Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.</p

The JWS online simulation database

Summary: JWS Online is a web-based platform for construction, simulation and exchange of models in standard formats. We have extended the platform with a database for curated simulation experiments that can be accessed directly via a URL, allowing one-click reproduction of published results. Users can modify the simulation experiments and export them in standard formats. The Simulation database thus lowers the bar on exploring computational models, helps users create valid simulation descriptions and improves the reproducibility of published simulation experiments. Availability and Implementation: The Simulation Database is available on line at https://jjj.bio.vu. nl/models/experiments/

Leukocyte function and health status of calves supplemented with vitamins A and E

Forty-four Holstein calves were fed milk replacers with varied concentrations of vitamins A and E from 3 to 45 d of age to determine their effects on concentrations of plasma vitamin A (retinol and retinyl palmitate) and vitamin E (a- tocopherol), lymphocyte and neutrophil functions, and health of calves. Plasma a-tocopherol was unaffected by increased vitamin A supplementation. Fecal scores, and eye and nose membrane responses were improved with increased vitamin A and lower vitamin E concentration, whereas the same treatment tended to reduce neutrophil cytotoxic and bactericidal activity by 6 wk of age. Increased supplemental vitamin E tended to enhance neutrophil functions. However, age appeared to have an effect on response to both vitamins

The M33 Variable Star Population Revealed by Spitzer

We analyze five epochs of Spitzer Space Telescope/Infrared Array Camera (IRAC) observations of the nearby spiral galaxy M33. Each epoch covered nearly a square degree at 3.6, 4.5, and 8.0 microns. The point source catalog from the full dataset contains 37,650 stars. The stars have luminosities characteristic of the asymptotic giant branch and can be separated into oxygen-rich and carbon-rich populations by their [3.6] - [4.5] colors. The [3.6] - [8.0] colors indicate that over 80% of the stars detected at 8.0 microns have dust shells. Photometric comparison of epochs using conservative criteria yields a catalog of 2,923 variable stars. These variables are most likely long-period variables amidst an evolved stellar population. At least one-third of the identified carbon stars are variable.Comment: Accepted for publication in ApJ. See published article for full resolution figures and electronic table

A Heuristic Image Search Algorithm for Active Shape Model Segmentation of the Caudate Nucleus and Hippocampus in Brain MR Images of Children with FASD

Magnetic Resonance Imaging provides a non-invasive means to study the neural correlates of Fetal Alcohol Spectrum Disorder (FASD) - the most common form of preventable mental retardation worldwide. One approach aims to detect brain abnormalities through an assessment of volume and shape of two sub-cortical structures, the caudate nucleus and hippocampus. We present a method for automatically segmenting these structures from high-resolution MR images captured as part of an ongoing study into the neural correlates of FASD. Our method incorporates an Active Shape Model, which is used to learn shape variation from manually segmented training data. A modified discrete Geometrically Deformable Model is used to generate point correspondence between training models. An ASM is then created from the landmark points. Experiments were conducted on the image search phase of ASM segmentation, in order to find the technique best suited to segmentation of the hippocampus and caudate nucleus. Various popular image search techniques were tested, including an edge detection method and a method based on grey profile Mahalanobis distance measurement. A novel heuristic image search method was also developed and tested. This heuristic method improves image segmentation by taking advantage of characteristics specific to the target data, such as a relatively homogeneous tissue colour in target structures. Results show that ASMs that use the heuristic image search technique produce the most accurate segmentations. An ASM constructed using this technique will enable researchers to quickly, reliably, and automatically segment test data for use in the FASD study

Organization of Multinational Activities and Ownership Structure

We develop a model in which multinational investors decide about the modes of organization, the locations of production, and the markets to be served. Foreign investments are driven by market-seeking and cost-reducing motives. We further assume that investors face costs of control that vary among sectors and increase in distance. The results show that (i) production intensive sectors are more likely to operate a foreign business independent of the investment motive, (ii) that distance may have a non-monotonous effect on the likelihood of horizontal investments, and (iii) that globalization, if understood as reducing distance, leads to more integration

Associations of Prenatal Nicotine Exposure and the Dopamine Related Genes ANKK1 and DRD2 to Verbal Language

Language impairment (LI) and reading disability (RD) are common pediatric neurobehavioral disorders that frequently co-occur, suggesting they share etiological determinants. Recently, our group identified prenatal nicotine exposure as a factor for RD and poor reading performance. Using smoking questionnaire and language data from the Avon Longitudinal Study of Parents and Children, we first determined if this risk could be expanded to other communication disorders by evaluating whether prenatal nicotine exposure increases risk for LI and poor performance on language tasks. Prenatal nicotine exposure increased LI risk (OR = 1.60; p = 0.0305) in a dose-response fashion with low (OR = 1.25; p = 0.1202) and high (OR = 3.84; p = 0.0002) exposures. Next, hypothesizing that the effects of prenatal nicotine may also implicate genes that function in nicotine related pathways, we determined whether known nicotine dependence (ND) genes associate with performance on language tasks. We assessed the association of 33 variants previously implicated in ND with LI and language abilities, finding association between ANKK1/DRD2 and performance on language tasks (p≤0.0003). The associations of markers within ANKK1 were replicated in a separate LI case-control cohort (p<0.05). Our results show that smoking during pregnancy increases the risk for LI and poor performance on language tasks and that ANKK1/DRD2 contributes to language performance. More precisely, these findings suggest that prenatal environmental factors influence in utero development of neural circuits vital to language. Our association of ANKK1/DRD2 further implicates the role of nicotine-related pathways and dopamine signaling in language processing, particularly in comprehension and phonological memory

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person’s ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14–q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits

Using Priming to Study Social Categorization

Do people spontaneously categorize stereotypically masculine and stereotypically feminine trait and job labels according to gender? The present experiment provided a methodologically stringent test of automatic gender-based categorization using a modification of a semantic priming methodology. Subjects processing goals were manipulated by asking questions about primes that either did or did not require semantic processing. Results provide support for a spontaneous gender-based categorization of trait labels regardless of the processing goals. However, semantic processing goals appear to be necessary for a spontaneous gender-based categorization of job labels