Yasuo Kamiyama

Fibronectin prevents D-galactosamine/lipopolysaccharide-induced lethal hepatic failure in mice.

Plasma fibronectin (FN) has a broad range of biological functions involved in cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, reticuloendothelial system function, and ischemic injury. In this study, we examined the effects of FN on D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant liver failure in mice. Female Balb/c mice received intraperitoneal injection of 50 μg/kg of LPS and 400 mg/kg of GalN simultaneously. Thirty minutes before GalN/LPS administration, human plasma FN (FN group) or the same dose of human serum albumin (control group) was given intravenously. GalN/LPS induced a marked decrease in plasma FN, which was reversed by FN pretreatment. The survival rate of the FN group was markedly improved in a dose-dependent manner compared with that of the control group (survival rate 0%). FN prevented increases in the concentrations of serum enzymes and total bilirubin related to liver injury. FN pretreatment significantly suppressed tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-6 levels, and enhanced IL-10 levels in serum and liver tissue compared with the control group. Moreover, TUNEL staining, caspase 3 and 8 activities, and necrosis in the remnant liver were significantly decreased in the FN-treated rats compared with the controls. Furthermore, FN pretreatment inhibited the activation of nuclear factor (NF)-κB and increased the expression of Bcl-xL protein in liver tissue. These results suggest that FN protected against GalN/LPS-induced liver failure by a mechanism involving inhibition of NF-κB activation, which caused down-regulation of TNF-α and involved up-regulation of IL-10, and elevation of Bcl-xL induced a blockage of apoptotic signals, by which apoptosis of hepatocytes caused by GalN/LPS was suppressed.

Less morbidity after pancreaticoduodenectomy of patients with pancreatic cancer.

Objectives: The pancreaticoduodenectomy with extended resection has been frequently performed in patients with pancreatic cancer in Japan. One result of this additional surgical stress may be that postoperative complications in patients with pancreatic cancer are more frequent than in patients with periampullary cancer. Methods: The 198 patients with pancreatic and periampullary cancer underwent pancreaticoduodenectomy. The operative mortality and morbidity between patients with pancreatic and periampullary cancer were compared, and the risk factors of postoperative complications and in-hospital death were determined. Results: Patients with pancreatic and periampullary cancer made up 52% and 48% of total patients. The duration of surgery and volume of intraoperative blood loss were significantly higher in patients with pancreatic cancer than in patients with periampullary cancer. Additional organ resections were frequently performed in patients with pancreatic cancer. However, significantly lower morbidity rates were observed in patients with pancreatic cancer. Among all complications evaluated, pancreatic fistula and abdominal abscess were found less frequently in patients with pancreatic cancer. Logistic regression analyses showed a positive correlation between periampullary cancer and an increased risk of complications, pancreatic fistula, and abdominal abscess. The in-hospital mortality rate has significantly reduced since 2000. When pancreatic fistula was clinically diagnosed, we immediately started a closed lavage using continuous administration of natural saline at 1000 to 4000 mL/d, after exchange of a nasogastric tube drain. Conclusion: Pancreaticoduodenectomy for patients with pancreatic cancer can be a safe procedure in spite of surgical stress. Further surgical strategies will be needed to reduce postoperative complications, especially in patients with periampullary cancer.

Duodenogastric reflux following biliary reconstruction after excision of choledochal cyst

Duodenogastric reflux (DGR) was assessed in patients surgically treated for choledochal cyst, with emphasis on two different biliary reconstruction methods: Roux-en-Y hepaticojejunostomy (HJ) and hepaticoduodenostomy (HD). Gastric bile monitoring with the Bilitec device revealed excessive DGR in patients in the HD group. Endoscopic findings demonstrated mild to moderate gastric mucosal erosion in patients after HD. In contrast, neither DGR nor gastritis was found in patients after HJ. This preliminary study suggests that HJ, rather than HD, should be recommended as a method of biliary reconstruction for pediatric patients with choledochal cyst. Careful observation of DGR should be continued in patients who have undergone HD.

Effect of Thiol-Containing Molecule Cysteamine on the Induction of Inducible Nitric Oxide Synthase in Hepatocytes

BACKGROUND Cysteamine, which is a known antioxidant and anti-inflammatory agent, is believed to be a key regulator of essential metabolic pathways in organisms. Cysteamine has beneficial effects in liver damaged by a variety of insults. During liver injury, inducible nitric oxide synthase (iNOS) is induced by lipopolysaccharide or proinflammatory cytokines, leading to excessive nitric oxide (NO) production. Accumulated evidence indicates that NO is an important factor associated with hepatic dysfunction. We examined whether cysteamine influences the induction of iNOS in hepatocytes. METHODS Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence and absence of cysteamine. NO production, iNOS induction, and iNOS signal were analyzed. RESULTS IL-1beta stimulated the inhibitory protein kappaB (IkappaB)/nuclear factor kappaB (NFkappaB) pathway, resulting in the activation of NFkappaB (nuclear translocation and DNA binding), which was followed by the induction of iNOS and NO production. The addition of IL-1beta and cysteamine (1-4 mmol/L) markedly inhibited NO production, with a maximal effect at 4 mmol/L (80%-90% inhibition). Cysteamine also decreased the levels of iNOS protein and mRNA. Transfection experiments revealed that cysteamine decreased the transactivation activity of the iNOS promoter. An electrophoretic mobility shift assay demonstrated that cysteamine inhibited the activation of NFkappaB. Furthermore, cysteamine decreased the mRNA levels of the NFkappaB subunit p65 but increased those of the inhibitory protein IkappaB. CONCLUSIONS These findings suggest that cysteamine inhibits iNOS induction at the step of NFkappaB activation. Further study is necessary to define the molecular basis of this effect of cysteamine on the regulation of NFkappaB and its pharmacologic implications.

Congenital biliary dilatation in dizygotic twins.

Congenital biliary dilatation (CBD) of different types was recently noted in dizygotic twins. Our cases suggest the possibility of hereditary involvement in CBD. On the other hand, CBD discordance in six sets of monozygotic twins has been reported, which would suggest that the occurrence of CBD is not compatible with single gene control, although environmental factors are plausible. To evaluate the genetic factors that may be implicated in CBD, it would be necessary to accumulate more familial cases and examine further studies on inheritance.

Structural development of PGP9.5-immunopositive myenteric plexus in embryonic rats

To investigate relationships between changes in the 3-dimensional structure of the myenteric plexus and the time at which functional movement of intestine begins in mammalian embryos, whole mounts of embryonic rat intestine were examined under confocal laser scanning microscopy on spacer-equipped glass slides after immunostaining with antiprotein gene product 9.5 antibody. At embryonic day 12.5, very few nerve cells were scattered throughout the small intestine, but no immunostained structures were apparent on the anal side of the large intestine. At embryonic day 13.5, immunostained fibers appeared on the oral side of the large intestine. Nerve cells and associated fiber bundles formed neuronal networks with large meshes in both intestines. Marked increases in number of nerve fibers and decreases in mesh size were seen in the small intestine between embryonic days 13.5 and 15.5. Similar changes were found in the large intestine between embryonic days 13.5 and 16.5. After embryonic day 16.5, nerve cells were arranged parallel to circular muscle fibers, and networks formed by cell fibers elongated until the neonatal period in both intestines. Meconium passed through the large intestine from embryonic day 17.5. Thin fiber bundles extended from the ganglion to the inner side of the myenteric layer, parallel (and occasionally extending) to the circular muscle fibers. Formation of nerve fiber networks and arrangement of nerve cells parallel to circular muscle fibers probably relate to movement coordination for inner circular muscle fibers in the intestinal wall, and development of this neural network may be important for acquiring intestinal movements before birth.