Biomedical subjects
Publications and source records attributed to A Naito.
A case of solitary bone cyst of rib was reported. The patient was 28-year-old man who was admitted to our hospital complaining of chest pain caused by pathological fracture of the left 10th rib. Chest x-ray film revealed a solitary cystic lesion of the 10th rib. The tumor was removed by extrapleural rib partial resection and the histological examination confirmed the diagnosis of solitary bone cyst.
Recombination in a bovine papillomavirus shuttle vector carrying direct repeats of Moloney murine leukemia virus LTR sequence was examined. Differently from similar vectors carrying direct repeats of SV40 polyA addition signal or neomycin resistance gene, the vector exhibited no homologous recombination between the repeats. Instead, illegitimate recombination took place. There were two major types of recombination products from the restriction cleavage pattern. The plasmids in independent cellular clones belonging to the same recombination type shared the identical crossover point. Thus, in this plasmid, illegitimate recombination occurred at preferential sites involving exactly the same sequences.
The transformed phenotype of C127 cells harboring bovine papillomavirus shuttle vector pdBPVMMT neo(342-12) was suppressed by direct contact with untransformed C127 cells. By repeated selections of rare foci developing on untransformed cell monolayers, we obtained a cellular clone of BPV transformants which formed foci on the untransformed C127 cells as efficiently as on plastic surface. The BPV genome in the mutant cells showed extensive genetic rearrangements, duplication of upstream regulatory region and deletion of pBR322-derived sequence and its flanking. There was an increase in BPV-transformant in contact with the untransformed C127 cells resulted in a marked reduction of the BPV transcripts, while in the case of the mutant transformant the reduction was much slighter. This indicates that the transcription level of the BPV genome was controlled by a cell-cell contact signal.
For evaluating hepatic tumors, ultrasonograms using carbon dioxide by arterial injection (CO2US) was performed in 37 patients, including 28 hepatocellular carcinomas, 11 hepatic metastases, and 3 hepatic hemangiomas. Hepatic tumors were enhanced by CO2US and easily identified. CO2US of hepatic tumors were classified into six patients. Generally, on CO2US hepatocellular carcinomas were well enhanced, and hepatic metastases had ring-like enhancement. Hepatic hemangiomas showed peripheral patchy enhancement. In the patients with hepatocellular carcinoma, the primary tumors were better identified on CO2US than conventional sonography. The daughter nodules with hepatocellular carcinoma were also better demonstrated than other examinations. CO2US is helpful in evaluating and differentiating hepatic tumors.
Relative orientation of recombination substrates, neo gene, strongly influenced homologous recombination events in a bovine papillomavirus shuttle vector. Between direct repeats, recombination occurred at a high frequency while between inverted repeats, it was rare. Double strand break near the mutation site increased the recombination frequency between inverted repeats but not between direct repeats. Formation of long heteroduplex as a recombination intermediate may explain this apparently paradoxical phenomenon.
The kinetic process of folding of bovine pancreatic ribonuclease A in a 2H2O environment at pH 1.2 was examined by a recently developed temperature-jump NMR method (Akasaka et al., (1990) Rev. Sci. Instrum. 61, 66-68). Upon temperature-jump down from 45 degrees C to 29 degrees C, which was attained within 6 s, the proton NMR spectral changes were followed consecutively in time intervals of seconds. There was a rapid spectral change, which was finished within the jump period, followed by a much slower process which lasted for a minute or longer. Rates of the slower process were measured at different positions of the polypeptide chain as intensity changes of individual His and Tyr proton signals of the folded conformer and as intensity changes of aliphatic and His protons of the unfolded conformer. Most of these rates coincided with each other within experimental error with an average value of 2.8 x 10(-2) s-1. The result gave clear experimental evidence that the slow folding of RNase A at low pH is a cooperative process involving most regions of the molecule, not only thermodynamically, but kinetically as well.
We recently reported that six 1,4-dihydropyridine derivatives out of 57 screened effectively over-came vincristine (VCR)-resistance in VCR-resistant (P388/VCR) leukaemia-bearing mice when the dihydropyridines and VCR were administered intraperitoneally (i.p.). Furthermore, among the six dihydropyridine derivatives, two compounds, NK-250 and NK-252, most effectively overcame VCR-resistance while exhibiting relatively low calcium antagonistic activity and toxicity. In this study, we examined whether NK-250 and NK-252 could potentiate the antitumour activities of etoposide in mice with drug-sensitive (P388/S) or VCR-resistant (P388/VCR) leukaemia cells when the anticancer agents and tumour cells were administered by various routes. In both groups of mice inoculated i.p. with P388/S- and P388/VCR-leukaemia cells, the oral (p.o.) administration of NK-250 combined with i.p. or intravenously (i.v.) administration of etoposide (ip-po-ip trials and ip-po-iv trials) dramatically potentiated the antitumour activity of etoposide. Although etoposide alone was less effective in treating mice inoculated i.v. with P388/S- and P388/VCR-leukaemia cells, p.o. administration of NK-250 combined with i.p. or i.v. administration of etoposide (iv-po-ip trials and iv-po-iv trials) potentiated the antitumour activity of etoposide to similar levels as in treating mice inoculated i.p. with leukaemia cells. These 1,4-dihydropyridines were therefore highly effective in potentiating anticancer drugs against both drug-sensitive and drug-resistant tumours.
The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.
Activities of the elbow flexors and extensors during the movement of the elbow flexion and extension were analyzed in six normal human volunteers by electromyography (EMG). In the flexors, the majority of the muscles showed EMG activities during both the flexion and extension phases, although patterns and amplitudes of EMG activities varied from individual to individual. The biceps brachii always became less active when the forearm was in pronation. In the extensors, increase of EMG activities was observed at the period of the maximum elbow extension in the majority of cases, while no EMG activity was shown throughout the movement in some cases. During the elbow movement except at the maximum extension, the triceps brachii was almost inactive and some of their three heads, in particular the long head, often showed no EMG activity. In contrast, the anconeus was usually active, sometimes showing strong EMG activity.
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The examination of internal rotation angle at the elbow is difficult on conventional radiographs. The angle of internal rotation has been measured with three dimensional reformatted CT image of GE CT/T9800. The angle of internal rotation with the cubitus varus deformity was measured both preoperatively and postoperatively. Postoperatively the angle of internal rotation became equal on both sides. Three dimensional CT reconstruction is useful in determining the internal rotation angle of elbow.
The locomotion of the hindlimbs of two adult female spinal dogs, who were able to walk steadily on their hindlimbs 10 months after transection of the spinal cord (T10), and of two normal dogs was analyzed on a treadmill by means of high-speed cinematography and electromyography. With increase in walking speed, the duration of the step cycle was shortened by reduction of the duration of the stance phase, and the stride length was extended mainly by elongation of the transfer distance during the swing phase in both normal and spinal dogs. The patterns of muscle discharges of the hindlimbs in spinal dogs were similar to those in normal dogs. With increase in walking speed, reductions in the burst duration of the extensors were observed in both normal and spinal dogs. These results indicate that spinal dogs can adjust their locomotion speed in the same manner as normal dogs; this supports the theory that a central pattern generator regulating the locomotive activities of the hindlimbs exists in the spinal cord below the transection site.
We investigated whether two representative 1,4-dihydropyridine derivatives, NK-250 and NK-252, could potentiate the antitumor activity of multiple anticancer agents including vincristine (VCR), vinblastine, vindesine and actinomycin D in drug-resistant tumor cells and their parental drug-sensitive tumor cells. NK-250 and NK-252 at 5-10 microM almost completely reversed VCR resistance in cultured VCR-resistant P388/VCR cells derived from the mouse drug-sensitive P388/S leukemia cell line and also potentiated the cytocidal activity of VCR in drug-sensitive P388/S cells. NK-250 and NK-252 at 1-10 microM inhibited the photoaffinity labeling by [3H]azidopine of the cell-surface 170,000-molecular-weight P-glycoprotein. In chemotherapeutic experiments with leukemia-bearing mice, NK-250 or NK-252 was orally administered in combination with different drugs of the MDR phenotype administered intraperitoneally. The antitumor activity of the various combinations was found to be augmented in mice bearing P388/S- and P388/VCR-leukemia. Among the combinations examined, the combination of NK-250 and VCR was the most effective. These two 1,4-dihydropyridines, NK-250 and NK-252, are unique compounds because they were effective not only in circumventing the drug resistance, but also in potentiating the action of antitumor drugs against drug-sensitive tumors.
WP-833 is an orally active new antiallergic drug. The effects of WP-833 metabolites on experimental allergic reactions were investigated in various animal models. MTCC [3'-(1H-tetrazol-5-yl) oxanilic acid], the main metabolite of WP-833, dose-dependently inhibited 48-hr homologous passive cutaneous anaphylaxis (PCA) in rats and 8-day PCA in guinea pigs after intravenous administration. The inhibitory effect of MTCC on PCA was nearly equal to that of WP-833. MTCC also inhibited 48hr PCA in rats after the peroral administration, although its inhibitory effect was about 6 times weaker than that of WP-833. MTCC also showed a dose-dependent inhibition on the release of histamine or slow reacting substance of anaphylaxis (SRS-A) from passively sensitized rat peritoneal mast cells and guinea pig lung fragments in vitro with a similar potency to WP-833. MTA [3-(1H-tetrazol-5-yl) aniline] and MTAA [3'-(1H-tetrazol-5-yl) acetanilide], other metabolites of WP-833, inhibited PCA and anaphylactic histamine release from rat peritoneal mast cells at considerably higher doses than WP-833, and they showed no effects on the release of histamine and SRS-A from guinea pig lung fragments. Moreover, only small amounts of MTA and MTAA were detected in the blood after the oral administration of WP-833. From these results, it was suggested that MTCC may be the main active metabolite of WP-833.
Airstepping of the hind limbs, which occurred when the adult chronic spinal dog was lifted up vertically, was analyzed by high-speed cinematography and electromyography (EMG). In the film analysis, the amplitude of the step increased with decreasing cycle period of the step. The time courses of changes in the joint angles of the hind limb throughout the step were not changed and the maximum flexion of each joint occurred in the knee, ankle and hip joint in that order at any cycle period. In the EMG analysis, alternating EMG activities of the ankle extensor and flexor, and also of the bilateral knee extensors appeared. The EMG burst durations of the knee and ankle extensors correlated closely with the cycle period of the step, although that of the ankle flexor was independent of changes of the cycle period. Since similar results were observed in analyses of treadmill locomotion in the normal and adult spinal dogs, it was thought that airstepping and treadmill locomotion were regulated by the same central pattern generator existing in the lower spinal cord.
The diseases known as the Vinyl Chloride Monomer (VCM) Syndrome include hepatic angiosarcoma, acroosteolysis and Raynaud's phenomenon. These, however, are known to be clinically recognizable from several to over 10 years after the actual exposure to VCM. By fluorescence microscopy the authors examined smeared samples of peripheral blood obtained from vinyl chloride workers, and observed the existence of basophilic stippled erythrocytes (BSE). In this paper, we report the changes of peripheral red cells during VCM exposure tests on mice. These changes in the peripheral blood could be observed as early as 24 hours after the start of the VCM exposure at higher concentrations, and in 72 hours even at comparatively lower VCM levels of 30 to 40 ppm. The tests have also confirmed that the rate of emergence of BSE differs according to the level of VCM and to the duration of VCM exposure.
For unresectable liver tumors, intermittent occlusion of the feeding artery by means of surgical placement of double lumen balloon catheter in the hepatic artery was combined with chemotherapy. Through the catheter, fluorouracil was continuously infused and one-shot injections of mitomycin or adriamycin were given at the time of balloon inflations. Nineteen patients with primary hepatocellular carcinoma (7 were at Stage III and 11 were at Stage IV) and 14 patients with metastatic liver tumors (4 were at H2 and 9 were at H3 stages) received this newly developed anticancer methodology. In terms of Karnofsky's criteria, 17 of 19 cases with hepatocellular carcinoma achieved Group I responses (89.5%). Fourteen were classified to I-B (73.7%), and one year survival rate was 51.6%. Of 14 cases with metastatic tumors, 13 achieved Group I responses (92.9%). Five were classified to I-B (35.7%), and one year survival was 23.1%. Intermittent occlusion method has advantages in minimizing adverse effects, enabling controlled arterial infusion of anticancer agents and stepwise occlusion of the feeding artery. Despite advanced stages and poor conditions of the patients, remarkable responses were achieved without any serious problems. We are at a conclusion that intermittent occlusion of the hepatic artery when combined with infusion-chemotherapy would, in synergism, be a potential modality against unresectable liver tumors.
The cDNA for human elongation factor-1 alpha was isolated from a cDNA library of human fibroblast cells. Using the cDNA as a probe, a number of chromosomal genes encoding the human elongation factor-1 alpha were isolated. Characterization of the clones by restriction enzyme mapping and nucleotide sequence analysis has revealed that only one of them is an active gene, whereas all of the other genes are processed pseudogenes. The active gene consists of 8 exons and 7 introns spanning about 3.5 kilobases, and the sequence of its exons is completely identical to that of the human elongation factor-1 alpha cDNA. The first non-coding exon of 33 base pairs is separated by a 943-base pair intron from the coding exons. The primer extension of human elongation factor-1 alpha mRNA has indicated that the transcription of human elongation factor-1 alpha gene starts from a C residue, and a "TATA" box was found 24 base pairs upstream of the initiation site. Three and five Sp1 binding sites are present on the 5'-flanking region and the 1st intron, respectively. Furthermore, one Ap-1 binding site is located in the 1st intron. By using nuclear extracts from HeLa cells, the promoter of human elongation factor-1 alpha gene could stimulate in vitro transcription better than the adenovirus major late promoter.