Background: In the Kii peninsula of Japan, high prevalences of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex have been reported. There are 2 major foci with a high prevalence, which include the southernmost region neighboring the Koza River (Kozagawa and Kushimoto towns in Wakayama prefecture) and the Hohara district (Mie prefecture). Objective: To delineate the molecular basis of ALS in the Kii peninsula of Japan, we analyzed hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene, which has recently been identified as a frequent cause of ALS and frontotemporal dementia in the white population. Design: Case series. Setting: University hospitals. Patients: Twenty-one patients (1 familial patient and 20 sporadic patients) with ALS from Wakayama prefecture, and 16 patients with ALS and 16 patients with parkinsonism-dementia complex originating from Mie prefecture surveyed in 1994 through 2011 were enrolled in the study. In addition, 40 probands with familial ALS and 217 sporadic patients with ALS recruited from other areas of Japan were also enrolled in this study. Main Outcome Measures: After screening by repeatprimed polymerase chain reaction, Southern blot hybridization analysis was performed to confirm the expanded alleles. Results: We identified 3 patients with ALS (20%) with the repeat expansion in 1 of the 2 disease foci. The proportion is significantly higher than those in other regions in Japan. Detailed haplotype analyses revealed an extended shared haplotype in the 3 patients with ALS, suggesting a founder effect. Conclusions: Our findings indicate that the repeat expansion partly accounts for the high prevalence of ALS in the Kii peninsula.
Accumulating evidence based on alpha-fetoprotein (AFP) cell binding and uptake has shown the presence of a receptor for AFP on the surface of fetal and neoplastic cells. In order to further study this receptor, monoclonal antibodies (MAbs) made against pooled human mammary tumor membrane extracts were screened for their ability to inhibit the binding of radiolabeled AFP to the Ichikawa and TA3/Ha malignant cell lines. IgM-producing clones 167H. 1 and 167H.4 were found to inhibit the binding of AFP to its receptor. Conversely, the MAb reaction was inhibited by an excess of AFP but not by serum albumin at an equal molar concentration. The possibility that these MAbs recognize AFP has been ruled out. In addition, we describe a method for the purification of the AFP receptor which yielded fractions reactive to both 167H.4 and AFP. The results obtained strongly suggest that 167H. 1 and 167H.4 are directed against the binding site for AFP on the AFP receptor. Using 167H.4 we found positive immunohistochemical staining in 6/6 human mammary tumor specimens whereas 3/3 benign mammary adenomas were negative. Immunostaining of fetal muscle with either 167H.4 or an anti-AFP antiserum yielded a similar staining pattern. The staining of live Ichikawa cells with 167H.4 showed a surface receptor distribution (capping) similar to the one described in previous reports using labeled AFP. The widespread expression of the AFP receptor observed previously is consistent with the results obtained using the MAbs described herein. The potential use of these MAbs for basic and clinical studies is discussed.
IntroductionHepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice.MethodsArthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4+ T cells stimulated with allogeneic spleen cells.ResultsThe intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4+ T cells stimulated with allogeneic spleen cells.ConclusionsThese results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4+ T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA.
IL-18 and IL-18R play roles in various kinds of function of ovary.
The findings of this study suggest that long (GT)n repeats in the HO-1 gene promoter are associated with a higher risk of malignant mesothelioma in the Japanese population.
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