Mechanisms underlying the enhanced elevation of IL-1beta and TNF-alpha mRNA levels following endotoxin challenge in rat alveolar macrophages cultured with low-Mg2+ medium.

We have previously shown that interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha mRNA levels in rat alveolar macrophages are increased in by endotoxin (lipopolysaccharide; LPS)- stimulation and further enhanced by culturing with low-Mg2+ medium. We have now investigated the mechanisms of underlying this enhancement by using some specific signal transduction inhibitors. The enhanced elevation of both mRNAs levels was suppressed by pretreatment with TMB-8 (which inhibits calcium release from the endoplasmic reticulum) or dexamethasone (which inhibits nuclear factor [NF]-kappaB and activator protein [AP]-1), but not with verapamil or nifedipine (which inhibits calcium channels). The enhancment of IL-1beta, but not TNF-alpha mRNA levels, was suppressed by pretreatment with W-7 (which inhibits calmodulin), whereas the enhancement of TNF-alpha mRNA levels was suppressed by pretreatment with U73122 (which inhibits phospholipase C). Curcumin (an inhibitor of AP-1), suppressed the increases in both mRNAs induced by low-Mg2+ medium alone, but had no suppressive effect on the levels of either mRNA after LPS-stimulation in low-Mg2+ medium. Pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB) prevented the elevation of TNF-alpha mRNA levels induced by low-Mg2+ medium without LPS-stimulation, but had no suppressive effect on IL-1beta mRNA levels. From these results, we conclude that the enhanced elevation of IL-1beta and TNF-alpha mRNA levels seen in LPS-stimulated alveolar macrophages in low-Mg2+ medium occurs partly via the same, and partly via different, signaling pathways.     

USEFULNESS OF EUS IN PORTAL HYPERTENSION WITH ESOPHAGEAL VARICES

We investigated the relationship between esophageal varices and the collaterals by endoscopy and endoscopic ultrasound (20 MHz ultrasonic miniprobe; UMP). Moreover, we investigated the correlation between the collaterals around the esophagus and recurrence of esophageal varices in patients with portal hypertension who had undergone EIS. The collaterals were divided into two groups: peri‐esophageal collateral veins (peri‐ECVs) and para‐esophageal collateral veins (para‐ECVs). These were scored as mild or severe according to the stage of development. According to endoscopy, the varix form was significantly larger in severe the peri‐ECVs group than in mild the peri‐ECVs group. The prevalence of perforating veins increased according to the varix form. With regard to variceal recurrence, in patients with variceal recurrences, UMP findings included a significantly higher incidence of severe peri‐ECVs, a significantly larger diameter of perforating veins compared with patients without recurrence. In conclusion, the presence of severe peri‐ECVs and large perforating veins in the esophageal wall strongly correlates with occurrence and recurrence of esophageal varices in patients with portal hypertension. An understanding of these UMP abnormalities on the basis of hemodynamics around the esophagus is thought to be important for management of esophageal varices in patients with portal hypertension.     

NEW METHOD OF STENTING TREATMENT FOR MALIGNANT DUODENAL STENOSIS: USING DOUBLE‐BALLOON ENTEROSCOPY

Recently, a self‐expandable metallic stent has been recognized for treatment of malignant duodenal stenosis. But the complications by stenting are important problems even now. In the present study, we report our new method of duodenal stenting by using of double‐balloon enteroscopy considered safe and effective.     

Serum immunoreactive beta-glucuronidase determined by an enzyme-linked immunosorbent assay in patients with hepatic diseases.

An enzyme-linked immunosorbent assay (ELISA) was developed for human beta-glucuronidase, using a specific polyclonal antibody raised against the purified enzyme. beta-Glucuronidase from human liver consisted of three subunits with molecular mass of 76, 64 and 18 kDa. The assay offered a specific, sensitive and convenient means of measuring immunoreactive beta-glucuronidase in human sera. beta-Glucuronidase activity determined by the conventional method appeared to be extremely low, indicating that in human sera beta-glucuronidase exists in an enzymatically inactive form. The sensitivity of the assay permitted the detection of 1-100 ng of purified beta-glucuronidase. A mean serum level in normal subjects was 108 +/- 25 ng/ml (mean +/- S.D.). A high level of beta-glucuronidase was found in sera of patients with severe hepatocellular necrosis, including liver cirrhosis (152 +/- 130 ng/ml) and chronic active hepatitis (220 +/- 99 ng/ml), whereas no significant increase of the enzyme protein was observed in chronic persistent hepatitis (102 +/- 42 ng/ml). beta-Glucuronidase was also increased in sera of patients with primary hepatoma (156 +/- 125 ng/ml). The immunoreactive beta-glucuronidase determined in this assay was thought to be a supplementary serological indicator for hepatocellular necrosis.     

The gastric antisecretory action of lipopolysaccharide is blocked by indomethacin.

We have recently found that bacterial lipopolysaccharide (LPS) at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to examine the mechanism by which LPS exerts its antisecretory action. The i.p. injection of LPS resulted in a dose-dependent (40-4000 ng/kg) decrease in gastric acid output in pylorus-ligated rats. However, preinjection of indomethacin (2-10 mg/kg s.c.), an inhibitor of prostaglandin biosynthesis, prevented the LPS-induced inhibition of gastric secretion in a dose-related manner, while these concentrations of indomethacin by themselves did not affect gastric acid output. These results suggest that LPS requires an intact prostaglandin system to exhibit its inhibitory action on gastric secretion.     

Acute hemorrhagic colitis induced by the neuraminidase inhibitor oseltamivir]

A 23-year-old woman had lower abdominal pain, diarrhea and bloody stool was admitted and given a diagnosis of influenza B. Her home doctor had started treatment by neuraminidase inhibitor (oseltamivir) the previous day. Colonoscopic examination revealed an area of hemorrhage and erosion in the left transverse colon. After halting oseltamivir treatment these symptoms disappeared and her colonoscopic findings improved. A drug-induced lymphocyte stimulation test was positive for oseltamivir. This case is the first reported case of acute hemorrhagic colitis induced by oseltamivir.     

The effect of IL-6 on the des-gamma-carboxy prothrombin synthesis in human hepatoma cells.

Effects of several cytokines on des-gamma-carboxy prothrombin (PIVKA II) synthesis in human hepatoma cells were investigated to know the process of PIVKA II production during a liver allograft rejection. Human recombinant interleukin-6 (IL-6) significantly stimulated the PIVKA II synthesis without any influence on the cell proliferation. The effect was almost completely neutralized by the specific anti-IL-6 antibody. Neither tumor necrosis factor (TNF), interleukin-1 (IL-1) nor interferon-gamma (IFN-gamma) had such a stimulative effect. IL-6 appears to stimulate PIVKA II production, and would be a candidate of factors that enhance the production of PIVKA II during a liver allograft rejection.