Biomedical subjects

M Makuuchi

Publications and source records attributed to M Makuuchi.

At least 109 records · Page 6Linked to original sources

PubMed2000

Altered p21(WAF1/CIP1) expression is associated with poor prognosis in extrahepatic bile duct carcinoma.

This study was designed to determine the clinical implications of p21(WAF1/CIP1) expression and the relationship between p21(WAF1/CIP1) expression and p53 status in extrahepatic bile duct carcinoma (EBDC). Low p21(WAF1/CIP1) expression was immunohistochemically detected in 23 (67.6%) of 34 EBDCs, moderate in six (17.7%), and high in five (14.7%). Kaplan-Meier curves showed that low and high p21(WAF1/CIP1) expressions were significantly associated with shortened disease-free survival (low vs. moderate, P=0.02; high vs. moderate, P=0.01). There was no correlation between p21(WAF1/CIP1) and p53 expression. These findings suggest that altered p21(WAF1/CIP1) expression exerts an adverse influence on the prognosis of EBDC.

Adenocarcinoma↗

PubMed2000

Loss of p16(INK4) protein, alone and together with loss of retinoblastoma protein, correlate with hepatocellular carcinoma progression.

To investigate the role of p16(INK4) protein absence in hepatocellular carcinoma progression, we examined p16(INK4) expression immunohistochemically in 81 primary and 23 metastatic lesions of hepatocellular carcinoma, in which retinoblastoma protein status had been determined. p16(INK4) protein was absent from 44% of the total of 104 tumors. The rate of p16(INK4) absence was twice as high in metastatic lesions (74%) compared with primary lesions (36%) (P=0.001). Loss of p16(INK4) and/or retinoblastoma protein was significantly associated with decreased tumor differentiation, vascular invasion and metastasis. In conclusion, p16(INK4) protein absence, alone and together with loss of retinoblastoma protein, contributes to hepatocellular carcinoma progression.

Carcinoma, Hepatocellular↗

PubMed2000

The significance of hepatitis B virus DNA detected in hepatocellular carcinoma of patients with hepatitis C.

BACKGROUND: Recently, it has been reported that hepatitis B virus (HBV) DNA is detected in cancerous liver tissues in some hepatitis B surface antigen negative chronic hepatitis C patients with hepatocellular carcinoma (HCC). However, the significance of HBV DNA detected in such cases remains unclear. METHODS: The authors determined the presence or absence and the titers of HBV DNA in the liver tissue of anti-hepatitis C virus (HCV) positive/HBs antigen negative patients with HCC by polymerase chain reaction (PCR) and Southern hybridization, and correlated them with clinicopathologic parameters. RESULTS: HBV DNA was found in cancerous liver tissues from 12 (50.0%) of the 24 patients studied. However, Southern hybridization of genomic DNA in the cancerous liver tissues led to detection of HBV DNA in only 3 (12.5%) of the 24 patients, suggesting that the copy number of HBV DNA may be very low in most cases. Indeed, the titration of HBV DNA in cancerous liver tissues performed by the end point dilution method revealed that most contained less than one copy of HBV DNA per cell, although cells of monoclonal origin carrying integrated HBV DNA should have at least one copy of it. There was no significant difference in HBV DNA positivity between the HCC patients with and without underlying cirrhosis. CONCLUSIONS: The results of this study corroborate previous reports of frequent detection of HBV DNA in the liver tissue of anti-HCV positive/HBs antigen negative patients with HCC, but do not support an essential role of HBV in hepatocarcinogenesis in patients with chronic hepatitis C and occult HBV infection.

Aged↗

PubMed2000

Virologic analysis of non-B, non-C hepatocellular carcinoma in Japan: frequent involvement of hepatitis B virus.

Serum and liver tissues from hepatitis B surface antigen-negative/anti-hepatitis C virus (HCV)-negative (non-B, non-C) hepatocellular carcinoma (HCC) patients in Japan were examined for the presence of hepatitis B virus (HBV), HCV, and TT virus (TTV) by polymerase chain reaction. The studies evaluated the contribution of these viruses to pathogenesis of HCC. HBV DNA was detected in the sera of 20 (47.6%) of 42 non-B, non-C HCC patients, which was significantly higher than in age-matched controls without liver disease (P<.001). In 8 of 12 patients with liver tissues available, HBV DNA was detected in cancerous and adjacent noncancerous liver tissues. No HCV RNA was detected. The positivity for TTV DNA was not significantly different between HCC patients and controls. These results indicate that HBV is associated with a substantial proportion of non-B, non-C HCC cases in Japan. The role of HBV in hepatocarcinogenesis in such patients needs to be clarified.

Adult↗

PubMed2000

Chronic inhibitory effect of insulin on plasma lipid concentrations in rats with transplanted pancreas.

BACKGROUND: Hyperinsulinemia, which is usually related to insulin resistance, is considered to be an important risk factor for coronary artery disease. Our study examines the influence of portal delivery of endogenous insulin after pancreas transplantation on plasma lipid metabolism, as compared with systemic delivery of insulin. METHOD: Pancreas was transplanted heterotopically in normal rats by anastomosis of the donor portal vein to the recipient portal vein (PPTx) or inferior vena cava (CPTx) as an in vivo model of endogenous hyperinsulinemia. RESULTS: The mean value of plasma insulin concentration of CPTx and PPTx rats was 149 and 165% that of control rats, whereas the plasma glucose concentration of CPTx and PPTx rats did not differ significantly from that of control rats. Plasma triglyceride (TG) concentrations were significantly lower in both PPTx and CPTx rats than control rats. During the intravenous glucose tolerance test, the area under the insulin concentration curves of CPTx and PPTx rats was 204 and 215% that of control rats, and they were correlated negatively with plasma TG concentrations. Plasma cholesterol and TG concentrations were significantly lower in PPTx rats than in control and CPTx rats. CONCLUSIONS: Chronic hyperinsulinemia has a dose-dependent inhibitory effect on the regulation of plasma TG concentrations in rats with a transplanted pancreas. Significant lower lipid levels in PPTx rats than in CPTx rats suggest that portal delivery of insulin from the transplanted pancreas is relatively preventive for the atherosclerotic process as compared with systemic delivery of insulin.

Anastomosis, Surgical↗

PubMed2000

Peri-operative blood lactate levels in recipients of living-related liver transplantation.

BACKGROUND: The role of changes in peri-operative blood lactate levels in recipients of living-related liver transplants has not yet been clarified. METHODS: Forty-three recipients were included in this study. Blood lactate, plasma total bilirubin, aminotransferase, body temperature, and gastric mucosal PCO2 levels were measured at six time points during surgery: just before the initiation of surgery, just after dissection of the hepatic vasculature, at the end of the anhepatic phase, and 30, 60, and 120 min after reperfusion. We calculated the rate of lactate accumulation during the pre-anhepatic and anhepatic phases and the elimination rate during reperfusion (neohepatic phase), and examined the correlation between these results and the clinical findings. RESULTS: The rate of lactate elimination during the neohepatic phase was correlated with the ratio of graft weight to standard liver volume (P<0.0001). There was also a significant correlation between the rate of lactate accumulation during the pre-anhepatic phase and the preoperative total bilirubin levels (P=0.0008). CONCLUSIONS: Each pre-anhepatic, anhepatic, and neohepatic phase had a characteristic blood lactate profile. The graft size strongly affected lactate levels during the early neohepatic phase.

Adult↗

PubMed2000

Methioninase gene therapy of human cancer cells is synergistic with recombinant methioninase treatment.

Results obtained over the past 40 years have demonstrated that tumor cells of all types tested have an elevated growth requirement for methioninase compared with normal cells. Recombinant methioninase (rMETase) cloned from Pseudomonas putida has been found previously to be an effective antitumor agent attributable to deprivation of the extracellular methionine source of the tumor. To degrade intracellular methioninase, we have now developed an adenoviral vector inserted with the P. putida methioninase (MET) gene (rAd-MET). The in vitro efficacy of rAd-MET was tested on the OVCAR-8 human ovarian cancer cell line, the HT1080 human fibrosarcoma cell line, and human normal fibroblasts. rAd-MET transduction of OVACAR-8 and HT1080 resulted in high levels of methioninase expression up to 10% or more of the total protein of the cells, depending on the multiplicity of infection. The IC50 of rAd-MET for OVCAR-8 cells in 96-well plates was approximately 2 x 106 plaque-forming units (pfu)/well. The IC50 of control adenovirus (control-rAd) was 4 x 10(7) pfu/well, 20 times higher than rAd-MET. In the presence of the IC50 of 2 x 10(6) pfu/well of rAd-MET, the addition of 0.025 units/ml of rMETase, which is 25% of the IC50, resulted in a 90% inhibition of tumor cell number. This indicated that rAd-MET enhanced the efficacy of rMETase. In contrast, 2 x 10(6) pfu/well of control-rAd in combination with 0.025 units/ml of rMETase had an efficacy of only 10% inhibition of cell number. The synergistic effect of the combination of rMETase and rAd-MET was quantitated by calculating the combination index (CI). The CIs for all combinations of rAd-MET and rMETase tested on OVCAR-8 were <0.7 with a mean of 0.5, indicating synergy. Similar synergy of rAd-MET and rMETase was seen on HT1080 human fibrosarcoma cells with a mean of 0.74. In contrast, the CIs of all combinations of rMETase and control adenovirus concentrations tested on both cell lines had a mean CI of approximately 1, which indicated that this combination had only an additive effect. The normal fibroblasts, on the other hand, appeared relatively resistant to the MET gene because in the presence of rMETase, 2.5 x 10(7) pfu/well of rAd-MET or control rAd had almost an identical effect on cell survival. The selectively strong synergy of rAd-MET and rMETase on cancer cells allows reduced levels of each agent to be used, thus decreasing potential side effects.

Carbon-Sulfur Lyases↗

PubMed2000

Left hemihepatectomy in living donors with a thick middle hepatic vein draining the caudal half of the right liver.

Donor safety is the first consideration in living related liver transplantation. Left hemihepatectomy including the middle hepatic vein is a reasonable donor procedure for obtaining a large graft for living related liver transplantation. This procedure, however, needs to be modified in donors with hepatic venous variation. While carrying out donor hepatectomy, we encountered two cases showing a variant form of hepatic venous drainage comprising a thick middle hepatic vein draining segment 6 of the liver. This variation made it necessary to preserve the middle hepatic vein in the donor liver remnant. Failure to recognize such a variant would result in congestion in the remaining right liver of the donor. To guarantee donor safety, evaluation of the drainage area of the corresponding hepatic vein is a matter of great importance in donor hepatectomy.

Adolescent↗

PubMed2000

Intraoperative Doppler color flow imaging combined with regulation of arterial inflow during surgery for intrahepatic arterioportal fistula.

Large fistulas associated with impaired liver function should be treated by direct obliteration or removal of the shunt orifice. In a large shunt with the portal branch lying on the arterial branch, identification of the exact site of the fistula can be a challenge. We report a case of impaired liver function due to a large intrahepatic arterioportal fistula. The site of the shunt orifice could not be located accurately by preoperative imaging. However, intraoperative color Doppler ultrasonography and the simple regulation of arterial inflow clearly demonstrated the shunt orifice. This original technique has allowed the precise definition of the problem and has optimized the surgical treatment for this critical condition. Consequently, it should be considered a new option for the definition and management of large intrahepatic arterioportal fistulas.

Aged↗

PubMed2000

Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide.

Nitric oxide (NO) regulates production of vascular endothelial growth factor (VEGF) by normal and transformed cells. We demonstrate that NO donors may up-regulate the activity of the human VEGF promoter in normoxic human glioblastoma and hepatoma cells independent of a cyclic guanosine monophosphate-mediated pathway. Deletion and mutation analysis of the VEGF promoter indicates that the NO-responsive cis-elements are the hypoxia-inducible factor-1 (HIF-1) binding site and an adjacent ancillary sequence that is located immediately downstream within the hypoxia-response element (HRE). This work demonstrates that the HRE of this promoter is the primary target of NO. In addition, VEGF gene regulation by NO, as well as by hypoxia, is potentiated by the AP-1 element of the gene. Our study also reveals that NO and hypoxia induce an increase in HIF-1 binding activity and HIF-1alpha protein levels, both in the nucleus and the whole cell. These results suggest that there are common features of the NO and hypoxic pathways of VEGF induction, while in part, NO mediates gene transcription by a mechanism distinct from hypoxia. This is demonstrated by a difference in sensitivity to guanylate cyclase inhibitors and a different pattern of HIF-1 binding. These results show that there is a primary role for NO in the control of VEGF synthesis and in cell adaptations to hypoxia. (Blood. 2000;95:189-197)

Base Sequence↗

PubMed2000

Randomized trial of the usefulness of a bile leakage test during hepatic resection.

HYPOTHESIS: An intraoperative bile leakage test will assist in decreasing postoperative bile leakage in patients undergoing hepatic resection. DESIGN: Randomized controlled trial. SETTING: University hospital. PATIENTS: One hundred three consecutive patients who were scheduled for hepatic resection without biliary reconstruction. Associated cirrhosis was present in 49 patients (48%), and only 24 (23%) had normal livers. Patients were randomized to undergo (n = 51) or to not undergo (n = 52) a bile leakage test, according to age, liver function, and hepatectomy method. The 2 groups were similar in baseline demographics. INTERVENTION: A bile leakage test was carried out by injecting isotonic sodium chloride solution through the cystic duct, and interrupted suturing was taken for a bile leak on the transected liver surface. MAIN OUTCOME MEASURES: The incidence of postoperative bile leakage and the length of the postoperative hospital stay. Bile leakage was defined as continuous drainage, with a bilirubin level of 86 micromol/L or more (> or =5 mg/dL), beyond 1 week. RESULTS: Twenty-one patients (41%) in the test group showed a bile leak, and a median of 1 site (range, 1-6 sites) was closed during the test. Postoperative bile leakage was observed in 3 patients (6%) in the test group and in 2 (4%) in the control group (P = .99). The odds ratio of the event was 1.53 (95% confidence interval, 0.25-9.44). The median postoperative hospital stay lasted 17 (range, 13-47) and 18 (range, 12-41) days for the test and control groups, respectively (P =.98). CONCLUSION: This randomized trial suggested no advantage in using a bile leakage test during hepatic resection.

Adult↗

PubMed2000

Reconstruction of small and fragile bile ducts without mucosa-to-mucosa anastomosis.

We describe a simple and easy technique for performing choledochojejunostomy without the need to suture the full thickness of the ductal and intestinal walls for patients in whom standard choledochojejunostomy is difficult because the stumps of the residual bile ducts are small and fragile. This technique is useful in partial liver transplantation or after hepatectomy that includes removal of the extrahepatic bile ducts. The procedure involves the placing of external biliary drainage tubes through a Roux-en-Y jejunal loop, positioned transanastomotically, and the use of an external jejunostomy to decompress the loop. The tubes are fixed to the jejunal loop by a purse-string suture and to the duct by simple ligation or a purse-string suture. Anastomosis is performed by suturing the connective tissue and liver parenchyma around the ductal stump to the seromuscular layer of the intestine. Choledochojejunostomy according to this method was performed in 5 cases; the biliary drainage tubes were removed 1 to 4 months after surgery. The only complications were cerebellar infarction and cholangitis, both of which resolved with conservative treatment. We consider that this technique will be helpful as a last-ditch measure when standard choledochojejunostomy, with suturing of the full thickness of the walls of the duct and intestine to secure mucosa-to-mucosa apposition, is impossible because of small and fragile bile ducts.

Anastomosis, Surgical↗

PubMed2000

A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia.

Genetically modified mice serve as a powerful tool to determine the role of specific molecules in a wide variety of biological phenomena including vascular remodeling. Several models of arterial injury have been proposed to analyze transgenic/knock-out mice, but many questions have been raised about their reproducibility and physiological significance. Here, we report a new mouse model of vascular injury that resembles balloon-angioplasty. A straight spring wire was inserted into the femoral artery via arterioctomy in a small muscular branch. The wire was left in place for one minute to denude and dilate the artery. After the wire was removed, the muscular branch was tied off and the blood flow of the femoral artery was restored. The lumen was enlarged with rapid onset of medial cell apoptosis. While the circumference of the external elastic lamina remained enlarged, the lumen was gradually narrowed by neointimal hyperplasia composed of smooth muscle cells. At 4 weeks, a concentric and homogeneous neointimal lesion was formed reproducibly in the region where the wire had been inserted. Similar exuberant hyperplasia could be induced in all strains examined (C57BL/6J, C3H/HeJ, BALB/c, and 129/SVj). This model may be widely used to study the molecular mechanism of post-angioplasty restenosis at the genetic level.

Angioplasty, Balloon↗

PubMed2000

Anatomical keys and pitfalls in living donor liver transplantation.

The surgery of living donor liver transplantation is more technically challenging than cadaveric whole liver transplantation and liver resection for the treatment of various pathological conditions. It requires a thorough understanding of the intra- and extra-hepatic anatomical relationships between the portal vein, hepatic artery, biliary tract, and hepatic vein, and also their respective contributions to liver physiology. Although a precise understanding of general anatomical principles is the key to correctly performing living donor liver transplantation procedures, anatomic anomalies are often present, and the means of detecting them and the surgical methods of coping with them represent technical challenges. In this monograph, we describe the anatomical keys and pitfalls of living donor liver transplantation surgery based on our own experience with more than 1800 hepatectomies, and 150 living donor liver transplantations. We also elaborate on techniques of selective intermittent vascular occlusion and their teleological and practical background.

Bile Ducts↗

PubMed2000