Yoshifumi Hiramatsu

Structural and functional alterations in the gut of parenterally or enterally fed rats

Various regimens of total parenteral nutrition (TPN) and enteral feeding were compared to determine their effects on the structural and functional changes of rat small intestine. Male Wistar rats, allocated randomly into five groups on the basis of delivery route and composition of nutrients, were fed as follows: standard rat chow ad libitum (CE-2 group), low-residue diet (LRD group), LRD supplemented with 1% (w/v) fiber (LRD + fiber group), elemental diet (ED group), and TPN (TPN group). At 2 weeks of feeding, villi in the terminal ileum decreased in height in the following order: CE-2 group greater than LRD + fiber group greater than LRD group greater than ED group greater than TPN group. Mucosal diamine oxidase activity remained unchanged in the CE-2 group and LRD + fiber group throughout the experimental period. However, mucosal diamine oxidase values were significantly lower in the remaining three groups, similar to the structural changes, and those values in the ED group were significantly decreased at 2, 3, and 4 weeks. There was a positive correlation between plasma diamine oxidase level and mucosal diamine oxidase content, with a coefficient correlation of y = 0.20x + 0.03, r = 0.55 (P less than 0.01). These results could be interpreted to indicate that addition of dietary fiber to LRD has a favorable effect on the maintenance of intestinal architecture and function during enteral feeding, and plasma diamine oxidase activity can be used as an index of functional and/or structural changes occurring in the small intestine during enteral or parenteral feedings.

Risk factors in relation to postoperative complications in patients undergoing esophagectomy or gastrectomy for cancer.

To clarify the risk factors contributing to postoperative complications in the elderly patients (over 70 years) undergoing esophagectomy and/or gastrectomy, 364 patients with primary cancer seen were evaluated. As a result, some characteristic patterns of stress response in the elderly could be detected as follows: the disorders of the vital organs were more important indices for the development of postoperative complications rather than age, and a reduction in the maximum response of the stress hormones to surgical procedures in aged patients was noted; moreover, the functional variability of target organ in the aged group was confirmed. Studies on the hormonal response to surgery suggest that the restriction of fluid replacement is advisable until the third postoperative day, maintaining the host on the dry side, to prevent cardiopulmonary complications. As the nutritional status in the patients with esophageal and gastric cancer goes from bad to worse with the advancing clinical stages, adequate perioperative nutrition is imperative to prevent complications such as anastomotic leakage, wound dehiscence, and/or infections. For the treatment of anastomotic leaks after esophagectomy and esophagogastrectomy, more than 45 kcal/kg/d must be provided, and the serum albumin level must be restored to 3.5 g/dL in order to achieve spontaneous healing of small anastomotic leakages.

Regulation of energy metabolism by interleukin-1 β, but not by interleukin-6, is mediated by nitric oxide in primary cultured rat hepatocytes

The effects of inflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) on energy metabolism were studied in primary cultured rat hepatocytes. Adenine nucleotide (ATP, ADP, and AMP) content, lactate production, the ketone body ratio (acetoacetate/beta-hydroxybutyrate) reflecting the liver mitochondrial redox state (NAD+/NADH), and nitric oxide formation were measured. Insulin increased ATP content in hepatocytes and had a maximal effect after 8-12 h of culture. Both interleukin-1beta and interleukin-6, but not tumor necrosis factor-alpha, significantly inhibited the ATP increase time- and dose-dependently. Interleukin-1beta and interleukin-6 also stimulated lactate production. During the same period, interleukin-1beta but not interleukin-6 decreased the ketone body ratio. Furthermore, interleukin-1beta markedly stimulated nitric oxide formation in hepatocytes, and this increase was blocked by NG-monomethyl-L-arginine (a nitric oxide synthase inhibitor) and by interleukin-1 receptor antagonist. NG-monomethyl-L-arginine reversed inhibition of the ATP increase, decrease in the ketone body ratio, and increase in lactate production, which were induced by interleukin-1beta. Interleukin-1 receptor antagonist completely abolished all of the effects induced by interleukin-1beta. These results demonstrated that interleukin-1beta and interleukin-6 affect the insulin-induced energy metabolism in rat hepatocytes by different mechanisms. Specifically, interleukin-1beta inhibits ATP synthesis by causing the mitochondrial dysfunction, a process which may be mediated by nitric oxide.

Effect of Various Lipid Emulsions on Total Parenteral Nutrition-Induced Hepatosteatosis in Rats

The effect of various lipid emulsions on the development of fatty liver during total parenteral nutrition (TPN) was investigated in rats given TPN for 7 days. Medium-chain triglycerides (MCT), long-chain triglycerides (LCT), chemically defined triglycerides (CDT; structured lipid with a high purity of 94.3%), and a mixture of MCT and LCT (MIX) were prepared as the lipid emulsions. TPN provided 350 kcal/kg/day, with a nonprotein calorie/nitrogen ratio of 160. The TPN-1 group received 10% nonprotein calories and the TPN-2 group received 30% nonprotein calories. MCT TPN was found to have some disadvantages, especially with regard to nitrogen balance and plasma albumin levels. Total cholesterol and phospholipids tended to be high in the MCT TPN group. The hepatic lipid content was higher in the lipid-free TPN and the MCT TPN groups, and lower in the CDT and LCT TPN groups. Histologically, the livers of the MIX, CDT, and LCT TPN groups showed less fatty change than those of the FREE and MCT groups.

Surgical treatment for poor-risk patients with carcinoma of the esophagus

During the period between 1979 and 1988, 145 patients with cancer of the esophagus were admitted to our department. They were examined for the preoperative risk factors associated with multiple organ function and classified into three groups according to the risk score. Special attention was paid to postoperative pulmonary complications, mortality and the long term results of surgery in the poor-risk patients and the findings analyzed in reference to the operative procedures. The resection rate for the poor-risk group was 41 per cent, however, esophagectomy was only able to be combined with a right thoracotomy and abdominal approach in 26 per cent of the patients in this group. Postoperative pulmonary complications developed in 64 per cent of the poor-risk patients who underwent a transthoracic esophagectomy and in only 25 per cent of those who received a transhiatal esophagectomy, although there was no significant difference in the overall survival rate beteeen these two subgroups. The present observations therefore raised the possibility that transhiatal esophagectomy may improve the results of surgical treatment for poor-risk patients with esophageal cancer.

Adenylate energy charge of rat and human cultured hepatocytes

SummaryA simple and rapid method for the assay of adenine nucleotides (ATP, ADP, and AMP) was established to evaluate the adenylate energy charge (ATP+ADP/2)/(ATP+ADP+AMP) of cultured hepatocytes. The effects of inhibitors of glycolysis, fatty acid oxidation, or oxidative phosphorylation on the energy charge were examined. The energy charges of cultured hepatocytes in rats and human were almost identical and were maintained at a high level between 6 and 24 h after changing the media (rat: 0.908±0.008n=9, human: 0.918±0.014n=6, mean ± SD). Inhibition of glycolysis with sodium fluoride or oxidative phosphorylation with antimycin A irreversibly reduced both the adenine nucleotide contents and the energy charge. However, the inhibition of fatty acid oxidation with 2-tetradecylglycidic acid did not affect the nucleotide contents, and the energy charge only decreased transiently to recover within 8 h. When the inhibitor of oxidative phosphorylation was removed, the recovery in the energy charge preceded the recovery in the adenine nucleotide contents. These findings suggest that the adenylate energy charge is a more sensitive measure of the changes in energy metabolism than the adenine nucleotide contents. Furthermore, energy charge regulates adenine nucleotide contents in cultured hepatocytes. It is important to confirm that the high energy charge of the cultured hepatocytes is maintained when these cells are used for metabolic studies.

Squamous Cell Carcinoma of the Esophagus with Cartilaginous Metaplasia at Metastatic Lesions

Subdermal metastatic nodules in a 62 year old male patient with esophageal carcinoma contained both car‐cinomatous and chondroid areas. The carcinomatous areas showed the histology of poorly differentiated squamous cell carcinoma, and light microscopically an apparent transition could be traced from carcinomatous cells to chondroid cells. In the chondroid cells, the characteristics of chondrocytes were demonstrated by light microscopic, electron microscopic, histochemical and immunohistochemical studies, although nuclear atypism was evident, suggesting their malignancy. Furthermore, immunohistochemical studies showed that some chondroid cells contained both keratin proteins and squamous cell carcinoma antigen, which were also found in the carcinomatous cells. These findings together with the light microscopic observations suggest that chondroid cells are derived from squamous cell carcinoma cells.

Different responses to surgical stress between extra domain A+ and plasma fibronectins.

1. Fibronectins (FN) are believed to have a role in haemorheological perturbation associated with tissue damage. Fibronectins exist in two antigenically related forms, plasma (p) and cellular fibronectin, which has the extra domain sequences A (EDA) or B (EDB). The present study was designed to determine changes in plasma p‐FN and EDA + FN under different types of surgical stress.

Increased extra domain-A containing fibronectin and hepatic dysfunction during septic response: an in vivo and in vitro study.

A massive inflammatory reaction resulting from systemic cytokine release is the common pathway underlying sepsis or multiple organ dysfunction. The role of extra domain sequence A-containing fibronectin (EDA+FN) formation during the septic response is not known. The present study investigates the role of EDA+FN during the septic response under in vitro and in vivo conditions. The direct effects of interleukin-1, interleukin-6, and tumor necrosis factor-alpha on EDA+FN production were evaluated in primary cultured human hepatocytes and fibroblasts. Serial plasma EDA+FN levels were measured using an enzyme-linked immunosorbent assay in 24 patients who developed postoperative sepsis following general abdominal surgery of which there were 17 survivors and 7 non-survivors. EDA+FN secretion was significantly increased in cultured hepatocytes but not fibroblasts at 24 and 48 h following exposure to IL-1 compared to controls. In the clinical setting plasma EDA+FN levels in non-survivors were significantly higher than in survivors. Moreover, the EDA+FN levels were correlated closely with liver function tests. EDA+FN levels may represent a specific marker of vascular injury or systemic inflammatory response syndrome that is associated with an adverse clinical outcome.

Effect of medium-chain triglycerides (MCT) as an energy substrate after hepatectomy in rats with streptozotocin-induced diabetes

SummaryThe suitability of energy substrates used by the remnant liver after a 70% partial hepatectomy was studied in relation to the hepatic energy status in diabetic rats. Rats with streptozotocin-induced diabetes mellitus underwent 70% hepatectomy, and were divided into three groups receiving total parenteral nutrition (TPN) for 24h. One group received standard TPN without fat, while two other groups received standard TPN with medium-chain triglycerides (MCTs) or long-chain triglycerides (LCTs) as a 10% lipid emulsion. All rats of the TPN group without fat died within 24 h. Blood ketone body ratios (acetoacetate/β-hydroxybutyrate), energy charge levels of the remnant liver, and cumulative amounts of 14CO2 in the expired breath during the 6 h following 14C-labeled fat emulsion administration (MCT or LCT) were all significantly higher in the MCT group than in the LCT group 24 h after hepatectomy. These findings suggest that medium-chain fatty acids (MCFAs) as an energy substrate are superior to long-chain fatty acids (LCFAs) during the immediate posthepatectomy phase in diabetics.