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Biomedical subjects

M Kiviniemi

Publications and source records attributed to M Kiviniemi.

5 recordsLinked to original sources
PubMed2006

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes.

AIMS/HYPOTHESIS: We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cell-specific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset. SUBJECTS AND METHODS: A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n = 574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case-control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms. RESULTS: The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio = 4.6, 95% CI 2.4-9.0; p = 0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5-11.6; and 1.6, 95% CI 1.1-2.4, respectively; p = 0.003). The strong effect of PTPN22 on disease susceptibility (p = 2.1 x 10(-8)) was more pronounced in males (p = 0.021) and in subjects with non-DR4-DQ8/low-risk HLA genotypes (p = 0.0004). CONCLUSIONS/INTERPRETATION: In the pathogenesis of type 1 diabetes the underlying mechanism of the PTPN22 C1858T polymorphism appears to involve regulation of insulin-specific autoimmunity. Importantly, it strongly affects progression from prediabetes to clinical disease.

Adolescent↗
PubMed2001

High-throughput genetic analysis using time-resolved fluorometry and closed-tube detection.

Robust methods for genetic analysis are required for efficient exploitation of the constantly accumulating genetic information. We describe a closed-tube genotyping method suitable for high-throughput screening of genetic markers. The method is based on allele-specific probes labeled with an environment-sensitive lanthanide chelate, the fluorescence intensity of which is significantly increased upon PCR amplification of a complementary target. Genomic DNA samples were analyzed in an insulin gene single nucleotide polymorphism (SNP) assay using universal amplification primers and probes that recognized the two different alleles. The feasibility of dry reagent based all-in-one PCR assays was tested using another diabetes-related genetic marker, human leukocyte antigen DQB1 allele *0302 as a model analyte in a dual-color, closed-tube end-point assay. There was a 100% correlation between the novel SNP assay and a conventional PCR restriction fragment length polymorphism assay. It was also demonstrated that using real-time monitoring, accurate genotyping results can be obtained despite strongly cross-reacting probes, minimizing the time and effort needed for optimization of probe sequence. Throughput can be maximized by using predried PCR mixtures that are stable for at least 6 months. This homogenous, all-in-one dry reagent assay chemistry permits cost-effective genetic screening on a large scale.

Alleles↗
PubMed2000

Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty.

Blood vessels are among the easiest targets for gene therapy. However, no data are available about the safety and feasibility of intracoronary gene transfer in humans. We studied the safety and efficacy of catheter-mediated vascular endothelial growth factor (VEGF) plasmid/liposome (P/L) gene transfer in human coronary arteries after percutaneous translumenal coronary angioplasty (PTCA) in a randomized, double-blinded, placebo-controlled study. The optimized angioplasty/gene delivery method was previously shown to lead to detectable VEGF gene expression in human peripheral arteries as analyzed from amputated leg samples. Gene transfer to coronary arteries was done with a perfusion-infusion catheter, using 1000 microg of VEGF or beta-galactosidase plasmid complexed with 1000 microl of DOTMA:DOPE liposomes. Ten patients received VEGF P/L, three patients received beta-galactosidase P/L, and two patients received Ringer lactate. Gene transfer to coronary arteries was feasible and well tolerated. Except for a slight increase in serum C-reative protein in all study groups, no adverse effects or abnormalities in laboratory parameters were detected. No VEGF plasmid or recombinant VEGF protein was present in the systemic circulation after the gene transfer. In control angiography 6 months later, no differences were detected in the degree of coronary stenosis between treatment and control groups. We conclude that catheter-mediated intracoronary gene transfer performed after angioplasty is safe and well tolerated and potentially applicable for the prevention of restenosis and myocardial ischemia.

Adult↗
PubMed2000

Cell cycle regulators p27 and pRb in lymphomas - correlation with histology and proliferative activity.

The cell cycle is a complex event in which multiple regulator-proteins participate. The G(1)/S checkpoint of the cell cycle is controlled by pRb protein, which functions in its hypophosphorylated form as a negative regulator of growth. p27 (Kip1), a member of CIP/KIP family of cyclin inhibitory proteins, participates in inhibition of forming complexes that allow pRb to phosphorylate and lead the cell into mitosis. The expression of these important cell cycle regulator proteins was studied in a total of 96 non-Hodgkin's lymphoma (NHL) samples, which were classified according to the REAL classification. The expression of p27, pRb and the cell proliferation marker Ki-67 (MIB-1) was evaluated in lymphomas using immunohistochemistry. This study showed that there were coordinate changes in the expression of p27 and pRb in NHL. When compared to low-grade lymphomas, high-grade lymphomas showed significantly reduced expression of p27 and inversely pRb expression was increased (P< 0.001). Increase in expression of Ki-67 was parallel with pRb expression, and was mainly seen in cells that lacked p27 expression (P< 0.0001). This study suggests that changes in the control of the cell cycle closely relate to the pathobiology of NHL.

Adolescent↗