Seigo Takano

High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells.

Background. The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens. Methods. CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were also performed. Results. Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose of AT-III, all grafts survived indefinitely (>100 days) and regulatory cells were generated. In vitro, AT-III suppressed proliferation of mixed leukocyte responses and generation of interleukin-2. Conclusion. AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.

Abnormal nucleotide repeat sequence in the TGF-βRII gene in hepatocellular carcinoma and in uninvolved liver tissue

Replication error (RER)‐related genetic alterations are associated with a subset of hepatocellular carcinomas (HCCs) with multiple primary cancers. This study investigated whether mutations in the nucleotide repeats of three putative target genes of RER are associated with hepatocarcinogenesis. The genes examined were those encoding transforming growth factor β type II receptor (TGF‐βRII), BCL‐2‐associated X protein (BAX), and insulin‐like growth factor II receptor (IGF‐IIR). Tumour and non‐tumour hepatic tissues were examined in 48 HCC patients, 34 with solitary HCC and 14 who had double cancer with gastric cancer. Four double‐cancer cases showed an abnormal signal in the single nucleotide repeat (A)10 of the TGF‐βRII gene. These four were among the six RER‐positive cases in this series. The genotypes of the poly A tract of the TGF‐βRII gene in the liver tumour tissue of the four cases with an abnormal signal were (A)9/10, (A)9/10, (A)9/10, and (A)9/9. Five uninvolved liver tissue specimens from these four patients showed (A)9/10 and (A)9/9, (A)9/10, (A)10/10 and (A)9/9, respectively. The genotype in the stomach cancer specimens of these four patients was (A)10/10, indicating no germline mutation of the TGF‐βRII gene. There were no mutations in the nucleotide repeats of the BAX and IGF‐IIR genes in any of the liver tissue specimens. Abnormality of the nucleotide repeat in the TGF‐βRII gene occurred in the uninvolved liver tissue as well as the HCC tissue in some HCC patients. Such genetic instability may be gene‐specific and tissue‐specific in carcinogenesis. Copyright

Expression of type 1 plasminogen activator inhibitor and nitric oxide generation in ischemic preconditioning of rat liver.

AIMS: Nitric oxide (NO) has protective effects against ischemia-reperfusion (I/R) injury and plays an important role in ischemic preconditioning. Type 1 plasminogen activator inhibitor (PAI-1) regulates plasminogen activators, which may have cytotoxic effects in I/R injury. I/R injury is reduced by the inhibition of fibrinolytic enzymes. To clarify the mechanism of ischemic preconditioning, PAI-1 induction and NO generation were studied in hepatic ischemic preconditioning. METHODS: Total hepatic ischemia was achieved by Pringles maneuver. FK409 was used as an NO donor. Plasma alanine aminotransferase (ALT) and hyaluronic acid (HA) were measured to estimate hepatic damage and serum nitrite (NO(2)(-)) and nitrate (NO(3)(-)) were also determined to assess NO generation. Reserve transcription-polymerase chain reaction (RT-PCR) and in situ hybridization were carried out to determine the quantitative changes in the expression of PAI-1 mRNA. Plasma PAI-1 concentration was determined using an enzyme-linked immunosorbent assay (ELISA) system. RESULTS: No increase in ALT or HA was found with 5 min I/R. NO and PAI-1 in plasma and PAI-1 mRNA in liver were not increased in the ischemic period, but were increased during the reperfusion period. Infusion of FK409 stimulated induction of PAI-1 mRNA dose dependently. In situ hybridization studies indicated that hepatocytes expressed PAI-1 mRNA after I/R treatment. CONCLUSIONS: I/R increased the concentration of plasma PAI-1. Reperfusion following ischemia was needed for the induction of PAI-1 mRNA and increase of plasma NO concentration. FK409 stimulated PAI-1 mRNA induction in the liver. These results indicate that PAI-1 is a component of the ischemic preconditioning mechanisms, which is stimulated by NO generation.

Radical surgery for Budd-Chiari syndrome. Direct Excision and repair for obstruction of the Vena Cava (Budd-Chiari syndrome) under hepatic vascular exclusion using a centrifugal pump

OBJECTIVE To attempt to reduce the incidence of hepatic and cardiac failure after radical surgery for the Budd-Chiari syndrome. DESIGN Retrospective case study. SETTING University hospital, Japan SUBJECTS Three patients with obstruction of the vena cava (Budd-Chiari syndrome) by a thick membrane, thrombus, and a long stenosis, respectively. INTERVENTION Direct excision and repair by patch dilatation under hepatic vascular exclusion using a Biomedicus centrifugal pump. RESULTS Hepatic vascular exclusion provides good visibility and enables accurate assessment of the obstruction, proper treatment, and relatively little blood loss. There were no complications, particularly liver failure or heart failure, and the inferior vena cava stayed patent in all cases. Liver function was improved in all three patients. CONCLUSION This technique is safe and reliable for removal of obstruction of the inferior vena cava (Budd-Chiari syndrome).