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- Almgren, Malin
(författare)
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Neural growth : with special emphasis on adult neurogenesis and the effect of antiepileptic drugs
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neurons were for a long time thought to not renew themselves. In the 1960ies the phenomenon of neurogenesis was discovered, but it was not until 1998 that neurogenesis was demonstrated in humans. In this thesis neurogenesis was studied using a unique genetic mouse model (mceph/mceph), with postnatal epilepsy and excessive brain growth, due to a truncated Kv1.1 subunit. The model was used to learn more about how a channelopathy can disturb hippocampal neurogenesis, leading to hyperplasia, and how this can be treated. First, the expression and trafficking of the truncated potassium ion channel Kv1.1 was described to reveal its molecular nature. It was shown that the defective Kv1.1 does not form functional channels and moreover has the potential to render other potassium channel subunits non-functional. Even though lack of Kv1.1 is enough for excessive hippocampal growth, the defect Kv1.1 peptide worsens the epileptic condition by blocking additional Kv1 subunits. Cells have previously been shown to be enlarged in the hippocampus of this mouse. In this thesis a doubling in number of neurons and astrocytes was demonstrated by stereology. The increase in number of neurons was due to increased neurogenesis and altered apoptosis. To identify transcripts involved in the overgrowth of the mceph/mceph hippocampus a genome-wide screen for transcripts expressed at different levels in mceph/mceph versus wild type was performed. The following genes, involved in regulation of cell number, were verified as differentially regulated in mceph/mceph; NPY, Penk, Fjx1 and Vgf. Previously it was shown that oral treatment with the antiepileptic drug CBZ protect mceph/mceph mice from developing enlarged hippocampus. This thesis shows that all hippocampal regions studied were protected from overgrowth and that the number of both neurons and astrocytes were normalized despite ongoing severe seizures. Transcripts potentially involved in the protection against the hippocampal overgrowth and hyperplasia were identified based on different expression levels in a microarray analysis. Verified genes include Mlc1, Sstr4, ApoD, Ndn, Aatk and Rgs2. These transcripts have a proposed function in proliferation, differentiation and/or apoptosis. Finally, an analysis of the effect of AEDs in utero, with focus on the head size of the newborn, was conducted on a large population-based Swedish cohort. This study revealed that the use of CBZ and VPA is increasing despite reports of malformations and growth retardations of the baby. Furthermore, CBZ and VPA monotherapy significantly reduced the head circumference (HC) and AED polytherapy increase the rate of small HC (> 2 SD). The implications of a smaller head on the development of the child is uncertain but should be explored. CBZ mono ] and polytherapy significantly reduced gestational age (GA) and there was a tendency for clonazepam and gabapentin monotherapy to reduce GA. The relevance of the reduced pregnancy duration is not clear but indicates a need for further studies in order to optimize treatment regimes for epileptic pregnant women.
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- Almgren, Malin, et al.
(författare)
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Population-based study of antiepileptic drug exposure in utero-Influence on head circumference in newborns
- 2009
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Ingår i: Seizure. - : Elsevier BV. - 1532-2688 .- 1059-1311. ; 18:10, s. 672-675
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study the effect of AED exposure on head circumference in the newborn. Methods: Data on all Swedish singletons births between 1995 and 2005, over 900,000 births, were obtained from the Swedish Medical Birth Registry. The effects of AEDs on birth-weight-adjusted mean head circumference (bw-adj-HC) were estimated by comparison with data from all births in an analysis which was adjusted for year of birth, maternal age, parity, maternal smoking, and maternal body mass index. Results: A significant reduction of mean bw-adj-HC was seen after both carbamazepine (CBZ) (standard deviation scores (SDS) = 0.15, p < 0.001) and valproic acid (VPA) (SDS = 0.10, p = 0.04) in monotherapy. No effect on mean bw-adj-HC was seen for phenytoin, clonazepam, lamotrigine and gabapentin. There was a significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 SD below the mean) after any AED polytherapy (OR = 2.85, 95% CI: 1.74-4.78) but not after AED monotherapy or monotherapy with CBZ or VPA. CBZ OF VPA was taken by 71% of the pregnant mothers on AED, and the usage increased over time. Conclusions: CBZ and VPA in monotherapy during pregnancy reduce mean bw-adj-HC. AED polytherapy increases the rate of microcephaly but no significant effect is seen of AED monotherapy. The possible significance for the further development of the child is uncertain but should be explored. (C) 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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