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Leiden, Netherlands

Spijker A.T.,PsyQ The Hague | Giltay E.J.,Leiden University | van Rossum E.F.C.,Erasmus Medical Center | Manenschijn L.,Erasmus Medical Center | And 4 more authors.
Psychoneuroendocrinology | Year: 2011

Introduction: The hypothalamus-pituitary-adrenal (HPA)-axis is often found to be dysregulated in bipolar disorder (BD) while stress and changes in day-night rhythms can trigger a new mood episode. Genetic variants of the glucocorticoid receptor (GR)- and mineralocorticoid receptor (MR)-gene influence both the reactivity of the stress-response and associate with changes in mood. In this study we tested the hypothesis that these polymorphisms associate with different clinical characteristics of BD. Methods: We studied 326 outpatients with BD and performed GR genotyping of the TthIIII, ER22/23EK, N363S, BclI, and 9β polymorphisms, as well as MR genotyping of the 2G/C and I180V variants. All patients were interviewed for clinical characteristics. Results: Seasonal patterns of hypomania are related to the BclI haplotype and the T. thIIII. +. 9β haplotype of the GR gene (respectively, crude p= .007 and crude p= .005). Carriers of the ER22/23EK polymorphism had an almost 8 years earlier onset of their first (hypo)manic episode than non-carriers (crude p= .004, after adjustment p= .016). No evidence for a role of the MR in modifying clinical manifestations was found. Conclusion: Polymorphisms of the GR-gene are factors which influence some clinical manifestations of BD, with respect to seasonal pattern of (hypo)mania and age of onset. © 2011 Elsevier Ltd. Source

Van Der Linden W.A.,Gorlaeus Laboratories | Willems L.I.,Gorlaeus Laboratories | Shabaneh T.B.,Norris Cotton Cancer Center | Li N.,Gorlaeus Laboratories | And 6 more authors.
Organic and Biomolecular Chemistry | Year: 2012

Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are β5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent β1 selective compound active in living cells reported to date. Source

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