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Objective. Aberrant splicing is one of the most significant components generating functional diversity in many pathological conditions. The objective of this study was to analyse the mutations or aberrant splicing of A20 transcript, the region encompassing the ovarian tumour (OTU) domain [which is functionally important as an inhibitor of nuclear factor (NF)-κB activation] in fibroblast-like synoviocytes (FLSs) from RA patients.Methods. Alterations in A20 transcripts were determined through sequence analysis of 10 clones of A20 cDNA in FLSs from each of the five RA patients. The levels of aberrant A20 transcript were measured by quantitative real-time RT–PCR with primers to specifically recognize the inserted introns. The functional role of A20 and its aberrant variants were examined by analysing NF-κB luciferase reporter activity and NF-κB-dependent target gene expression.Results. In RA FLSs, we discovered four novel aberrant A20 transcripts, most of which resulted from insertion of partial intron 2, intron 4 and/or deletion of exon 4. In each of these FLSs, sequence analysis revealed that these aberrant insertional sequences were flanked by consensus splice donor and acceptor sequences without nucleotide substitution, suggesting alternative splicing as the likely mutational mechanism. These variants elicited a codon frame shift by creating a premature translational stop codon, and eventually, disruption of the OTU domain (which is functionally important as an inhibitor of NF-κB activation) of A20. The expression level of aberrant A20 transcript was correlated well with persisitently enhanced status of NF-κB signalling, as evident by the phosphorylation of inhibitor of NF-κB (IκB)-α and transcription of NF-κB target genes.Conclusion. The results suggest that A20 inactivation by the novel aberrant splicing may contribute to RA progression by inducing persistent NF-κB activation. [ABSTRACT FROM PUBLISHER]

Objective. NSAIDs are commonly prescribed to control gout attacks in patients with hyperuricaemia. We investigated risk factors for NSAID-induced acute kidney injury (AKI) in patients with hyperuricaemia.Methods. We identified 328 patients with hyperuricaemia treated with NSAIDs at Seoul National University Hospital between December 1998 and January 2008 to investigate risk factors for NSAID-induced AKI. The risk factors evaluated included age, sex, BMI, comorbidity, NSAID COX-2 selectivity, baseline glomerular filtration rate (GFR), serum uric acid, serum albumin, haemoglobin level, ratio of blood urea nitrogen and serum creatinine and the use of allopurinol. After extracting possible risk factors through univariate analysis, multivariate logistic regression analysis was performed with backward selection to derive a risk model for NSAID-induced AKI in patients with hyperuricaemia.Results. Thirty (9.1%) NSAID users developed AKI. Univariate analysis revealed that old age (P = 0.008), low GFR (P = 0.001), low serum albumin (P < 0.001) and low haemoglobin levels (P < 0.001) were possible risk factors. Multivariate logistic regression analysis showed that low baseline GFR [odds ratio (OR) 4.86, 95% CI 1.27, 18.55, P = 0.021, for GFR 15–29 vs &geq;60 ml/min/1.73 m2] and low serum albumin (OR 4.43, 95% CI 1.82, 10.80, P = 0.001, for albumin &leq;4 vs >4 g/dl) are risk factors for NSAID-induced AKI in patients with hyperuricaemia.Conclusion. Low GFR and low serum albumin are risk factors for AKI in hyperuricaemic patients treated with NSAIDs. Our results suggest that NSAIDs should be used with caution in patients with low serum albumin. [ABSTRACT FROM PUBLISHER]

Objective: To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study., Methods: A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population., Results: The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively., Conclusion: The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies.

Background/aims: Percutaneous ethanol injection therapy (PEIT) is widely used for the treatment of hepatocellular carcinoma (HCC). However, its long-term therapeutic efficacy is not verified in Korea, one of hepatitis B virus (HBV) endemic areas. Thus, this study was to assess its efficacy and prognostic factors affecting tumor-free survival following PEIT in Korean HCC patients., Methods: From 1997 to 1999, 100 consecutive patients who had 1 to 3 HCC nodules of maximum diameter less than 3 cm and underwent PEIT were enrolled. Therapeutic efficacy, overall and tumor-free survival rates were assessed during follow-up periods., Results: In 83 patients, HCC nodules were completely ablated by PEIT. The cumulative 1, 2, and 3 year overall survival rates were 98%, 96%, and 88%, respectively. The cumulative 1, 2, and 3 year tumor-free survival rates were 73%, 50%, and 37%, respectively. Larger tumors (>or= 2 cm) were associated with a higher local recurrence rate., Conclusions: These results demonstrate that PEIT is therapeutically useful in patients with HCC less than 4 in number and less than 3 cm in diameter. However, since multiple or large tumors are associated with low tumor-free survival or high local recurrence rates, PEIT for these tumors and the subsequent post-treatment follow-up should be performed carefully.