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Levamisole, an agent acting upon depressed cellular immunity, enhancing and normalizing it and consequently showing antitumor activity in the cancer-bearing body, was administered to patients with gastrointestinal cancer at a daily dose of 150 mg for three consecutive days every other week, starting as a rule, three days before operation. The patients were evaluated for survival. Of the 143 patients (66 with curative resection, 40 with noncurative resection and 37 without resection) who received levamisole therapy for one month or more, 57 survived postoperatively six months and of 44 treated 37 survived one year. In this study, 185 patients with gastrointestinal cancer were used for comparison purposes. The six-month survival rate was 100% (23/23) in the levamisole treated group and 95.3% (102/107) in the control group after curative resection (p greater than 0.5), 100% (23/23) and 90.5% (49/54) after noncurative resection (p less than 0.01), and 72.5% (8/11) and 33.3% (9/24), respectively, in non-resectable patients (p less than 0.01). The one-year survival rate was 100% (21/21) and 95.3% (102/107) after curative resection (p greater than 0.5), 77.8% (14/18) and 59.3% (32/54) after noncurative resection (0.05 less than p less than 0.1), and 40% (2/5) and 8.3% (2/24) in non-resectable patients (0.05 less than p than 0.1) in the levamisole group and in the control group, respectively. The difference in survival in survival rates between levamisole-treated and control groups was most prominent in the non-resectable patients followed by those undergoing noncurative resection and curative resection.

Enzyme deviations in injured livers were studied by analyzing isozyme patterns of phosphorylase using a newly developed electrophoretic method, which separates six molecular species of this enzyme, i.e. M,FM,F,L,L', and FL'. In hepatic injuries caused by CCl4 and galactosamine intoxications of rats, F appeared in early stages and L' (and FL') in later stages of the injuries with a concurrent decrease or loss of L, which is a sole isozyme component of adult liver. In injured livers of patients with hepatitis and cirrhosis of the liver, increases in FL' activity were also found. Appearance of F was found only in hepatocellular carcinoma. The results obtained with phosphorylase isozyme analysis support the idea that an undifferentiated gene expression takes place in the injured livers of non-malignant hepatic disorders.

Micromethods for estimation of bilirubin uridine diphosphate-glucuronyl and -xylosyl transferases in liver are described. With these methods, a liver specimen as small as 10 mg is sufficient for assay of either enzyme activity and 15 mg is sufficient for assay of both enzymes. Normal values for livers with minimal elevation of SGOT and minimal histological change were 0.260-0.400 U/g protein for glucuronyl transferase and 0.142-0.302 U/g protein for xylosyl transferase.

In view of comparatively-high incidence of papillary, well or moderately-well differentiated, transitional cell carcinomas in urology, and of frequent recurrence of carcinomas after appropriate procedures, we have undertaken the correlative study on urinary cytology with cystoscopy, pathology and the amount of fibrinogen and degradation products of fibrinogen and fibrin (FDP). Cytopathologically, 191 cases were confirmed histologically for cancers out of 442 cases studied cytologically; among these 442 classes IV and V were found in 136 cases, and 99 of 136 cases (72.8%) had cancers. Admittedly, we were unable to suspect tumors cytologically in 24.5% of the cases. As to histological gradings and cytology, 48.7% of classes I and II in well differentiated were found against 52.9% and 57.1% of classes IV and V in moderately-well and poorly differentiated carcinomas, respectively. Urinary FDP assay was quite promising; out of 19 cases with both positive cytology and FDP, 18 (94.7% had carcinomas histologically, whereas 12 of 56 cases (21.4%) with both negative cytology and FDP bore cancers. Subsequently, several proposals for improving the diagnostic accuracy were discussed. We concluded the importance of accumulating more cases by combining several diagnostic procedures, especially among well and moderately-well differentiated carcinomas.

The incidences, distribution and histopathological findings of N, N'-dimethylnitrosourea (DMNU)-induced brain microtumors in Sprague-Dawley rats were studied. Subcutaneous injections of DMNU in young adult rats one a week resulted in the induction of 122 gliomas in 38 animals with an incidence of 69% after a time lapse of between 157 and 246 days from the first injection. Of these tumors, 66 were classified as microtumors (diameter less than about 1 mm) by detailed light microscopy observation of serial sections. The microtumors were of 3 types: 55 oligodendrogliomas, 8 astrocytomas and 3 mixed gliomas. As the tumors became larger in size, anaplasia appeared, especially in the central part of the tumors. The microtumors developed randomly throughout the brain. It was concluded that, in adult rat brains, the target cells of DMNU were well differentiated glial cells which had already migrated from the matrix layer.

Normal development of the human stapes footplate was investigated in serial sections by light microscopy. Materials were obtained from 35 Japanese embryos from the 6th to 32nd week of embryonal age. Eighteen embryos up to 16 weeks of age (3.5mm to 105mm in crown-rump length) were examined, focusing particularly on the lamina stapedialis of the otic capsule. The present study showed that primordial formation of the lamina stapedialis appeared in 16mm embryo and that the lamina was completely formed and fused to the base of the annular stapes in a 35mm embryo. In a 50mm embryo, the adult form of stapes was found with a rim and annular ligament. The results, therefore, seemed to essentially agree with the theory of dual origin and development of the footplate proposed by Cauldwell and Anson, and teratogenic agents might affect any stage of the process producing anomalies,

The correlation between the systolic time interval and abnormal contraction in ischemic myocardium was studied in anesthetized open-chest dogs. A strain-gauge was sutured on the surface of the left ventricular wall perfused by the left anterior descending coronary artery (LAD) for measuring segment-length. The left ventricular stroke volume decreased progressively after occlusion of LAD. The left ventricular ejection time (LVET) was progressively shortened in close correlation with the elongation of segment-length at the onset of isometric relaxation in 20 seconds after LAD occlusion when early systolic myocardial contraction and isometric contraction time (ICT) were not affected. ICT was gradually prolonged and closely related with the lengthening of the early systolic segment-length, while LVET recovered toward the control level in spite of further decrease in stroke volume. A close relationship was observed between ICT/LVET and stroke volume (gamma = 0.76, P less than 0.01). The results suggested the possibility that LVET was normalized even when the left ventricular function was impaired, and ICT/LVET ratio was the most sensitive index of LV dysfunction.

Endotoxin (lipopolysaccharide, LPS) and LPS antibody in the blood were studied in 61 cases of ulcerative colitis (U.C.) by radioimmunoassay. Lysozyme (LZM) concentration was also studied by the turbidimetric method. As a result, it was found that the blood LPS value as well as serum LZM concentration reflects the clinical observations. The case of endotoxemia in the active phase group showed a positive correlation between the LPS value and LZM concentration. LPS antibody which could not be detected in many cases of the active phase, had a high titer in cases of remission with a long history of the disease. These results would suggest that in U.C. with damaged intestinal mucosal barrier, LPS originating from intestinal flora enters into the blood and aggravates the disease and further that this invading LPS releases LZM into the blood. The same studies were performed on 7 cases of Crohn's disease and the same result was obtained.

Using in vivo and in vitro experimental models, the uptake and excretion of 67Ga-citrate in tumor cells and normal cells were studied. The time-lapse accumulation of 67Ga in the tumor of rats bearing Yoshida sarcoma reached its peak 24 h after the administration of 67Ga and gradually decreased thereafter. However, the excretion of 67Ga from the tumor was less than that from normal lung. For culture cells in vitro, the uptake of 67Ga increased with lapse of contact time between 67Ga and the cells, but there was no distinct difference between the results of tumor cells and normal skin fibroblasts. The excretion of 67Ga from the cells tended to decrease with prolongation of the contact time, the excretion from tumor cell being only about 10% after a contact time of 24 h. This indicated a significant delay in excretion in comparison with that of normal skin fibroblasts. This delay in the excretion of 67Ga may be an important factor in the tumor accumulation of 67Ga.

The effect of Cd2+ on the respiration of rat liver mitochondria was investigated. The uncoupling effect of Cd2+ was partially restored by the addition of Mg2+. The influence of Cd2+ on adenine nucleotide concentrations in the reaction mixture consisting of mitochondria and ATP was also studied using high performance liquid chromatography. In the presence of added Mg2+, a two-fold increase in AMP concentration was brought about by the addition of Cd2+. There was a concomitant decrease in ATP. In the prence of added ADP, an increase in AMP concentration was also brought about by addition of Cd2+. The results are discussed in relation to ATPase and adenylate kinase activity in mitochondria.

A mixture with essential and nonessential amino acids high in branched chain amino acids and low in aromatic amino acids (Fischer solution), and another synthetic mixture of branched chain amino acids containing 3 amino acids associated with the urea cycle (Hep-OU) were infused to control subjects and patients with severe hepatic disease. Alterations in serum aminograms, blood ammonia levels and electroencephalograms following the infusion were studied and compared with those obtained by a commercially available amino acid mixture. Short-term or continuous infusion of a commercially available amino acid solution to cirrhotic patients caused an increase in methionine, phenylalanine and tyrosine and a decrease in branched chain amino acids. These post-infusion results were similar to the patterns seen in hepatic encephalopathy. In cirrhotic patients, infusion of Fischer solution which contains small quantities of methionine and phenylalanine produced an increase in the concentrations of these 2 amino acids, probably because of impaired utilization by the injured liver. No marked alterations in serum aminograms, however, were observed in cirrhotic patients either immediately after, or 3 h after, the end of the Hep-OU infusion. Reduction of methionine, tyrosine and phenylalanine levels and elevation of the molar ratio of (valine+leucine+isoleucine) / (phenylalanine+tyrosine) were significant. The infusion of Hep-OU to patients with liver cirrhosis or subacute hepatitis resulted in clinical and neurological improvements and the restoration of the molar ratio of branched chain amino acids/aromatic amino acids.

The homovanillic acid (HVA) concentrations in the lumbar cerebrospinal fluid (CSF) were determined in 38 epileptic and 39 control patients. The mean concentration of HVA was 23.9 ng/ml +/- 2.8 SEM for the epileptic group and 30.2 ng/ml +/- 2.1 SEM for the control group, respectively. Thus, HVA was significandly reduced in the patients with epilepsy compared with the controls. The mean HVA in the female patients was higher than in the male patients in both groups but this failed to reach statistical significance. There was no apparent relationship between the degree of reduced HVA concentration and other clinical indexes of the epilepsy (age, type and frequency of seizures, and anticonvulsant medication). For the determination of concentration gradient of HVA three fractions of the spinal CSF were obtained from 11 patients. A pronounced gradient of HVA concentration was found with a ratio of 1 : 1.46 : 1.97 for the first, second and third fractions. This suggests that a standardized conditions for collecting CSF should be employed to study HVA levels in humans.

Phosphorylase activities (total and a form) were determined in the livers of experimental hepatic injuries with carbon tetrachloride or galactosamine and the livers of patients with liver diseases. Experimental liver injuries caused a slight decrease in total activity in later stages and a marked increase in a form activity in earlier stages. In human livers, low values of total activity were found in acute hepatitis and cirrhosis of the liver with no consistent alteration in a activity. Phosphorylase activities in hepatocellular carcinomas were also low. The importance of the altered phosphorylase activities in hepatic injuries is discussed in relation to the disorder in glycogen metabolism in the injured liver.

Effects of synthetic neurotensin on the endocrine pancreas were studied in nine normal and six hypophysectomized (10th to 14th day post-hypophysectomy) dogs. Synthetic neurotensin was administered into the superior pancreaticoduodenal artery, and plasma insulin and glucagon concentrations were measured radioimmunologically. In normal dogs, ten microgram/kg neurotensin administration brought about a mild hyperglycemic response and sharp and rapid increase of plasma insulin and glucagon concentrations in the superior pancreaticoduodenal vein. A biphasic insulin response was noted in the pancreatic vein. The results suggest that a large dose of neurotensin acts directly on the endocrine pancreas causing secretion of these hormones. In hypophysectomized dogs, basal levels of plasma insulin and glucagon were decreased and neurotensin had little effect on the endocrine pancreas even with the administration of a large dose.

The in vitro effects of phenol and p-halogenated phenols on mitochondrial energy transfer reactions were examined using isolated rat liver mitochondria. The relationship between physiochemical properties of phenolic compounds and their effects on mitochondria were studied. Phenol and p-halogenated phenols induced the release of K+ ions from mitochondria, suggesting a change in permeability to K+ ions. A decrease in the respiratory control index, an increase in K+ release and stimulation of latent ATPase activity were observed with these compounds in the descending order of p-iodophenol, p-bromophenol, p-chlorophenol, p-fluorophenol and phenol. The concentrations of the phenolic compounds resulting in fifty percent inhibition of the respiratory control index and those resulting in fifty percent release of K+ ions significantly correlated with Hammett's substituent constant (sigma) and the hydrophobic binding constant (pi) of the compounds.

The three-dimensional arrangement of ductular structures formed by oval cells in rats fed 2-acetylaminofluorene (2-AAF) was studied by scanning electron microscopy (SEM) of biliary tract casts and light microscopy of sections of liver injected with india ink via the biliary tract. Both resin and india ink were well injected up to bile ductules, and the findings of each method correlated with each other. By the second week after 2-AAF administration, a few oval cells appeared in the periportal areas forming ductular structures which connected with the portal bile ducts. At the 4th week, increased ductular structures occupied two thirds of the lobule and formed networks communicating with each other, and with the portal bile ducts. At the 8th week, such ductular structures were compressed around hyperplastic nodules and appeared like a basket in biliary casts examined by SEM. Although a histochemical study of gamma-glutamyl transpeptidase revealed activity both on the luminal side of the ductular structures and hepatocytes in hyperplastic nodules, no transition was observed between these two cell populations. These results suggest that oval cells have characteristics more similar to those of biliary epithelia than of hepatocytes, and have no relation to the development of hyperplastic nodules.

To study the polarity of the efferent pathway of the myenteric plexus, recordings were made of the mechanical activity of the longitudinal muscle of isolated guinea-pig ileal segments upon stimulation with an electrical field around the myenteric plexus contained within strips of longitudinal muscle (LM-MP) continuous with each end of ileal segment. The amplitude of the contractile response to stimulation of the anal LM-MP was always larger than that to the oral LM-MP. After cholinergic and adrenergic transmission was suppressed by atropine (10 microM) and guanethidine (1 microM), and the tone of the segment was enhanced by histamine (1 microM), the LM-MP stimulation produced non-cholinergic, non-adrenergic (NCNA) ascending contraction and NCNA descending relaxation. The NCNA contraction, but not the NCNA relaxation, was abolished or reduced by desensitization to substance P. The present results suggest that the NCNA innervation of the myenteric plexus participates in the polar effects observed in the guinea-pig ileum, that the NCNA excitatory response may be mediated at least in part by myenteric substance P neurons, and that the NCNA inhibitory response is mediated by non-adrenergic neurons.

The stability of recombinant human superoxide dismutase (r-hSOD) in buffer solutions was studied in solutions at various pH and temperatures. Additionally, we studied the effects of incubation with proteases, serum and two types of hypothermic perfusates. R-hSOD was stable in the pH range of 6-11 and at temperatures up to 80 degrees C for 30 min. R-hSOD activity was not affected by incubation with trypsin, aminopeptidase M or serum for 2 h. R-hSOD activity determined at various temperatures (4-37 degrees C) did not vary remarkably. R-hSOD in hypothermic perfusates was stable at 4-37 degrees C for 24 h.

We studied the dermatoglyphics of 353 severe mental retardates (excluding those with chromosomal abnormalities and major limb malformations), using multivariate analysis, to determine how early intrauterine factors are related to the etiology of mental retardation. First, dermatoglyphics were compared between 140 individuals with undefined prenatal factors and 700 normal controls. After 6 and 9 dermatoglyphic traits were chosen as discriminative variables for males and females, respectively, the data were subjected separately for each sex to the constellation graphical method for discriminant analysis. The same formula as obtained in the idiopathic group was subsequently applied to data from cases in other etiological categories. When the misclassification rate was 0.03, the rates of correct classification of the male patients into the etiological categories of undefined prenatal, defined prenatal, perinatal, postnatal and unknown (no anamnestic data available) categories were 19.7% (13/66), 20.0% (3/15), 8.8% (5/57), 5.0% (1/20) and 7.7% (2/26), while the correct classification rates of females were 24.3% (18/74), 42.1% (8/19), 18.9% (7/37), 5.1% (1/16) and 13.0% (3/23), respectively. The results suggest that early intrauterine factors such as those producing dermatoglyphic deviations may contribute to the pathogenesis of severe mental retardation not only in patients with undefined prenatal etiological factors but also in those with perinatal factors, especially those of the female sex.

Patients with multiple myeloma were treated chemotherapeutically with a combination of melphalan, ifosfamide, prednisolone, nitrosourea and vincristine (MIP-NV therapy). The M-protein kinetics during the course of MIP-NV therapy was studied. The kinetics of serum and urinary M-protein in the first cycle of the chemotherapy was classified into four patterns, and the mode of change in the M-protein level over the entire course of chemotherapy was classified into four prototypes. There were intimate relationships among M-protein kinetics patterns in the first cycle of the chemotherapy, the effect of the chemotherapy on M-protein reduction, maturity of myeloma cells, pretreatment labeling index and clinical stage of the disease. Moreover, analyzing the prototypes, it was found that both the time for maximum M-protein reduction and the rate of increase in the M-protein level after maximum M-protein reduction affected the survival time. To predict the effect of the chemotherapy on M-protein reduction and survival time, it was useful to analyze subgroups, which were classified according to the M-protein kinetics pattern in the first cycle, the time for maximum M-protein reduction and the rate of increase in the M-protein level after maximum M-protein reduction.