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Antigenicity of clozapine was studied in rabbits, comparing with that of chlorpromazine as control. The results indicate that chlorpromazine produces antibody in rabbit as revealed by passive hemagglutination test, giving the titer of 1 : 2, 000 or higher in all the five cases observed, though specific precipitin lines has not been obtained and PCA test proves to be negative. Clozapine failed to produce anti.clozapine antibody giving negative passive hemagglutination test, passive cutaneous anaphylaxis and precipitin reaction, in all forms tested. Some remarks were made on the possible close relation between the antigenicity of the drug and its affinity to protein.

Oncogenesis of human adenovirus type 12 in the brain of rats was examined. Newborn rats of Sprague-Dawley and Donryu　strains were injected intracranially with human adenovirus type 12.　The incidence of intracranial tumors was 91% (30/33) in SpragueDawley　and 56% (14/25) in Donryu rats. Except for one tumor nodule　located in the parietal cortex of a Sprague.Dawley rat, all tumors　developed in the paraventricular areas or in the meninges. Tumors were quite similar histologically to those induced in hamsters and　mice resembling the undifferentiated human brain tumors such as medulloblastoma,　ependymoblastoma and embryonic gliomas. From　the histological features and primary sites of tumor development, it is　suggested that the tumors in the brain of rats induced by adenovirus type 12 originate from the embryonic cells in the　paraventricular area　and also from the undifferentiated supporting cells of the peripheral　nerves in the　leptomeninges.

For the purpose to reveal the changes in stimulatory effect of dibutyryl-cyclic- AMP on erythropoiesis during ontogenetic development, the author studied syntheses of DNA, RNA and protein of erythroid cells in fetal liver, neonatal and adult bone marrows of rats. In the bone marrow of neonatal animals erythropoiesis was stimulated by the intraperitoneal injection of cyclic nucleotide with enhanced DNA, RNA and protein syntheses of erythroid cells. Enhancing effect of dibutyryl-c-AMP on the erythropoiesis decreased gradually with advance of neonatal days. Autoradiographic observations revealed that in erythoid cells isolated from fetal liver and neonatal bone marrows, DNA-, RNA- and protein-snythesis was markedly stimulated by incubating with cyclic nucleotide, but not in those from adult bone marrow. Discussion was made on the changes in the regulatory mechanism of erythropoiesis according to the transition of hematopoietic organs during development.

Folic acid contents of plasma, whole blood, liver and spleen in Rauscher leukemic mice were estimated. Plasma and liver folate in the leukemic mice was lower than that of normal mice, suggesting that folic acid was deficient in Rauscher leukemia. Folic acid contents in whole blood and spleen were even higher in the leukemic mice than those in normal mice. Clearance study by injecting folic acid intravenously into leukemic mice showed faster disappearance of folic acid from the circulating blood, suggesting that folic acid demand of Rauscher leukemia is increased. Methotrexate administered shortly after inoculation of the virus did not prevent Rauscher leukemia. But anemia, reticulocytosis and erythroblastosis, which are commonly seen 3-4 weeks later in leukemic controls, were not marked as compared with controls. It can be concluded that the requirement of folic acid is greater in Rauscher leukemia than in controls, and methotrexate is effective for preventing hematological changes commonly seen in this type of leukemias.

Effect of inorganic phosphate on ferrous ion- and ascorbate-induced lipid. peroxidations of isolated rat liver mitochondria was investigated. As a result it has been shown that phosphate accelerates the ferrous ion.induced lipid peroxidation; namely, phos. phate shortens the induction lag period of the lipid peroxidation reaction but the malondialdehyde after onset of its production is yielded at the same rate in various concentrations of phosphate. On the other hand, phosphate inhibits ascorbate.induced lipid peroxidation. There are stoichiometric interactions between the concentration of phos. phate and the induction period. Oxygen uptake by mitochondria was observed in the presence of both ferrous ion and phosphate at initial step of the reaction without being accompanied by malondialdehyde production, and afterwards there occurred malondialdehyde production with rapid rate of the oxygen uptake. Possible mechanisms and interactions among ferrous ion, ascorbate and phosphate were discussed.

Hematological changes and serum iron, vitamin B12 and folate levels after administration of iron plus folic acid were com· pared with changes and levels after supplement of iron alone in 100 pregnant women. No hematological benefits by adding folic acid was revealed. It is concluded that folic acid deficiency in pregnant women is mild and routine supplementation of folic acid is not necessary except for proved cases of folate deficiency. As to the reason why folic acid deficiency is so mild and megaloblastic anemia is so rare in Japan, uniformity of dietary habits, i. e. boiled rice as basic food, was discussed.

Antitumor effects of the combination chemotherapy with hemolytic streptococcus preparation, OK-432, and various anticancer agents were observed on experimental tumors and human cancers. Experimental studies revealed that combined use of OK-432 with Mitomycin C, Nitrogen mustard N-Oxide or Bleomycin was remarkably effective on rodent transplantable tumors such as Ehrlich carcinoma, sarcoma-lOO and rat ascitic hepatoma AH-66. As for the mode of action of OK-432, besides a direct action on cancer cells, a host-mediated action appears to be also involved. Clinical trials were made on 14 cases with various advanced cancers, and favorable response was obtained in 5 with lung cancer. Fever was the major side effect of OK-432 and there was no evidence of bone marrow suppression.

Neocarzinostatin (NCS), an antibiotic with a high molecular weight, showed an inhibittory effect on Rauscher mouse leukemia. In normal mice, no significant changes were found in peri· pheral blood pictures except a tendency of lymphocytopenia, when O. 05mg/kg/day and O.50mg/kg/day of NCS were injected intraperi. toneally to two groups of mice for three days. On the other hand, peripheral nucleated cells of Rauscher leukemic mice decreased after intraperitoneal administration of NCS in a dose over O.25mg/kg/day for three days. The cells affected by NCS were mainly erythroblasts and smudged cells. Spleens of Rauscher leukemic mice treated with NCS have been reduced in weight, and histological examinations of livers showed a signicant decrease of infiltrating cells. In three groups treated with 0.25mg/kg/day of NCS for seven days, O.25mg/kg/day for three days and O.50mg/kg/day for three days, the.5()% survival time was longer than in the control group. Particularly, the 50% survival time in Rauscher leukemic mice treated with 0.50 mg/kg/day for three days was over twice that of the control group.

To obtain a useful rat liver cell line for in vitro carcinogenesis, two rat diploid epithelial cell lines were established from a 7-day-old male rat by the repeated colonial clone method. More than 80% of cells from each cell line have maintained normal diploid karyotype for over 30 months in vitro. The diploid cells were identi. fied as normal diploid karyotype by conventional Giemsa and trypsin. Giemsa techniques. They showed little difference in morphology and growth rate between early and late passages. Without cloning, they tended to be heterogenous in cell morphology, became heteroploid in chromosome and showed increased growth potential with time. Highly heteroploid cells which were derived from one of the lines produced ascites and solid tumors when inoculated into syngeneic rats intraperitoneally. Histologically, the tumors were diagnosed as poorly differentiated hepatocarcinomas. One of these diploid epithelial cell lines in early passage contained some activity of tyrosine transaminase and liver type aldolase and .glycokinase. Therefore, it is suggested that these epithelial cell lines represent liver parenchymal cells.

Clinical features were studied in 125 patients with sarcoidosis (72 females and 53 males) diagnosed at Okayama University Hospital during a recent 10-year period. The age distribution had two peaks in patients in their 20s and the 50s. Over half of the patients were detected at health screening check and were asymptomatic, while the remaining were symptomatic. Twelve patients were in stage 0, 41 were in stage I, 54 were in stage II, 16 were in stage III, and 2 were in stage IV according to the chest x-ray findings. Serum angiotensin converting enzyme levels and serum lysozyme levels were elevated in 60% and 76% of the patients, respectively. The bronchoalveolar lavage fluid showed lymphocytosis, especially of helper T-cells. The clinical features of sarcoidosis appear to depend on the duration of the disease.

Extracorporeal Membrane Oxygenation (ECMO) has been adopted as a means of strong respiratory support. In lung transplantation, reimplantation response is still a serious problem. It causes severe respiratory failure which is refractory to mechanical ventilation in some cases. The purpose of this study was to evaluate the effects of veno-venous ECMO after lung transplantation using a canine autotransplantation model. The autotransplantation model was created by keeping the left lung in a warm ischemic state for 2 h. After reperfusion, the right pulmonary artery was ligated. The following two groups were studied: Group 1, Control group, (no ECMO group) (n = 6). After reperfusion, both lungs were ventilated without ECMO. Group 2, ECMO group (n = 7). After reperfusion, veno-venous ECMO support was introduced with reduction of mechanical ventilation. In the no ECMO group, four of the animals died within 210 min after reperfusion. In the ECMO group, two of the animals died of severe pulmonary edema. Data of blood gas analyses (PaO2, PaCO2, and SvO2) after reperfusion were significantly better in the ECMO group, whereas there were no significant differences in both shunt fraction and pulmonary vascular resistance index. In this model with severe pulmonary edema induced by warm ischemia, veno-venous ECMO contributed to the improvement of hypoxemia and hypercapnia, but did not improve pulmonary hemodynamics.

To evaluate urinary albumin index (UAI), the relationship between albumin excretion rate (AER) in the urine stored for 24 h and UAI in the urine collected arbitrarily on the morning of the same day was studied in 123 inpatients. The patients were admitted to our hospital from September 1, 1988 to August 31, 1989, consisting of 67 non-insulin dependent diabetics (Group 1), 40 patients with collagen disease (Group 2), and 16 patients with primary renal disease (Group 3). The relationship between log(e) AER and log(e)UAI was plotted on a graph. Pearson's rank correlation coefficients of Groups 1-3, Group 1, Group 2, and Group 3 were as follows: r = 0.725, r = 0.691, r = 0.855, and r = 0.611, respectively. The formula obtained by using Pearson's rank correlation coefficients to estimate log(e)AER from log(e)UAI in 123 cases of Groups 1-3, 67 cases of Group 1, 40 cases of Group 2, and 16 cases of Group 3 were: log(e)AER/log(e)UAI = 0.815, log(e)AER/log(e)UAI = 0.860, log(e)AER/log(e)UAI = 0.830, log(e)AER/log(e) = 0.722, respectively. In the present study, log(e)UAI was found to correlate well with log(e)AER. As AER is generally accepted to be the most reliable index to know the stage of albuminuria, UAI is considered to be clinically useful.

An etoposide-resistant subline, SBC-3/ETP, from a human small cell lung cancer cell line, SBC-3, was developed by continuous exposure to increasing concentrations of etoposide in culture. The SBC-3/ETP was 52.1-fold more resistant to etoposide than the parent cell line. The SBC-3/ETP was highly cross-resistant to teniposide, adriamycin, vinca alkaloids, 4-hydroperoxycyclophosphamide, CPT-11 and mitomycin C, and marginally cross-resistant to cisplatin, while the subline showed a collateral sensitivity to bleomycin. Topoisomerase I activity in the SBC-3/ETP was reduced to an extent of one half and topoisomerase II activity to an extent of one eighth in comparison with those of the SBC-3. Intracellular accumulation of [3H]-etoposide in the SBC-3/ETP was significantly lower in comparison to the SBC-3. An overexpression of MDR1 mRNA, and the presence of its product, P-glycoprotein, were detected in the SBC-3/ETP by Northern blotting and flowcytometry using a monoclonal antibody of the protein, MRK16. These results indicate that a decreased activity of topoisomerase II is the major factor for the development of etoposide resistance, and that an overexpression of the MDR1 gene is responsible, in part, for the development of resistance to the drug and some structurally unrelated compounds such as adriamycin and vinca alkaloids.

The influences of ventricular pacing at a rate of 70 beats/min (bpm) on the systemic and coronary hemodynamics, myocardial metabolism, and cardiac work efficiency were evaluated in five patients with bradycardia. The results were compared to those obtained in six normal subjects at rest. In order to elucidate the effects of a relatively high rate of ventricular pacing, cardiovascular and metabolic variables were also obtained at 120 bpm in the normal subjects. It was observed that the patients eventually benefited from ventricular pacing at a rate of 70 bpm and improved in systemic hemodynamics. Although coronary hemodynamics and myocardial metabolism were accelerated, the cardiac work efficiency was not improved. A pacing rate of 120 bpm in the normal subjects did not appear to accelerate systemic hemodynamics, but adverse accelerations of coronary hemodynamics and myocardial metabolism were observed, and the cardiac work efficiency was remarkably reduced as a result. Our observations indicated that the coronary reserve capacity was very important for ventricular pacing, and suggested that an undue increment of the pacing rate not only might be meaningless but also might induce ischemic angina. Therefore, we should be cautious in using a rate-responsive pacing mode, particularly in determination of the upper limit of pacing rates, although many benefits with this pacing mode have recently been advocated.

The present study was undertaken to determine whether a biventricular bypass system operated in an independent variable rate (VR) mode can maintain the entire circulation. Two pusher-plate pumps which incorporated the Hall effect position sensors were used to bypass the right and left ventricles in 10 sheep under fibrillation. The flow distributions of the pump output to the carotid and renal arteries were investigated every 6 h using ultrasonic blood flow meters for 24 h in 5 animals, and the controllability of the VR mode was evaluated in 5 long-term experiments. The carotid artery flow ratio to the pump output decreased significantly from 4.7 +/- 0.8% before the bypass to 2.7 +/- 0.9% after 24 h. However, the renal artery flow ratio did not change throughout the experiments. In the long-term experiments, the animals were kept alive from 3 to 48 days (mean 15.6 days). The mean pump output had been maintained at more than 90 ml/min/kg for the first 7 days. After the surgery, the pump driving conditions were not readjusted in any experiment. The results indicate that the biventricular bypass system operated in the independent VR mode automatically maintains the entire circulation at a satisfactory level.

We measured hepatitis C virus antibody titers in 13 patients with chronic hepatitis C to determine whether titration of hepatitis C virus antibody was useful or not, to predict and evaluate the efficacy of interferon (IFN) treatment. During administration of IFN, hepatitis C virus titers declined in all patients. Antibody titers performed before treatment as well as just at the end of treatment did not correlate with change of the alanine aminotransferase levels during administration of IFN. Antibody titers declined continuously after treatment in 5 patients with normal alanine amino-transferase levels for over 6 months after discontinuation of IFN. Antibody titers rose again in 6 patients whose alanine aminotransferase levels fluctuated after treatment. An exceptional pattern of change occurred in 2 patients whose antibody titers declined continuously although their alanine aminotransferase levels fluctuated after treatment. Repeated titration of hepatitis C virus antibody appears to be useful for evaluating the long-term efficacy of IFN treatment.

Trans-sternal bilateral thoracotomy was performed to resect the right upper lobe and the left S1 + 2 + S3, and to complete lymphadenectomy in a 35-year-old female case of lung cancer in whom multiple lesions were suspected. Trans-sternal bilateral thoracotomy was considered to be useful for one-stage surgery in patients in whom bilateral lung cancer is suspected or confirmed, because it provides a sufficient surgical field enabling the resection of lung and lymph nodes. This may be the first case report of trans-sternal bilateral thoracotomy to treat multiple primary lung cancer.

Radiological findings on the fate of grafted Kiel bone implants for the treatment of bone tumors were evaluated in 25 lesions. The mean follow-up period was 14.8 years, ranging from 5 to 21.8 years. We classified the radiological findings into 4 grades; Excellent (4 lesions), Good (14 lesions), Fair (2 lesions), and Poor (5 lesions). All cases of the Poor grade were polyostotic fibrous dysplasia. The younger the patient at the time of the operation, the more rapidly Kiel bone grafts tended to be incorporated. The grafted bone can become enmeshed in the structure of the recipient bed (Good or Excellent grades) within 10 years in most cases, except in polyostotic fibrous dysplasia.

In an attempt to predict the clinical activity of newly developed anthracycline analogues, ME2303, KRN8602, and SM5887 in the treatment of lung cancer, we compared antitumor activity of these drugs with that of adriamycin, using six human lung cancer cell lines and two drug-resistant human lung cancer sublines. Taking the pharmacokinetic data into consideration, we evaluated the relative antitumor activity: the ratio of area under the concentration-time curve of each drug to the 50% inhibitory concentration of the drug. Regarding this ratio, ME2303 was more potent than adriamycin, SM5887, and KRN8602. Cross-resistance of the new analogues to adriamycin was investigated using an adriamycin-resistant small cell lung cancer subline, SBC-3/ADM100 and an etoposide-resistant subline, SBC-3/ETP. SBC-3/ADM100 being 106-fold more resistant to adriamycin than the parent SBC-3 showed less resistance to the analogues: 1.80-fold to KRN8602, 3.80-fold to SM5887, and 8.60-fold to ME2303. SBC-3/ETP which was 52.1-fold more resistant to etoposide and 39.5-fold more resistant to adriamycin were also less resistant to the new analogues: 3.27-fold to KRN8602, 9.07-fold to SM5887, and 17.3-fold to ME2303. In conclusion, ME2303 was found to be the most potent agent among drugs tested for the treatment of lung cancer, and KRN8602 can be expected to be beneficial for the treatment of drug-resistant small cell lung cancer.

Since detection of hepatitis C virus RNA by the polymerase chain reaction (PCR) showed that there existed anti-C100-3 (anti-HCV) antibody negative patients infected with HCV, we attempted to find out whether there were any clinical or viral genomic differences between the anti-HCV antibody positive and negative groups. One hundred and fifty-nine patients with chronic liver diseases with hepatitis C virus RNA in their sera were selected. Anti-HCV antibody was tested for anti-C100-3 antibody by an enzyme linked immunosorbent assay. The incidence of anti-HCV antibody was 129/159. The concentration of serum gamma-globulin, the titier of ZTT, and the positive rate of the PCR with the primers of the NS3/4 region (NS3/4PCR) were significantly higher in the anti-HCV antibody positive group than in the negative group. However, the other data such as alanine aminotransferase activity or past history were not significantly different. Nucleotide sequence of the cDNA fragments of NS3/4 region amplified by the PCR did not differ significantly between isolates from anti-HCV antibody positive and negative sera. The sequences observed in the present study did not differ significantly from those reported previously. Although there remains the possibility that the variation of viral genomic sequences may cause the absence of anti-HCV antibody, these results suggested that the individual clinical backgrounds or immunoreactivity of the patients might influence the antibody development.