to maintain the integrity of geochemical data and inherent constrained behaviour in multivariate relationships. The widely used normal score transform is compared with the use of a stepwise conditional transform technique. The Tellus Project, managed by GSNI and funded by the Department of Enterprise Trade and Development and the EU’s Building Sustainable Prosperity Fund, involves the most comprehensive geological mapping project ever undertaken in Northern Ireland. Previous study has demonstrated spatial variability in the Tellus data but geostatistical analysis and interpretation of the datasets requires use of an appropriate methodology that reproduces the inherently complex multivariate relations. Previous investigation of the Tellus geochemical data has included use of Gaussian-based techniques. However, earth science variables are rarely Gaussian, hence transformation of data is integral to the approach. The multivariate geochemical dataset generated by the Tellus project provides an opportunity to investigate the appropriate use of transformation methods, as required for Gaussian-based geostatistical analysis. In particular, the stepwise conditional transform is investigated and developed for the geochemical datasets obtained as part of the Tellus project. The transform is applied to four variables in a bivariate nested fashion due to the limited availability of data. Simulation of these transformed variables is then carried out, along with a corresponding back transformation to original units. Results show that the stepwise transform is successful in reproducing both univariate statistics and the complex bivariate relations exhibited by the data. Greater fidelity to multivariate relationships will improve uncertainty models, which are required for consequent geological, environmental and economic inferences.