Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations.

AIMS/HYPOTHESIS: Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case-control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. METHODS: Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case-control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. RESULTS: In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75-0.96, p=0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82-0.93, p=4.5 x 10(-5)). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86-0.92; p=4.9 x 10(-11)). CONCLUSIONS/INTERPRETATION: In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes.

Canine leucocyte adhesion deficiency in Irish red and white setters.

Seventy-six Irish red and white setter samples were tested for the recently documented CD18 point mutation which manifests as canine leucocyte adhesion deficiency (CLAD) in Irish setters. Six carrier dogs were identified, all originating from a lineage within which sporadic deaths from symptoms consistent with CLAD had been observed. This is the first demonstration that the CLAD mutation exists outside the Irish setter population, confirming that the mutation is present in a significant minority of Irish red and white setters. Routine testing by breeders to identify carrier animals will enable the eradication of CLAD from the Irish red and white setter population.

Multivalency effects in protein--carbohydrate interaction: the binding of the Shiga-like toxin 1 binding subunit to multivalent C-linked glycopeptides.

A series of monovalent and bivalent glycopeptides displaying a C-linked analogue of the Pk trisaccharide, the in vivo ligand for the pentavalent Shiga-like toxin binding subunit (SLT-1B), were prepared and evaluated as ligands for SLT-1B by isothermal titration microcalorimetry and competitive enzyme-linked immunosorbent assay (ELISA). Although none of the monovalent ligands showed any enhancement in affinity compared to O-methyl glycoside, two bivalent ligands show significant enhancements in affinity in assays. This observation represents the first calorimetric observation of an enhancement in affinity for this system. In contrast, only one of the two ligands shows an enhancement in the competitive ELISA. Together, these data signal a difference in the means by which the two ligands achieve affinity, apparently triggered by a change in the nature of the linker domain. These results provide a rationalization for apparently contradictory reports from the recent literature and again emphasize the importance of investigating complex binding phenomena by multiple techniques.

N-Tetrachlorophthaloyl (TCP) for ready protection/deprotection of amino sugar glycosides.

The tetrachlorophthaloyl (TCP) group can be utilized when imidic protection of an amine is desired and durability of the protecting group to conditions ranging from mildly basic to harshly acidic is required. Installation can be accomplished in two steps by treating the free base with the commercially available TCP anhydride, and then closing the imidic ring with acetic anhydride and pyridine. Cleavage is effected by 2-4 eq of ethylenediamine under very mild conditions under which esters and glycopeptides have been shown to be stable, and racemization of amino acid residues does not occur. Unsubstituted phthalimides, even within the same molecule, are also unaffected during TCP cleavage. TCP protecting groups serve as beta-directors on donors and can also be present on acceptor species during electrophilic couplings in oligosaccharide synthesis.

Effects of two antihistamine drugs on actual driving performance.

A double blind placebo controlled experiment was conducted measuring the effects of the centrally active antihistamine triprolidine and the peripherally acting antihistamine terfenadine on actual driving performance in a group of experienced women drivers. Triprolidine greatly impaired driving behaviour, whereas terfenadine did not. Triprolidine also impaired subjective and objective measures of mood and arousal, and despite an awareness that their driving was impaired while they were taking this agent subjects could not correct their performance. This study suggests that drivers who need antihistamine drugs should avoid those that act centrally.