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- Abdel-Halim, SM, et al.
(författare)
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Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes
- 1998
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 47:3, s. 498-504
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Tidskriftsartikel (refereegranskat)abstract
- Glucose-induced insulin release is decreased in the spontaneously diabetic GK rat, a nonobese rodent model of type 2 diabetes. Forskolin restores the impaired insulin release in both the isolated perfused pancreas and isolated islets from these rats (Abdel-Halim et al., Diabetes 45:934-940, 1996). We demonstrate here that the insulinotropic effect of forskolin in the GK rat is due to increased generation of cAMP and that it is associated with overexpression of adenylyl cyclase (AC)-III mRNA and gene mutations. The AC-III mRNA overexpression was demonstrated by in situ hybridization using oligonucleotide probes binding to different regions of the rat AC-III mRNA. It was associated with the presence of two point mutations identified at positions -28 bp (A --> G) and -358 bp (A --> C) of the promoter region of the AC-III gene and was demonstrable in both GK rat islets and peripheral blood cells. Transfection of COS cells with a luciferase reporter gene system revealed up to 25-fold increased promoter activity of GK AC-III promoter when compared with normal rat promoter (P < 0.0001). In conclusion, forskolin restores the impaired insulin release in islets of the GK rat through enhanced cAMP generation. This is linked to overexpression of AC-III mRNA in GK islets due to two functional point mutations in the promoter region of the AC-III gene.
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- Fogdell, A, et al.
(författare)
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Linkage analysis of HLA class II genes in Swedish multiplex families with multiple sclerosis
- 1997
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 48:3, s. 758-762
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Tidskriftsartikel (refereegranskat)abstract
- Article abstract-We assessed the influence of human leukocyte antigen (HLA) class II as susceptibility genes in multiple sclerosis (MS) by linkage analysis. Other research groups, who have shown negative results in studies on affected sibling pairs, have questioned the influence of the HLA class II genes, although they confirmed the association of the DR15,DQ6,Dw2 haplotype to MS. In this report, we find a significant lod score (>3) when using a 2-point linkage analysis of 49 small Swedish nuclear MS families with at least two affected family members, typed for HLA class II alleles by PCR amplification with sequence-specific primers. We obtained maximum lod scores when we used dominant or intermediate models with low penetrance. We found that the positive effect on the total lod score was not confined to those families carrying the presumed susceptibility HLA-haplotype Dw2. This observation supports the notion of a functional role of the HLA class II molecules themselves in MS. In addition, we observed significant transmission distortion and an intrafamilial association of the MS-associated class II haplotype HLA-Dw2. These results indicate that the HLA class II genes are of clear importance for MS in the studied population.NEUROLOGY 1997;48: 758-762
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- Söderström, M, et al.
(författare)
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Expression of IFN-gamma, IL-4, and TGF-beta in multiple sclerosis in relation to HLA-Dw2 phenotype and stage of disease
- 1995
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 1:3, s. 173-80
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is associated with upregulation of both proinflammatory (interferonγ, IFNγ) and immunosuppressive (transforming growth factorβ, TGFβ) cytokines. To examine a possible relation between the MS-related HLA haplotype Dw2 and cytokine prof iles, we used in situ hybridization with labeled cDNA oligonucleotide probes to detect transcripts of the T helper type I (ThI) cell related IFNγ, the Th2 cell related interleukin-4 (IL-4) and of TGFβ in blood and cerebrospinal fluid (CSF) mononuclear cells from 62 patients with MS. Compared to patients with other neurological diseases and healthy controls, MS patients had elevated numbers of IFNγ, IL-4 and TGFβ mRNA expressing cells in blood and further augmented in CSF. Although several HLA-Dw2-positive individuals showed very high numbers of cells expressing these cytokines, no significant difference was found in comparison with Dw2-negative patients. However, expression of IL-4 and TGFβ mRNA was significantly increased in patients with shorter duration and minor disability and, for IL-4, in patients still in the relapsing-remitting phase compared to patients with secondary chronic progressive MS. Surprisingly, these changes which favour a beneficial, disease-downregulating effect of IL-4 and TGFβ in MS, were found to be confined to HLA-Dw2-positive patients. Our findings suggest that the HLA phenotype does not influence the overall level of immune reactivity in MS, but may distinguish subgroups characterized by particular cytokine expression patterns.
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