5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.

The Arabidopsis gene ZIM encodes a putative transcription factor containing a novel GATA-type zinc-finger domain with a longer spacer between its two sets of conserved cysteine residues (C-X2-C-X20-C-X2-C). In Arabidopsis, ZIM and homologous proteins, ZML1 and ZML2, were identified as GATA factors containing the C-X2-C-X20-C-X2-C motif, a CCT domain, and an uncharacterized conserved domain. Proteins that possess this domain structure were found exclusively in plants, indicating that they belong to a novel family of plant-specific GATA-type transcription factors. When ZIM was overexpressed using a CaMV 35S promoter in Arabidopsis, hypocotyls and petioles were elongated. The elongation phenotype was observed under all wavelengths of light tested and even in the presence of biosynthetic inhibitors of either brassinosteroid or gibberellin. In ZIM-overexpressing plants, XTH33 which is predicted to function in cell wall modification was detected as an up-regulated gene by microarray analysis, and this could account for the elongation phenotype. Genes in ZIM-overexpressing plants were identified that were up-regulated in a tissue-specific manner, which suggests that transcriptional regulation by ZIM and its consequent effects are spatially controlled.

Objective. To evaluate whether matrix metalloproteinase 3 (MMP-3), a proteinase that is expressed in rheumatoid synovial tissue and shows potent activity in degrading the proteoglycan of cartilage, plays a pivotal role in the joint destruction seen in early rheumatoid arthritis (RA).Methods. In a prospective study of patients with early RA, the relationship between the serum concentration of MMP-3, as determined by a sandwich enzyme immunoassay system, and the progression of joint destruction in patients with early RA, as measured by the Larsen radiologic score, was investigated.Results. Serum MMP-3 levels were elevated in the RA patients compared with healthy controls, not only in the late stage, but also in the early stage of the disease in patients whose duration of RA was <4 months. The serum MMP-3 level at entry into the study had a strong correlation with the Larsen score at 6 months and 12 months after entry (r ‫؍‬ 0.58 and r ‫؍‬ 0.49, respectively). Similarly, the serum MMP-3 level at 12 months and 24 months after entry showed a positive association with the Larsen score in the subsequent 6-12 months. Suppression of the serum MMP-3 level in the first year led to a decline in joint damage in the second year.Conclusion. The serum concentration of MMP-3 is a useful marker for predicting bone damage in the early stage of RA, and the suppression of MMP-3 production may be an effective therapeutic approach for patients with early RA.

Objective. To develop and validate a self-administered instrument for measuring functional status in Japanese-speaking rheumatoid arthritis patients. Methods. We translated the Stanford Health Assessment Questionnaire (HAQ) into Japanese (original HAQ), and then made a tentative Japanese version of the HAQ (J-HAQ) with culturally appropriate modifications of the arising, eating, and reach category questions. The questionnaire was then administered to 3,763 RA patients (82.6% female; mean age 58.0 years; mean onset age 47.4 years; mean disease duration 10.5 years). Results. This instrument showed excellent internal reliability (Cronbach

Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a promising target for prevention of recurrence.