Islet transplantation using donors after cardiac death: report of the Japan Islet Transplantation Registry.

BACKGROUND: This report summarizes outcomes of islet transplantation employing donors after cardiac death (DCD) between 2004 and 2007 as reported to the Japan Islet Transplantation Registry. METHOD: Sixty-five islet isolations were performed for 34 transplantations in 18 patients with insulin-dependent diabetes mellitus, including two patients who had prior kidney transplantation. All but one donor (64/65) was DCD at the time of harvesting. RESULTS: Factors influencing criteria for islet release included duration of low blood pressure of the donor, cold ischemic time, and usage of Kyoto solution for preservation. Multivariate analysis selected usage of Kyoto solution as most important. Of the 18 recipients, 8, 4, and 6 recipients received 1, 2, and 3 islet infusions, respectively. Overall graft survival defined as C-peptide level more than or equal to 0.3 ng/mL was 76.5%, 47.1%, and 33.6% at 1, 2, and 3 years, respectively, whereas corresponding graft survival after multiple transplantations was 100%, 80.0%, and 57.1%, respectively. All recipients remained free of severe hypoglycemia while three achieved insulin independence for 14, 79, and 215 days. HbA1c levels and requirement of exogenous insulin were significantly improved in all patients. CONCLUSION: Islet transplantation employing DCD can ameliorate severe hypoglycemic episodes, significantly improve HbA1c levels, sustain significant levels of C-peptide, and achieve insulin independence after multiple transplantations. Thus, DCD can be an important resource for islet transplantation if used under strict releasing criteria and in multiple transplantations, particularly in countries where heart-beating donors are not readily available.

Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population.

The MUTYH gene encodes a DNA glycosylase that can initiate the base excision repair pathway and prevent G:C > T:A transversion by excising adenine mispaired with 8-hydroxyguanine. Biallelic germline mutations of MUTYH have been shown to predict familial and sporadic multiple colorectal adenomas and carcinomas, however, whether there is an association between single nucleotide polymorphisms (SNPs) of MUTYH and sporadic colorectal cancer (CRC) risk has remained unclear. In this study we investigated four MUTYH SNPs, IVS1+11C > T, IVS6+35G > A, IVS10-2A > G, and 972G > C (Gln324His), for an association with increased CRC risk in a population-based series of 685 CRC patients and 778 control subjects from Kyushu, Japan. A statistically significant association was demonstrated between IVS1+11T and increased CRC risk (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.012-2.030; P = 0.042) and one of the five haplotypes based on the four SNPs, the IVS1+11T - IVS6+35G - IVS10-2A - 972C (TGAC) haplotype containing IVS1+11T, was demonstrated to be associated with increased CRC risk (OR, 1.43; 95% CI, 1.005-2.029; P = 0.046). Subsite-specific analysis showed that the TGAC haplotype was statistically significantly (P = 0.013) associated with an increased risk of distal colon, but not proximal colon or rectal cancer. Furthermore, IVS1+11C > T was found to be in complete linkage disequilibrium with -280G > A and 1389G > C (Thr463Thr). The results indicated that Japanese individuals with - 280A/IVS1+11T/1389C genotypes or the TGAC haplotype are susceptible to CRC.

Effects of cyclosporin A on the activation of natural killer T cells induced by alpha-galactosylceramide.

BACKGROUND: Natural killer T (NKT) cells play crucial roles in preventing autoimmune diseases and inducing transplantation tolerance. We investigated whether cyclosporin A (CsA), which is generally used in clinical transplantation and autoimmune disease therapy, could modulate the NKT cell activation induced by alpha-galactosylceramide (alpha-GalCer) treatment. METHODS: C57BL/6 (B6) mice were given daily intraperitoneal injections of CsA (30 or 50 mg/kg) from day -1 and injected intravenously with alpha-GalCer (2 mug/mouse) on day 0. The kinetics of NK1.1CD3 or NK1.1Thy1.2 cells in the liver and spleen were analyzed by flow cytometry. Apoptosis of NK1.1CD3 cells, cytokine levels (interleukin [IL]-2, IL-4, IL-10 and interferon [IFN]-gamma) in the recipient serum and changes in dendritic cell activation in the spleen were analyzed. RESULTS: In B6 mice treated with alpha-GalCer, NK1.1CD3 cells rapidly decreased in both the liver and spleen, and repopulated to their normal levels by day four, while NK1.1Thy1.2 cells rapidly decreased, expanded by day four and reduced to their normal level by day 15. When B6 mice were treated with alpha-GalCer plus 30 or 50 mg/kg CsA, NK1.1CD3 or NK1.1 Thy1.2cells were similarly decreased and then expanded via extensive proliferation by day seven or four, respectively. When B6 mice were treated with alpha-GalCer, substantial amounts of IL-2, IL-4 and IFN-gamma were produced, and the surface markers of dendritic cells were upregulated. However, these cytokine productions and maturation of dendritic cells were profoundly suppressed after treatment with alpha-GalCer and CsA. Apoptosis of NK1.1CD3 cells was not affected in mice treated with alpha-GalCer or alpha-GalCer and CsA. CONCLUSIONS: CsA suppresses alpha-GalCer-induced cytokine productions and dendritic cell maturation of mouse NKT cells but does not decrease NK1.1CD3 cells on day one. The modulation of NKT-mediated immunoregulatory functions by CsA requires careful consideration in clinical transplantation and autoimmune disease therapy.

Genetic polymorphism in cytochrome P450 7A1 and risk of colorectal cancer: the Fukuoka Colorectal Cancer Study.

Bile acids have long been implicated in the etiology of colorectal cancer, but epidemiologic evidence remains elusive. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acids from cholesterol in the liver, and thus may be an important determinant of bile acid production. We examined the association between the CYP7A1 A-203C polymorphism and colorectal cancer. The CYP7A1 A-203C polymorphism was determined by the PCR-RFLP method in 685 incident cases of colorectal cancer and 778 controls randomly selected from a community in the Fukuoka area, Japan. The CC genotype was slightly less frequent in the case group, and the adjusted odds ratio for the CC versus AA genotype was 0.88 (95% confidence interval, 0.65-1.20). In the analysis by subsite of the colorectum, a decreased risk associated with the CYP7A1 CC genotype was observed for proximal colon cancer, but not for either distal colon or rectal cancer. The adjusted odds ratios (95% confidence intervals) of proximal colon cancer for the CC genotype were 0.63 (0.36-1.10) compared with the AA genotype, and 0.59 (0.37-0.96) compared with the AA and AC genotypes combined. A decreased risk of proximal colon cancer in relation to the CC genotype of CYP7A1 A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis.