Biomedical subjects

Claus T Ekstrøm

Publications and source records attributed to Claus T Ekstrøm.

6 recordsLinked to original sources

PubMed2006

The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients.

CONTEXT: Activation of peroxisome proliferator-activated receptors (PPARs)-gamma by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPARalpha/gamma agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema are worrying side effects with these drugs. OBJECTIVE: The objective of the present study was to investigate any variation in the PPARG and PPARA genes associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPARalpha/gamma agonist ragaglitazar. DESIGN: Single-nucleotide polymorphism and haplotype analyses of the PPARA and PPARG genes were performed on DNA obtained from 345 type 2 diabetic patients randomized to 26-wk monotherapy with the dual-acting PPARalpha/gamma agonist ragaglitazar. RESULTS: At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar, and Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as biologically the most important risk factor (hazard ratio 4.42, P = 0.0081) for edema. Other risk factors included female gender (hazard ratio 3.34, P = 0.0005) and weight change during treatment (hazard ratio 1.20, P = 0.0017). CONCLUSIONS: A population-attributable risk of approximately 50% for the Pro12Pro genotype indicates that testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPARgamma agonist-induced fluid retention and edema in patients with type 2 diabetes.

DNA↗

PubMed2005

Pixel-level signal modelling with spatial correlation for two-colour microarrays.

Statistical models for spot shapes and signal intensities are used in image analysis of laser scans of microarrays. Most models have essentially been based on the assumption of independent pixel intensity values, but models that allow for spatial correlation among neighbouring pixels can accommodate errors in the microarray slide and should improve the model fit. Five spatial correlation structures, exponential, Gaussian, linear, rational quadratic and spherical, are compared for a dataset with 50-mer two-colour oligonucleotide microarrays and 452 probes for selected Arabidopsis genes. Substantial improvement in model fit is obtained for all five correlation structures compared to the model with independent pixel values, and the Gaussian and the spherical models seem to be slightly better than the other three models. We also conclude that for the data set analysed the correlation seems negligible for non-neighbouring pixels.

Journal Article↗

PubMed2005

Metabolic engineering of dhurrin in transgenic Arabidopsis plants with marginal inadvertent effects on the metabolome and transcriptome.

Focused and nontargeted approaches were used to assess the impact associated with introduction of new high-flux pathways in Arabidopsis thaliana by genetic engineering. Transgenic A. thaliana plants expressing the entire biosynthetic pathway for the tyrosine-derived cyanogenic glucoside dhurrin as accomplished by insertion of CYP79A1, CYP71E1, and UGT85B1 from Sorghum bicolor were shown to accumulate 4% dry-weight dhurrin with marginal inadvertent effects on plant morphology, free amino acid pools, transcriptome, and metabolome. In a similar manner, plants expressing only CYP79A1 accumulated 3% dry weight of the tyrosine-derived glucosinolate, p-hydroxybenzylglucosinolate with no morphological pleitropic effects. In contrast, insertion of CYP79A1 plus CYP71E1 resulted in stunted plants, transcriptome alterations, accumulation of numerous glucosides derived from detoxification of intermediates in the dhurrin pathway, and in loss of the brassicaceae-specific UV protectants sinapoyl glucose and sinapoyl malate and kaempferol glucosides. The accumulation of glucosides in the plants expressing CYP79A1 and CYP71E1 was not accompanied by induction of glycosyltransferases, demonstrating that plants are constantly prepared to detoxify xenobiotics. The pleiotrophic effects observed in plants expressing sorghum CYP79A1 and CYP71E1 were complemented by retransformation with S. bicolor UGT85B. These results demonstrate that insertion of high-flux pathways directing synthesis and intracellular storage of high amounts of a cyanogenic glucoside or a glucosinolate is achievable in transgenic A. thaliana plants with marginal inadvertent effects on the transcriptome and metabolome.

Amino Acids↗

PubMed2005

A class of goodness of fit tests for a copula based on bivariate right-censored data.

The copula of a bivariate distribution, constructed by making marginal transformations of each component, captures all the information in the bivariate distribution about the dependence between two variables. For frailty models for bivariate data the choice of a family of distributions for the random frailty corresponds to the choice of a parametric family for the copula. A class of tests of the hypothesis that the copula is in a given parametric family, with unspecified association parameter, based on bivariate right censored data is proposed. These tests are based on first making marginal Kaplan-Meier transformations of the data and then comparing a non-parametric estimate of the copula to an estimate based on the assumed family of models. A number of options are available for choosing the scale and the distance measure for this comparison. Significance levels of the test are found by a modified bootstrap procedure. The procedure is used to check the appropriateness of a gamma or a positive stable frailty model in a set of survival data on Danish twins.

Algorithms↗

PubMed2004

CVD: the intestinal crypt/villus in situ hybridization database.

UNLABELLED: The intestinal crypt/villus in situ hybridization database (CVD) query interface is a web-based tool to search for genes with similar relative expression patterns along the crypt/villus axis of the mammalian intestine. The CVD is an online database holding information for relative gene expression patterns in the mammalian intestine and is based on the scoring of in situ hybridization experiments reported in the literature. CVD contains expression data for 88 different genes collected from 156 different in situ hybridization profiles. The web-based query interface allows execution of both single gene queries and pattern searches. The query results provide links to the most relevant public gene databases. AVAILABILITY: http://pc113.imbg.ku.dk/ps/

Animals↗

PubMed2003

Evidence for an association between the Leu162Val polymorphism of the PPARalpha gene and decreased fasting serum triglyceride levels in glucose tolerant subjects.

The aim of the study was to investigate whether genetic variation in the peroxisome proliferator-activated receptor-alpha (PPARalpha) is associated with type 2 diabetes and altered lipid or carbohydrate metabolism in glucose tolerant subjects. Mutation analyses of PPARalpha were performed in 56 type 2 diabetic patients. Six variants were identified: IVS3 + 76T>C, IVS3-19C>T, IVS4 + 35C>T, Leu162Val, Arg178Gly and Ala268Val. In a case-control study comprising 738 type 2 diabetic patients and 524 glucose tolerant subjects, the three exon variants did not show any significant differences in allele frequencies between type 2 diabetic patients and control subjects. The functional Leu162Val polymorphism was further investigated in genotype-phenotype studies involving 340 young, healthy subjects and 502 middle-aged glucose tolerant subjects. The young, healthy subjects who were heterozygous for the Leu162Val variant had, on average, a 20% decrease in fasting serum triglyceride levels (P=0.014). This finding was replicated in middle-aged subjects (P=0.023). The Leu162Val polymorphism was not related to alterations in insulin sensitivity, insulin release or level of glycaemia. In conclusion, the Leu162Val polymorphism of PPARalpha is associated with a decreased level of fasting serum triglyceride in glucose tolerant white subjects.

Adult↗