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We have measured the plasma PIVKA-II levels in 188 cases of various liver disease with HCC and malignant diseases in other organs by an EIA, using a monoclonal antibody (E-1023 kit, Eisai), and also have measured the plasma vitamin K levels in cases of HCC and cholestasis by an HPLC. Plasma PIVKA-II was detected in many cases of HCC (67%, 35 of 52 cases) and cholestasis (60%, 6 of 10 cases). In contrast, the positivities of PIVKA-II in the other diseases including benign liver diseases were very low. Combination assays of PIVKA-II and vitamin K revealed that PIVKA-II correlates with vitamin K in cholestasis but not in HCC, suggesting that PIVKA-II in HCC does not depend on a systemic deficiency of vitamin K. From these results, it was concluded that PIVKA-II is a reliable marker which can reflect the clinical course of HCC.

Digoxin was administered orally to eight anemic patients in their anemic and convalescent stages, and serum digoxin concentration was determined by radioimmunoassay. In the anemic patients a significantly lower level of serum digoxin concentration was observed in anemic state compared with convalescent stage at 72 hours after the drug administration (p less than 0.01). In usual clinical use, a full digoxin effect is expected to be attained as 72 hours. Tritiated digoxin was administered intravenously to anemic and control rats and the tritium in samples of the blood, myocardium and urine were counted in a liquid scintillation counter. The anemic rats showed significantly lower level of serum 3H-digoxin at 6 hours (p less than 0.01) and lower myocardial concentration at 24 hours (p less than 0.01). Larger amount of urinary excretion of 3H-digoxin was observed in the anemic rats 6 hours after the drug administration. No significant difference in fecal excretion of 3H-digoxin was found between the anemic and control rats.

A 20-yr-old woman with known diabetes insipidus complained of high fever and jaundice. Liver specimens biopsied under peritoneoscopy showed proliferating histiocytic or foamy cells in periportal areas. Immunocytochemical investigation demonstrated the presence of S-100 protein, but the absence of lysozyme in their histiocytic cells, and ultrastructural study revealed Birbeck granules in them. Vinblastine therapy reduced jaundice and high fever, and diabetes insipidus was controlled. Clinical, immunohistological, and cytological features suggested Letter-Siwe disease with jaundice, which responded well to treatment.

The healing process of cysteamine-induced duodenal ulcer was studied by [3H]thymidine autoradiography. After the development of ulcer in the duodenum, cell proliferation was markedly activated not only in the crypts but also in the Brunner's glands near the ulcer. In the initial stages of ulcer healing, they both contributed to form the surface covering regenerating epithelium. Granulation tissue also proliferated at the base of the ulcer. In later stages of ulcer healing, new crypts were formed in the floor of the ulcer. New villi regenerated from these crypts and Brunner's glands regenerated by proliferation in situ. The ulcer base then was completely covered with new villi and granulation tissue was replaced by dense fibrous connective tissue. The present study suggested that the Brunner's glands, together with the crypts of Lieberkühn, play an important role in the healing process of cysteamine-induced duodenal ulcer.

Distribution of serotonin-immunoreactive nerve fibers (5-HT fibers) in the subthalamic nucleus (STN) of the rat, cat and monkey was examined with a modified peroxidase-anti-peroxidase method using 5-HT antiserum without pretreatment. Fine varicose 5-HT fibers formed a fine network in the STN. Overall density of 5-HT fibers in the STN was highest in the monkey, and lowest in the rat. In the rat and cat, these fibers were distributed almost diffusely in the STN, whereas in the monkey they were particularly abundant in the ventral and medial parts of the STN. Many thick 5-HT fibers ran through the monkey STN.

To investigate the clonal origin of refractory anaemia, we carried out cytogenetic studies on single haematopoietic colonies derived from granulocyte-macrophage precursors (CFU-GM) and erythroid precursors (BFU-E). Marrow cells from a patient with refractory anaemia revealed the coexistence of a normal and an abnormal karyotype; 46,XY/45,XY,-15,-18,+der(15q18q). Cytogenetic studies on CFU-GM- and BFU-E-derived colonies obtained from the bone marrow showed the presence of the same karyotypic abnormality carrying the der(15q18q). Colonies carrying a normal diploid karyotype were also detected in the same culture dish. These results indicate that the clone with the der(15q18q) chromosome abnormality arises in a stem cell which can differentiate to at least both granulocyte-macrophage and erythroid lineages.

Recently we experienced 2 adult post-renal transplantation cases with gastroduodenal cytomegalic inclusion body. In one case, it was possible to carry out close endoscopic observation from onset to resolution a - very rare opportunity. A 39-year-old man developed continuous occult blood in the stool for 1 month after renal transplantation. Multiple erosive lesions from the upper corpus of the stomach to the bulb of the duodenum were revealed by the endoscopic study. A biopsy specimen from the erosion showed the cytomegalic inclusion body. One month later, the erosive lesions had disappeared. The second case is a 40-year-old man who developed tarry stools 5 days after renal transplantation. Multiple erosions partially covered with blood coagula from the upper portion of the gastric corpus to the antrum were revealed by the endoscopic examination. A biopsy specimen from the erosion in the antrum contained the cytomegalic inclusion body.

Rat livers were perfused with 0.5% Triton X-100 for 30 to 60 min and studied by scanning electron microscope. Three-dimensional filamentous networks were visualized in the cytoplasm of hepatocytes in situ. Branching and end-to-side contacts of intermediate filaments, and intermediate filaments which were connected with microtubules and microfilaments were noted. Numerous filaments were observed in the perinuclear region and at the cell border. Filaments were attached to polyribosomes and nuclei. No differences were observed in the cytoplasmic cytoskeleton after treatment of the sample at 4 degrees C. These results support the concept that intermediate filaments mechanically integrate the cytoplasmic space.

Through X-ray and endoscopic examination of stomach, a 77 year-old man, who complained of epigastralgia, he was diagnosed to have Borrmann III type gastric carcinoma on the antrum. The gastric biopsy specimen obtained from the tumor revealed to be well differentiated adenocarcinoma. Since the patient refused receiving surgical treatment, a combined administration of futraful and uracil (UFT therapy) was performed. 4 weeks after receiving UFT therapy, the patient became less aware of subjective symptom and the gastrofiberscopic picture showed smaller mass lesion compared to that of prior to the treatment. 8 weeks later, the tumor was remarkable reducing its size. When compared 14 cases of gastric carcinoma receiving UFT therapy with 26 cases receiving Futraful therapy (FT therapy), the UFT group responded more effectively than the FT group. In the UFT therapy, complete (CR) and partial response (PR) were obtained in 4 of 13 cases of gastric carcinoma with an effective rate of 30.8% according to the response criteria proposed by the Koyama-Saitoh group and with a Karnofsky scale of IA or better in 6 (42.8%) of 14 cases. On the other hand, in the FT therapy CR and PR were obtained in 5 of 26 cases with that of 19.2%, while a Karnofsky scale of IA or better was achieved in 6 (23.1%). As for 3 cases of PR in the UFT therapy the microscopic view of the biopsy specimen from gastric carcinoma showed well differentiated adenocarcinoma, which responded to the UFT therapy remarkably 4-5 weeks after receiving UFT therapy.

The efficacy of tiopronin (2-mercaptopropionyl glycine) 600 mg daily in the treatment of chronic active or chronic persistent hepatitis has been assessed in a double-blind controlled clinical trial of 12 weeks involving 165 Japanese patients with histologically proven disease. Treatment with the drug was associated with a significant improvement in abnormalities of serum transaminase and gamma glutamyl transpeptidase, with reversion towards baseline values on stopping the drug. Improvement was independent of the histological classification of the disease, or HBsAg status. The drug was well tolerated with few side-effects. The results of this short-term study indicate that tiopronin may be of value in the treatment of chronic hepatitis.

Rats with decreased insulin response and with normal glucose tolerance were concentrated by repeated selective breeding of normal Wistar rats with low insulinogenic index. In general, the mean insulinogenic index of the inbred offsprings showed a tendency to decrease more than their parents generation. Thus mean insulinogenic indices in second (F2), third (F3) and fourth (F4) generations were significantly reduced more than the normal rats without glucose intolerance. Pancreatic islets from the F3 and F4 rats lost partially their ability to release insulin at 20 mM glucose in vitro. It is suggested that a defect responsible for the decreased insulin response in the F2, F3 and F4 rats resulted from a loss of the ability to secrete insulin in each islet, and that this defect was concentrated by repeated selective breeding of normal Wistar rats.

A 13-yr-old Japanese female with acute lymphoblastic leukemia (ALL) that was associated with a Philadelphia chromosome (Ph1) as well as a 14q+ chromosome abnormality is reported. The cell surface phenotype of leukemic cells was determined to be non-T, non-B ALL on the basis of positive Ia-like antigen, terminal deoxynucleotidyl transferase activity, and lack of receptors for sheep erythrocytes, surface immunoglobulin, or intracytoplasmic mu-chain immunoglobulin. The combination of both a Ph1 and a 14q+ has not been reported previously in patients with ALL.

Characteristics of taurine (2-aminoethanesulfonic acid) transport were studied in freshly isolated rat hepatocytes prepared by a collagenase perfusion technique. The uptake of taurine at 37 degrees C was linear up to 30 min of incubation, but gradually decreased thereafter and reached a plateau at 90 min after initiation of the incubation. Taurine uptake at 4 degrees C by isolated hepatocytes was not saturable, whereas that at 37 degrees C was saturable with the following parameters: Km, 37 microM; Vmax, 0.043 nmoles/mg prot./min; and EA, 5.6 Kcal/mol. The taurine uptake at 37 degrees C was found to be sodium dependent, and this was inhibited competitively by guanidinoethyl sulfonate and beta-alanine with the Ki values of 1.75 mM and 285 microM, respectively. Conjugated cholate, conjugated chenodeoxycholate, alanine, isethionate and leucine had no effect on the taurine uptake. The present results indicate that taurine uptake by isolated hepatocytes consists of unsaturable and energy independent, and carrier-mediated and energy dependent transport processes.

The authors present a case of hepatitis, which was due to repeated self-administered inhalation of methoxyflurane in subanaesthetic concentrations for insomnia. The diagnosis of viral hepatitis, type A or type B, was excluded on the basis of serologic findings. This case is of particular interest in that methoxyflurane even in subanaesthetic concentrations caused hepatic damage on repeated exposure.

The alteration of amino acids in cerebrospinal fluids (CSF) from 14 cases of Parkinson's disease, five cases of cerebellar degeneration and five cases of headache (control) was studied using high performance liquid chromatography. In patients with Parkinson's disease, it was found that the CSF level of GABA showed a significant decrease, while that of taurine had an increase. The degree of disability in Parkinson's disease and the decreased GABA levels had a positive correlation, especially at its advanced stages. In patients with cerebellar degeneration, it was also found that there was a significant decrease in CSF GABA. The present results suggest that the CSF level of GABA may be a good indicator of the severity of Parkinson's disease as well as the presence of cerebellar degeneration. Possible involvement of the increase of CSF taurine in the pathogenesis of Parkinson's disease is also suggested.

Six patients with chronic myelogenous leukemia and a complex Philadelphia (Ph1) translocation are described. The complex Ph1 translocations were a three-way translocation in five patients and a five-way translocation in one. Additional chromosomal aberrations were detected in four of five patients when the blastic crisis supervened. The median survival time was 42 months. The remaining patient died of acute myocardial infarction 23.5 months after the diagnosis of CML was made. There seems no difference between these six patients and those with the standard Ph1 with respect to clinical, hematologic and cytogenetic findings.

We measured 2',5'-oligoadenylate synthetase activities in serum and peripheral blood mononuclear cells from 10 patients with chronic hepatitis B who were being treated with interferon so as to determine whether 2',5'-oligoadenylate synthetase activity in serum reflected 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells, and whether it could be used to monitor interferon treatment. Pretreatment values of 2',5'-oligoadenylate synthetase activity in patients' serum and peripheral blood mononuclear cells were not statistically different from values from control subjects. When interferon was administered, serum levels of 2',5'-oligoadenylate synthetase began to rise within 3 hr, reached peak values at 12 hr and then declined. The levels of 2',5'-oligoadenylate synthetase activity both in serum and peripheral blood mononuclear cells increased substantially during interferon treatment, ranging 2- to 50-fold greater than initial levels. The levels of 2',5'-oligoadenylate synthetase in serum correlated closely with levels in peripheral blood mononuclear cells. In addition, when the levels of 2',5'-oligoadenylate synthetase rose during interferon administration, serum hepatitis B virus DNA polymerase values fell, and, in some cases, DNA polymerase rose again when 2',5'-oligoadenylate synthetase fell after discontinuation of interferon. These findings suggest that 2',5'-oligoadenylate synthetase activity in serum accurately reflects the antiviral effect of interferon and could be used to monitor interferon treatment.

The cytoskeletons of hepatocytes and biliary epithelial cells in bile duct ligated rate livers were investigated by transmission and scanning electron microscopy. The three dimensional organization of the intermediate filaments (IFs) of hepatocytes and biliary epithelial cells was clearly demonstrated by scanning electron microscopy. Cell borders and dilated bile canaliculi were well preserved after perfusion with detergent solution. A very dense filamentous network of IFs was seen throughout the cytoplasm, especially around the dilated bile canaliculi and at the cell borders. IFs in biliary epithelial cells were more numerous compared with hepatocytes. Morphometric analysis showed that the IFs of hepatocytes significantly (p greater than 0.001) increased in amount in bile duct ligated rats. The IFs of biliary epithelial cells showed no significant changes in bile duct ligated rats compared to controls. These results suggest that the increase in IFs in hepatocytes results from the adaptation of the hepatocytes to the stress imposed by bile duct ligation. It may be that the resulting intracanalicular pressure and back diffusion of bile induces a metaplastic change in hepatocytes so that they acquire more IFs to function like the bile duct epithelium to conduct bile flow.

Hepatic ethanol metabolism in the liver from carbon tetrachloride (CCl4)- treated animals was studied using non-recirculating hemoglobin-free liver perfusion system. CCl4-administration decreased ethanol uptake by the liver to 56% and 30% of the control values following the acute (24 hrs. after treatment) and chronic (8-12 weeks) treatments, respectively. In addition, 4 mM fructose, a well-known agent to increase ethanol metabolism in the liver, did not increase the hepatic uptake of ethanol in CCl4-treated livers. Hepatic alcohol dehydrogenase activity was not changed following acute and chronic CCl4 treatments. The lactate/pyruvate (cytosolic NADH/NAD) ratio as well as beta-hydroxybutyrate/acetoacetate (mitochondrial NADH/NAD) ratio significantly increased, whereas both hepatic oxygen uptake and oxidation of NADH in mitochondria remarkably decreased in parallel with the magnitude of liver injury induced by CCl4. Histological studies revealed that the liver had centrilobular coagulative necrosis with fatty droplet formations at acute phase, while bridging fibrosis between central and portal areas and the pattern of cirrhosis with conspicuous changes in the mitochondria were seen at chronic phase. These data indicate that CCl4-treatment significantly reduces hepatic ethanol metabolism via the inhibition of reoxidation of NADH, a rate limiting step of ethanol metabolism in the liver.

Livers from 12 mice fed griseofulvin for 4 to 6 months were perfused in situ with a detergent solution to extract lipid membranes leaving the cytoskeleton intact. Seven control mice were similarly studied. After 30 to 120 minutes perfusion, liver samples were examined by scanning electron microscopy and transmission electron microscopy. By light microscopy, Mallory bodies (MBs) were observed in pericentral hepatocytes. These were confirmed by transmission electron microscopy. Intermediate filaments (IFs) were observed in close apposition to MBs. Numerous IFs were seen throughout the cytoplasm. The 3-dimensional organization of the cytoskeleton and MBs were clearly visualized by scanning electron microscopy. The IFs were disorganized in the hepatocytes and formed small MBs in griseofulvin-treated mice. In the case of hepatocytes containing large MBs, there was an apparent decrease in the concentration of IFs. Transition forms of dense networks of IFs between the normal cytoskeleton and the MBs were noted in the cytoplasm between small MBs and the nucleus and also at the cell border. The IFs connected to the nucleus and invaded the MBs. The MBs appeared to form as a result of condensation or collapse of the IFs.

The efficacy and the safety of a combination regimen using cefbuperazone (CBPZ) and amikacin (AMK) were evaluated in severe infections in patients with hematological diseases. Twenty two patients were subjected to this combination therapy; among these, 18 patients were evaluable for the effectiveness. They included 9 cases of leukemia, 5 cases of malignant lymphoma, 2 cases of aplastic anemia, and 2 cases of angio-immunoblastic lymphadenopathy with dysproteinemia. Excellent responses were obtained in 5 patients and good responses in 5 patients, with a total effectiveness of 55.6%. Efficacy rates for individual types of infections were; 2/2 in sepsis, 6/14, or 42.9% in suspected sepsis, 1/1 in urinary tract infection, and and 1/1 in upper respiratory infection. The combination treatment was also effective in 4 of 6 cases in which neutrophil counts were less than 500/mm3 prior to therapy. Side effects were observed in only one patient. Mild proteinuria occurred in a 80-year-old male in 6 days after the regimen was started, but was not serious. These results indicate that a combination of CBPZ and AMK is safe and effective for the treatment of infections even in patients with compromised immunodefenses.

A case of Dipetalonema perstans infection in a 34-year-old Japanese male is presented and from his past history there is no doubt that he obtained the infection in Zaire, Africa. The morphology and periodicity of the microfilaria were studied in detail and the clinical manifestations of the infection documented. This is the first report of imported D. perstans infection in Japan.