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In this time-frame the test has evolved from a single enzyme measurement using ultra-high performance liquid chromatography (UHPLC) in peripheral blood mononuclear cells (PBMCs) to a combined enzymatic and genetic test of four variants in the DPYD gene (DPYD*2A, DPYD*13, c.2846A>T and 1129-5923C>G). [...]at this moment a combination of a...

Objective: Children born small for gestational age are at increased risk of developing type 2 diabetes in adulthood. The satiety signal leptin that regulates food intake and energy expenditure might be a possible molecular link, as umbilical cord leptin levels are positively correlated with birth weight. In the present study, we examined whether common single nucleotide polymorphisms (SNPs) in the leptin (LEP; 19G>A) gene and its receptor (LEPR; Q223R and K109R) are associated with birth weight and adult metabolic risk factors for type 2 diabetes in twins. Design: SNPs were genotyped in 396 monozygotic and 232 dizygotic twins (286 men and 342 women, mean age 25 years) recruited from the East Flanders Prospective Twin Survey. Data were analysed using linear mixed models. Results: The LEPR K109R SNP was associated with birth weight (KK, KR and RR (95% confidence interval, CI): 2511 (2465-2557), 2575 (2516-2635) and 2726 (2606-2845) gram; Padditive=0.001). Also the LEPR Q223R SNP showed a significant association with weight at birth (QQ, QR and RR (95% CI): 2492 (2431-2554), 2545 (2495-2595) and 2655 (2571-2740) gram; Padditive=0.003). Furthermore, an interaction between the LEPR K109R and the Q223R SNP on birth weight was observed (P=0.014). G allele carriers of the LEP 19G>A SNP had higher high-density lipoprotein (HDL) cholesterol levels compared to 19A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol l-1; Precessive=0.013). Conclusions: This study indicates that leptin may act as a growth-promoting signal during fetal development, and suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adulthood. Additionally, these results suggest that the LEP 19G>A SNP affect HDL cholesterol levels.

Objective: The maternally imprinted insulin-like growth factor 2 (IGF2) gene is an important fetal growth factor and is also suggested to have postnatal metabolic effects. In this study, we examined whether common polymorphisms in IGF2 (6815_6819delAGGGC, 1156T>C and 820G>A (ApaI)) and a microsatellite marker in the close vicinity of IGF2 were linked to or associated with birth weight and adult metabolic risk factors. Design and participants: Polymorphisms were genotyped in 199 monozygotic complete twin pairs, 109 dizygotic complete twin pairs, 15 single twins, 231 mothers and 228 fathers recruited from the East Flanders Prospective Twin Survey. Conventional and parent-of-origin specific linkage and association analyses were carried out with birth weight, adult body height and parameters quantifying obesity, insulin sensitivity and dyslipidaemia measured at adult age (mean age 25 years). Results: In the parent-of-origin specific association analysis, in which only the paternally inherited allele was incorporated, the 1156T>C SNP (single nucleotide polymorphism) showed significant association with IGF-binding protein 1 (IGFBP1) levels (T and C (mean (95% CI)): 13.2 (12.1–14.3) and 16.2 (14.6–18.0) ng ml-1, P=0.002). No linkage was observed in either the conventional or in the parent-of-origin specific linkage analysis. Conclusion: This study suggests that paternally inherited alleles of a common polymorphism in the IGF2 gene affect IGFBP1 levels.

Recently we demonstrated that the t(11;18)(q21;q21. associated with extranodal marginal zone B cell lymphomas of MALT type results in the expression of a chimeric transcript fusing 5′ API2 on chromosome 11 to 3′ MLT on chromosome 18. Here we report the development of an RT-PCR approach for the detection of the API2- MLT fusion transcript and its application for the analysis of 58 cases of gastric lymphoma. Initially nested PCR amplification was combined with Southern analysis using internal API2 and MLT probes. A genuine API2- MLT fusion transcript of variable length was demonstrated in 11 out of 58 cases. Sequence analysis revealed that in all cases the breakpoint on chromosome 11 occurred between exons 7 and 8 of the API2 gene. In contrast, the breakpoints on chromosome 18 appeared to be heterogeneous as fusions to bp 814, 1123, and 1150, respectively, of MLT were observed. These observations allowed us to work out a highly sensitive diagnostic test for the API2- MLT fusion on an ABI Prism 7700 sequence detector that confirmed the results of our initial approach. The API2- MLT fusion was found in 48% of gastric marginal zone cell lymphomas of MALT type that did not contain a large cell component and it was lacking in all other lymphomas of the stomach.

Correction to: International Journal of Obesity advance online publication, 20 May 2008; doi:10.1038/ijo.2008.68 Owing to a typesetting error in Tables 1 and 2 of the above paper some cells and the background of some text in the legend are gray, while they should have been white. The correct tables are reproduced below.

Basal cell nevus syndrome (BCNS) is an inherited disorder characterized mainly by the development of basal cell carcinomas (BCCs) at an early age. BCNS is caused by heterozygous small-nucleotide variants (SNVs) and copy-number variants (CNVs) in the Patched1 (PTCH1) gene. Genetic diagnosis may be complicated in mosaic BCNS patients, as accurate SNV and CNV analysis requires high-sensitivity methods due to possible low variant allele frequencies. We compared test outcomes for PTCH1 CNV detection using multiplex ligation-probe amplification (MLPA) and digital droplet PCR (ddPCR) with samples from a BCNS patient heterozygous for a PTCH1 CNV duplication and the patient’s father, suspected to have a mosaic form of BCNS. ddPCR detected a significantly increased PTCH1 copy-number ratio in the index patient’s blood, and the father’s blood and tissues, indicating that the father was postzygotic mosaic and the index patient inherited the CNV from him. MLPA only detected the PTCH1 duplication in the index patient’s blood and in hair and saliva from the mosaic father. Our data indicate that ddPCR more accurately detects CNVs, even in low-grade mosaic BCNS patients, which may be missed by MLPA. In general, quantitative ddPCR can be of added value in the genetic diagnosis of mosaic BCNS patients and in estimating the recurrence risk for offspring.