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S Menzel

Publications and source records attributed to S Menzel.

At least 19 recordsLinked to original sources
PubMed2005

Interaction between two quantitative trait loci affects fetal haemoglobin expression.

The biological mechanisms controlling complex quantitative traits are likely to be affected by interactions between genetic factors, sometimes referred to as epistasis. The identification of interacting loci through genetic analyse faces many challenges, and few examples of replicated findings of interaction exist for humans and model system organisms. The replication of an interaction, or the non-independence, of two quantitative trait loci (QTL) affecting the developmental switch from the expression of fetal to adult haemoglobin is reported here. Fetal haemoglobin expression in adults is a highly heritable, yet complex, phenotype. Using a sample of 874 dizygotic twin pairs of European descent, we found linkage to a QTL on chromosome 8 to be conditional on the twin pairs' genotypes at a polymorphism in the beta-globin complex; an interaction originally identified in a large Asian Indian kindred. The beta-globin polymorphism has been previously shown to be associated with fetal haemoglobin levels in adults. This study reports the first known replication of a genetic interaction between QTLs influencing a complex human trait.

Chromosomes, Human, Pair 8↗
PubMed2003

AES and SIMS investigation of diffusion barriers for copper metallization in power-SAW devices.

Barrier layers for Cu-metallization in surface acoustic wave (SAW) devices were investigated by AES and SIMS depth profiles. Two layered systems on LiNbO(3) substrate have been analyzed after annealing in air up to 400 degrees C. The investigated systems were (A) Ta(20 nm)/Cu(150 nm)/Ti(30 nm), deposited by electron beam evaporation, and (B) Ta(30)Si(18)N(52)(50 nm)/Cu(150 nm)/Ta(30)Si(18)N(52)(50 nm) deposited by magnetron sputtering. In system A the Ta layer shows oxidation in air for T>or=300 degrees C. Ti from the buffer layer diffuses into the Cu at about 100 degrees C, and segregates at the Ta/Cu interface for T>or=200 degrees C. Oxidation of the Ti layer starts at 300 degrees C. But no remarkable amounts of oxygen could be found in the Cu film. The depth profiles show that the TaSiN layer in system B operates as a more effective barrier for the Cu-SAW technology up to more than 300 degrees C.

Journal Article↗
PubMed2002

Genetic and molecular analyses of complex metabolic disorders: genetic linkage.

Wide efforts have taken place with complex metabolic disorders to emulate the success that linkage analysis has had in explaining the nature of monogenic metabolic diseases such as MODY (maturity-onset diabetes of the young) and FH (familial hypercholesterolemia). New linkage methods are being specifically developed and tested for complex disorders since some of the basic assumptions of traditional linkage analysis used with Mendelian traits are not valid. The nature of complex diseases precludes the use of extended families under the hypothesis that the same disease allele acts in most affected individuals throughout a pedigree. Rather, a multitude of genes and of rare and common alleles creates an apparently chaotic pattern of heterogeneity within and between families. Therefore, very simple family structures, in many studies even isolated sibling pairs, form the basis of efforts to compare the inheritance of disease with that of the chromosomal regions under investigation. Also, assumptions about how individual loci contribute to the overall disease inheritance used for the models applied in linkage computation have to be kept to a minimum. The overall effect of this, together with the potentially weak influence of many loci, is a heavy toll on the statistical power to detect individual contributing genes. This may be the reason why very few scans so far have yielded disease loci that meet genome-wide significance criteria. The confirmation of original loci in secondary studies has proven, as predicted, to be very difficult. Nevertheless, the overall emerging picture is very encouraging: one of the genome scans in type 2 diabetes has been carried through to the positional cloning of the underlying genetic variant, namely, the calpain 10-associated polymorphism in type 2 diabetes. Several other loci have been detected repeatedly throughout studies in various human racial groups, such as the chromosome 1q and 20q diabetes loci, and have become the target of collaborative fine-mapping efforts. Modifications to present methodology are in development with the goal to increase statistical power: examples are the use of intermediate traits with potentially increased genetic homogeneity, the investigation of admixed populations, and the study of linkage disequilibrium over wide genomic regions.

Diabetes Mellitus, Type 2↗
PubMed2001

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

Chromosome Mapping↗
PubMed2001

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Alleles↗
PubMed2001

Transcriptional mechanism of protein kinase C-induced isoform-specific expression of the gene for endothelin-converting enzyme-1 in human endothelial cells.

Isoform-specific expression of endothelin-converting enzyme (ECE)-1, the major big endothelin-processing enzyme, is controlled by alternative promoters. Signaling pathways and transcriptional mechanisms of ECE-1 mRNA expression are largely unknown. To investigate ECE-1 isoform expression after protein kinase C (PKC) activation, we used phorbol 12-myristate 13-acetate (PMA) to stimulate primary cultured human umbilical vein endothelial cells and the related EA.hy926 cell line. ECE-1a mRNA was up-regulated (approximately 3-fold), whereas mRNA of alternative isoforms (b, c, and d) was unchanged, which was confirmed on the protein level. PMA effects on mRNA expression were suppressed by the PKC inhibitors H-7 and Calphostin C. Because increased ECE-1a expression was preceded by induction of the transcription factor Ets-1, we performed gel shift assays and demonstrated specific DNA/protein interactions involving the ETS binding motif GGAA. Luciferase reporter assays showed that PMA induced ECE-1a promoter activity about 2.5-fold in EA.hy926 cells. Similarly, coexpression of Ets-1 protein resulted in a dose-dependent increase in ECE-1a promoter activity (more than 8-fold). Using gel shift assays and mutation analysis, we identified two tandemly arranged Ets-1 binding sites (EBS) at -638 and -658, respectively, that are involved in transcriptional activation of the ECE-1a promoter by PMA or Ets-1. Moreover, we also found evidence for binding of a transcriptional repressor to EBS -638. The inhibitor of mitogen-activated protein kinase kinase, PD98059, inhibited PMA effects on ECE-1a mRNA expression and promoter activity, respectively. Our results provide the first detailed analysis of signaling pathways and transcriptional mechanisms involved in isoform-specific ECE-1 gene expression.

Antibodies↗
PubMed2000

Dual interaction of agmatine with the rat alpha(2D)-adrenoceptor: competitive antagonism and allosteric activation.

In segments of rat vena cava preincubated with [(3)H]-noradrenaline and superfused with physiological salt solution, the influence of agmatine on the electrically evoked [(3)H]-noradrenaline release, the EP(3) prostaglandin receptor-mediated and the alpha(2D)-adrenoceptor-mediated inhibition of evoked [(3)H]-noradrenaline release was investigated. Agmatine (0.1-10 microM) by itself was without effect on evoked [(3)H]-noradrenaline release. In the presence of 10 microM agmatine, the prostaglandin E(2)(PGE(2))-induced EP(3)-receptor-mediated inhibition of [(3)H]-noradrenaline release was not modified, whereas the alpha(2D)-adrenoceptor-mediated inhibition of [(3)H]-noradrenaline release induced by noradrenaline, moxonidine or clonidine was more pronounced than in the absence of agmatine. However, 1 mM agmatine antagonized the moxonidine-induced inhibition of [(3)H]-noradrenaline release. Agmatine concentration-dependently inhibited the binding of [(3)H]-clonidine and [(3)H]-rauwolscine to rat brain cortex membranes (K(i) values 6 microM and 12 microM, respectively). In addition, 30 and 100 microM agmatine increased the rate of association and decreased the rate of dissociation of [(3)H]-clonidine resulting in an increased affinity of the radioligand for the alpha(2D)-adrenoceptors. [(14)C]-agmatine labelled specific binding sites on rat brain cortex membranes. In competition experiments. [(14)C]-agmatine was inhibited from binding to its specific recognition sites by unlabelled agmatine, but not by rauwolscine and moxonidine. In conclusion, the present data indicate that agmatine both acts as an antagonist at the ligand recognition site of the alpha(2D)-adrenoceptor and enhances the effects of alpha(2)-adrenoceptor agonists probably by binding to an allosteric binding site of the alpha(2D)-adrenoceptor which seems to be labelled by [(14)C]-agmatine.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.

Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed1999

Imidazoline recognition sites and stomach function.

Radioligand binding experiments carried out in cell membranes from rat and human stomach revealed the existence of non-adrenoceptor [3H]clonidine and [3H]idazoxan binding sites and of [3H]DTG (1,2-di-(2-tolyl)guanidine) binding sites. In rat stomach, specific binding was inhibited by imidazolines and guanidines and by non-imidazoline sigma-site ligands, respectively, at different rank orders of affinity, suggesting the existence of non-I1/non-I2 [3H]clonidine binding sites, I2-imidazoline binding sites as well as sigma 2-like-sites. These sites are not directly related to a postsynaptic contractile effect on rat gastric smooth muscle or to acid release from isolated gastric glands. Finally, we demonstrated that the gastric pathogen Helicobacter pylori is able to form and to release the endogenous imidazoline receptor ligand agmatine and that considerable amounts of agmatine are present in human gastric juice. The quantities of agmatine were higher in gastric juice from H. pylori-positive than H. pylori-negative patients.

Animals↗
PubMed1999

Imidazoline derivatives and agmatine induce histamine release from the rat stomach.

Strips from rat glandular stomach were used to investigate whether the imidazoline derivatives clonidine, tolazoline and BDF 6143 (4-chloro-2(2-imidazolin-2-ylamino)-isoindoline) and the guanidine derivative agmatine are able to release histamine from histamine-storing cells. Histamine was detected and quantified by HPLC. Clonidine, tolazoline and agmatine concentration-dependently induced a release of histamine from the gastric strips, whereas BDF 6143 was ineffective. However, BDF 6143 abolished the release-inducing effect of clonidine and agmatine. It is concluded that imidazoline and guanidine derivatives can induce histamine release from histamine-storing cells in the stomach by a specific mechanism (possibly via imidazoline receptors) which in turn might lead to a relevant increase in gastric acid secretion.

Adrenergic alpha-Agonists↗
PubMed1998

A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene.

One form of maturity-onset diabetes of the young, Type 3 (MODY3), results from mutations in the gene coding for hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor first described in the liver. MODY3 is characterized by a defective glucose-stimulated insulin secretion. Earlier observations of glycosuria with normal blood glucose levels in some MODY families suggest an additional renal manifestation of the respective genetic defect. We measured the renal threshold for glucose in five diabetic carriers of a missense mutation (Arg 272 His) in HNF-1alpha and, for comparison, in eight Type 1 diabetic patients, applying a non-invasive protocol of frequent parallel blood and urine sampling during a slow shift in blood glucose levels. We found that the mean renal threshold for glucose was lowered in the HNF-1alpha diabetic patients compared to those with Type 1 diabetes (6.5 +/- 0.9 mmol l(-1) vs 10.7 +/- 0.5 mmol l(-1); p < 0.01). This lowered glucose threshold might be an indication of an extra-pancreatic effect of HNF-1alpha gene mutations in humans. Defects in HNF-1alpha may lead to an altered tubular glucose reabsorption, possibly due to decreased expression of the renal glucose transporter proteins involved in reabsorption of glucose from the urine.

Absorption↗
PubMed1998

[Granuloma eosinophilicum faciei--successful cryosurgery treatment of 6 patients].

Six patients with granuloma faciale, including patients with multiple lesions, were treated successfully with cryosurgery. Granuloma faciale is known to be difficult to treat. Cryosurgery is an effective and minimally invasive therapy for this granulomatous inflammation of the skin. It should be considered as an alternative to dapsone.

Adult↗