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It should be considered that the causes of refractory gastroesophageal reflux disease (GERD) are multifactorial. Esophageal manometry study is useful when we make distinguish patients with esophageal motility disorders from those with refractory GERD. Endoscopic ultrasonography is also performed to observe the thickness of esophageal wall which represents the disturbance of esophageal motor function. Esophageal pH monitoring is useful to detect the acid clearance disturbance and phenomenon of nocturnal acid breakthrough. Both are occurred at night, and are recently considered to be responsible for refractory GERD. Catheter-free pH monitoring system, Bravo, makes it possible to measure esophageal pH under quite physiological conditions. Genotype of CYP2C19 is sometimes checked in patients with PPI resistance GERD. Intra-gastric pH with omeprazole and lansoprazole depends on patient's genotype of CYP2C19. Monitoring of 24-hour bilirubin, Bilitec, is also useful to detect duodeno-gastro-esophageal reflux.

We are always exposed to oxidative stress, when oxygen is used for production of energy for our daily activity. Mild to moderate oxidative stress affects intracellular signal transduction, accelerating the protective system for oxidation; thereby inflammatory cytokines are produced leading to increased levels of acute phase proteins. Vascular endothelial cells protect the vessels from oxidative stress, however, when they are damaged by shear stress to the vascular wall, oxidation spreads into the subendothelial matrix, leading to oxidation of low-density lipoproteins(LDL) accumulated there. Oxidized LDL is easily and abundantly taken up into macrophages via the scavenger receptors such as LOX-1, which leads to the formation of atherosclerosis. Markers for oxidative stress in vivo are being sought for prevention and treatment of cardiovascular diseases. There are a number of parameters as candidates, and among them, we chose biopyrrins, oxidative products of bilirubin, and have studied their role in coronary heart diseases. Urinary excretions of biopyrrins are significantly elevated in patients with coronary arterial stenosis and with ischemic changes on electrocardiogram. Similar finding have been obtained in patients with vasospastic angina. These findings suggest that markers for oxidative stress will be a good laboratory test for evaluation of coronary heart diseases.

To evaluate the usefulness of ambulatory intraesophageal bilirubin monitoring in the diagnosis of GER, 38 patients with reflux symptoms and 7 controls were studied, using Bilitec 2000. The % time of bilirubin and acid reflux was less than 5% in all of the controls. In 3 patients of NUD, % time of acid reflux was less than 5%, but that of bilirubin was more than 8% in 2 patients. Acid reflux was found only in 1 of 4 patients who had a history of subtotal gastrectomy, but abnormal bilirubin reflux was found in all of 4 patients. In the other 31 patients, a significant difference was found in the % time of bilirubin reflux by the severity of reflux esophagitis, whereas this difference was not found in that of acid reflux. Intraesophageal bilirubin monitoring is useful in the diagnosis of GER and is essential in patients with hypochlorhydria or minimal reflux.

The incidence of gallstone has been gradually increased in the last few decades in Japan and the recent study revealed that approximately 15% of the autopsy cases had biliary stones. In the last 25 year interval, the nature of gallstones was greatly changed. In detail, the incidences of cholesterol gallstone and black stone were increased from 46.7% to 66.9% and from 0.8% to 12.1%, respectively, whereas that of calcium bilirubinate stone was decreased from 41.5% to 21.0% of the whole cholelithiasis cases. The factors influencing these changes were probably due to recent increase of fat diet intake and decrease of ascariasis by improvement of environmental hygiene. However, the factors that caused the change in black stone has not been defined.

The concentrations of metal elements in gallstones were measured by absorption spectrometry. Crystallographic analysis by the powder X-ray diffraction method was also performed. For all stones calcium was the major component. In calcium carbonate stones aragonite form, one of the CaCO3 polymorphs and usually unstable in nature, was dominant. As a whole, black-stones contained highest proportions of all metal elements. But these stones were crystallographically grouped into three types; they are calcium carbonate-, calcium phosphate-, and other-one. In each type, the concentration of metal element differed greatly. It is suggested that in black-stones the amount of Mn is remarkable and Cu is highly correlated to black residue. It was true, but Mn was remarkable especially in calcium phosphate-type and Cu was the highest in other-type.

Biliary tree of gastrectomized patients was examined with ultrasonography to investigate the factors affecting post-gastrectomy gallstone formation. Only gallbladder stone was found in 57 (18.9%). In 11 (20.0%) of 55 patients, stones had developed within 2 years after surgery, but no difference in incidence were observed by sex and age. Sixty four gastrectomized gallstone patients were examined in respect to the kind of gallstone. Patients with cholesterol gallstones were 18 (28.1%), patients with black gallstones were 29 (45.3%) and patients with calcium bilirubinate gallstones were 17 (26.6%). The incidence rate of cholesterol gallstones was lower and the rate of black gallstones and calcium bilirubinate gallstones was higher than that of non-gastrectomized patients. In conclusion, the incidence of pigment gallstones is very high in gastrectomized patients.

Macroscopic classification of gallstones as proposed by the Japanese Society of Gastroenterology is based on the presence of characteristic structures on the cut surface. According to this classification, gallstones can be broadly divided into three types: cholesterol gallstones, pigment gallstones and rare gallstones. This classification is widely accepted in Japan because of its clinical applicability. A more accurate classification requires analysis of the constituents of gallstone. In particular, infrared absorption spectroscopy has been utilized for this purpose because it enables a rapid and easy analysis, requiring only small amounts of sample. In the selection of patients with gallstones for non-surgical treatment, such as ESWL and dissolution therapy, qualitative diagnosis is necessary. With this in mind, we have attempted to produce CT-Profile curves of individual gallstones, depicting changes in CT values assessed along cross-sectional lines passing from the center of the stone to their maximum diameters. This method allowed qualitative diagnosis almost of all gallstones.

Based on the mucosal findings in gallbladder patients, intestinal metaplasia was found in 18.4% of such cases without a stone or a carcinoma, in 30% of the with a bilirubin stone, in 37.7% of those with a cholesterin stone, in 69.1% of those with a carcinoma but without a stone and in 78.9% of those with both a carcinoma and a stone. In contrast the incidence of a well differentiated adenocarcinoma was more frequent in the cases with a stone (more often a cholesterin stone than a bilirubin stone) than in cases without a stone. Similarly, the incidence of intestinal metaplasia was more frequent in those with a cholesterin stone than in those with a bilirubin stone. Further, small size lesions were found to be more frequent in the cases of a cancer with a stone. Granular early carcinomas within the superficial muscle layer are usually resected under the diagnosis of gallstone, whereas early carcinoma that protrude are resected as a carcinoma.

Effects of some bile acids on the biliary flow, BSP output and composition (phospholipid, cholesterol, bilirubin and bile acids) were studied in dogs. Ursodeoxycholic acid (UD), chenodeoxycholic acid (CD) and dehydrocholic acid (DC) caused a dramatic increase in biliary flow and BSP output. Relative potencies of these effects were DC greater than CD greater than or equal to UD. UD increased the phospholipid, bile acids and cholesterol concentration but had little effect on bilirubin concentration. Furthermore, UD greatly increased the output of four bile components. CD slightly decreased the phospholipid, cholesterol and bilirubin concentration without the bile acids, while CD increased the output of bile components. After UD or CD administration, the bile acid of each appeared markedly in the bile, dose dependently. On the other hand, DC caused a dramatic decrease of phospholipid, cholesterol and bilirubin concentration but had little effect on bile acids concentration. Output of bile components was increased by DC the first 1 hr but decreased at 2 hr. After DC administration, 3alpha, 7alpha-dihydroxy-12keto-5beta-cholanic acid appeared in the bile while DC did not. Therefore, it is concluded that UD and CD are cholanereticas and DC is a hydrocholeretica.

Heterotopic liver transplantation utilizing intraportal hyperalimentation was studied in dog for the purpose of temporary hepatic support for acute liver failure. The liver graft was transplanted in the right lower abdomen of the recipient, and its suprahepatic IVC was anastomosed end-to-side to the infra-renal IVC of the recipient. The celiac artery of the graft was anastomosed end-to-end to the right internal iliac artery of the recipient. An infusion catheter was placed in the donor's portae and intraportal hyperalimentation with insulin was performed. A polyethylene tube (1.7 mm bore) was inserted into the CBD of the graft and led through the body wall as an external biliary drain, after which the recipient's CBD was ligated and transected. The grafts functioned well and excreted bile for 6 days in a non-immunosuppressed group and until death in an immunosuppressed group. Serum bilirubin levels of the recipients increased slightly or were within normal range. At autopsy, the grafts showed no atrophy. Heterotopic liver transplantation with intraportal hyperalimentation will be useful as a temporary hepatic support for acute liver failure in the future.

Heinz body anemia was induced in dogs by consecutive oral administration of 200 mg/kg and 60 mg/kg of aminopyrine, 200 mg/kg of phenacetin and 5 mg/kg of acetylphenylhydrazine, for either 8 or 16 weeks. Biochemical analysis showed a decrease of haptoglobin in plasma and reduced-glutathion in red blood cells in association with anemia. Hematologically, an increase in osmotic fragility and cell volume of erythrocytes were also noted. Pathological examination revealed marked erythrophagia and hemosiderosis in the reticuloendothelial system of treated animals. A new anti-inflammatory analgesic 31252-S (3-(1-hydroxy-2-piperidinoethyl)-5-phenylisoxazole citrate) was also tested for the hemolytic effects in dogs. Blood analyses revealed a slight increase of Heinz bodies and a decrease of reduced-glutathion in red blood cells without anemia. These findings suggest that 31252-S have weaker oxidant properties than those of aminopyrine and phenacetin. The present studies showed that the concentration of reduced-glutathion in red blood cells of non-treated dogs was approximately 50% lower than that of the erythrocytes of normal human beings. This finding appeared to correspond with high susceptibility of red blood cells to hemolytic effects of oxidant-drugs in dogs.

We analyzed 24 intrahepatic gallstones for their components by chemical assay and evaluation of atomic absorbance. Those with high cholesterol and fatty acid contents were noted in addition to conventional bilirubin-calcium gallstones, and a mean cholesterol content of over 50% was observed in one fourth of the hepatic gallstones. Measurement of biliary bilirubin and calcium levels conducted to investigate the causative factors of bilirubin gallstones showed that they occur more readily in bile containing less bilirubin, suggesting that their development is largely dependent on the amount of bile acids in hepatic bile determined by the biliary acidity, presence of unconjugated bilirubin, and ionization of calcium. Our results suggest the necessity of treating hepatolithiasis as a hepatic disease with constitutional implications and, in the absence of clear insight into its etiology, of selecting surgical modes always with proper consideration to the possibility of recurrence. Therefore, choledochojejunostomy combined with jejunostomy is our primary surgical procedure.

In vivo reflectance spectra in the visible region were recorded on the blanched skin on the foreheads, chests, arms and legs of 140 newborn infants using an organ scanning spectrophotometer, and corresponding total serum bilirubin levels were determined. An elevation in the absolute spectra was observed in the 460 nm region for the higher bilirubin level, and the isosbestic point was located in the 510 nm region. A linear relationship was observed between the reflectance spectra difference and the serum bilirubin level. Although the best analysis results were obtained from the measurements of the reflectance spectra difference between 460 nm and 510 nm on the chests (r = 0.954, Y = 40.62X + 1.36), or on sums of 4 measuring sites (r = 0.973, Y = 46.59X + 0.61), there was no statistical difference from the values obtained between 460 nm and 550 nm on the foreheads (r = 0.913, Y = 33.55X + 5.30). The slopes and the Y-intercepts of the linear regressions differed considerably at various measuring sites. Marked decreases in the reflectance spectra differences were observed during the phototherapies and prominent rebounds followed for 24 hours after the cessation of phototherapies. The noninvasive and simple reflectance method was sensitive to the bilirubin level in the tissue and might be a better indicator of neonatal risk of kernicterus. However, the optical method has a certain limitations in representing the bilirubin concentration in the blood stream, especially during, and for 24 hours, after phototherapies.