Biomedical subjects
Publications and source records attributed to Y Tsukada.
A 68-year-old man developed hepatic injury with no hypersensitivity reaction after three years of hydralazine therapy. The liver injury histologically showed centrilobular zonal necrosis. Clinical, biochemical, and histological recovery followed discontinuation of the drug. Challenge tests and serial liver biopsies revealed that this liver injury was induced by hydralazine.
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Shiverer is an autosomal recessive mutant characterized by dysmyelination in the central nervous system. The myelin in the shiverer is devoid of the major dense line. The pattern of increase of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) in the various parts of central nervous system during postnatal development was identical with that of controls. Subcellular fractionation of the brain from shiverer showed that the recovery of CNPase activity of the P2A was only 14% of the control, but those of P2B and P3 were several times higher than the controls. The specificity activity of CNPase of the purified myelin and P2A from shiverer did not differ significantly from that of the controls. The combined P2 and P3 (P2 + P3) fraction was subjected to linear sucrose density gradient (0.32--1.3 M) centrifugation. By measuring CNPase activities of the fractions obtained after centrifugation, shiverer showed two peaks of CNPase activities in the sucrose gradient, although that of the control showed a single peak. The main peak obtained from shiverer was found in the region of higher sucrose concentration than that of the control, while a small peak was found in the region of lower sucrose concentration.
Immunohistochemical reactions were conducted, using the antibodies against GFA and S-100 proteins on sections of cerebellum from the homozygous (jj) and the heterozygous (Jj) Gunn rats. Hypertrophy of the fibrous astrocytes was observed but hyperplasia of the glial cells was not. Although the molecular layer was very thin, the Bergmann fibre appeared normal. Among the free amino acids in the cerebellum from the jj rat, glutamate concentration decreased to two-thirds of the control level. The protein profile of the cerebellum from the jj rat obtained by SDS-polyacrylamide gel electrophoresis revealed that the amount of P400 protein that is characteristic of Purkinje cells decreased considerably and there were also some changes of the other unidentified proteins. By two-dimensional electrophoresis, it was observed that in the supernatant from the jj rat cerebellum one protein spot diminished and in the particulate fraction from the jj rat one spot was enormously increased. The activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) in the cerebellum from the jj rat did not differ significantly from that of the control; however, activities of choline acetyltransferase and acetylcholinesterase of the jj rat were about twice as high as those of the control. 2-Deoxyglucose incorporation was maximum in the granular layer from both the jj and the Jj rat cerebella. However, the incorporation in the jj cerebellum was not higher than in the Jj control and even lower in some parts of the jj cerebellum than in the control Jj cerebellum.
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Erythrocyte membrane Na,K-ATPase activity of manic patients was studied. The activity of patients in acute manic phase was higher than that of normal controls, while that of patients in normal phase was not. Even in the same patient, the activity in acute phase was higher than that in normal phase. Mg-ATPase activities did not differ between controls and patients. These findings clearly indicate a possible correlation between change in clinical phase in manic patients and change of erythrocyte membrane Na,K-ATPase activity.
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The effects of horse anti-human alpha-fetoprotein (AFP) immunoglobulin (IgG) on growth, serum AFP concentration and histopathology of human endodermal sinus tumor serially xeno-transplanted in nude mice were examined. Anti-AFP IgG given in amounts sufficient to neutralize the serum AFP secreted by the tumor moderately reduced tumor size and significantly decreased the serum AFP levels of treated nude mice. On histopathologic examination, spindle shaped tumor cells of reticular pattern often fell into the state of necrosis. But little change was observed on the cells consisting of both solid patterns and Schiller-Duval bodies. With a growth rate of re-transplanted tissues respectively, which were obtained from both antibody administrated and control tumors, no disparity was found between two groups. Indeed this result is preliminary report, but inhibitory effects of anti-AFP IgG against tumor growth and AFP producing ability of endodermal sinus tumor xeno-transplanted in nude mouse is hopeful to apply these data on clinical cancer immunochemotherapy.
The expression of two markers of fetal liver, alpha-fetoprotein (AFP) and gamma-glutamyltranspeptidase (GGT), and the relationship between these markers and tumorigenicity were studied in 17 continuous epithelial-like cell lines derived from normal rat livers and ascitic hepatoma cells. Fourteen cell lines positive for GGT activity included 6 non-transplantable lines. Out of 10 cell lines transplantable to syngeneic rats and/or immuno-depressed hamsters, 2 showed no activity of GGT cytochemically. AFP production was seen in the culture fluid of 4 out of 15 cell lines tested. They consisted of 1 GGT-positive, transplantable, 1 GGT-negative, transplantable, and 2 GGT-positive, non-transplantable cell lines. These results indicate that no correlation exists among these 3 parameters related to neoplastic and preneoplastic states of cells.
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The relation between the activities of arylamidase (one of the non-specific carboxylesterases) located exclusively in smooth endoplasmic reticulum (SER), and microscopical changes of the hepatocytes, was studied in three patients treated with phenobarbital and twenty-five patients injured by various other drugs. A micro-method was used for the determination of the enzyme activity in small pieces of liver (5-15 mg) obtained by needle biopsy. The arylamidase activity in seven normal livers was 0.43 +/- 0.05 (SD) nmol benzylhydrazine/micron protein/hr formed from isocarboxazid. The mean value in the livers treated with phenobarbital was statistically different from the value before phenobarbital treatment (P less than 0.05). Of sixteen cytotoxic type samples, seven showed low activity and eight high activity, respectively. Of the seven mixed-type samples, three showed mildly low activity and four normal activity. The frequency of the cytotoxic type is statistically different from that of the cholestatic (mixed and pure cholestatic) type comparing the abnormal activity with normal activity (P less than 0.05). The degree of enzyme activity was related to changes such as pyknosis, enlarged nuclei and centrilobular zonal necrosis. The ultrastructure of the material taken from three patients after phenobarbital treatment and one patient with ibuprofen-induced injury showed prominent increase and vesiculation of SER respectively. The study shows that drug-induced liver injury is closely related to the activity of SER, and that the changes in hepatocytes in cytotoxic type may result from the functional abnormality of SER.
Dysmyelination in the central nervous system of the quaking mutant mouse was studied biochemically and immunohistochemically. We found, by measuring CNPase activity, that myelination in the central nervous system of quaking mice was affected to a different degree in different areas. The pallium cerebri was the most severely affected and the medulla and spinal cord were least affected. The density of astroglia observed by GFA staining wash higher in the white matter of quaking mice than in controls, but the total area of the white matter in the cerebellum was smaller in the quaking mice than in the controls. The DNA content in the pallium cerebri and brain stem showed no increase and that of the cerebellum was even lower in quaking mice than in the controls. Hypertrophy of the astroglia was observed in the white matter of the cerebellum of quaking mice, though Bergmann astroglial fibers in the molecular layer did not show any hypertrophy. The cerebella of quaking mice in primary culture showed very poor myelination under the phase-contrast microscope. However, Purkinje cells from the quaking mutants appeared normal with regard to Bodian silver impregnation, hematoxylineosin staining, and Purkinje cell specific P 400 protein. Addition of the conditioned culture medium of qk/qk to the culture of the control cerebellum did not interfere with the myelination. We concluded that the cause of dysmyelination in the quaking mouse could be a genetic defect of the oligodendroglia rather than hypertrophy of the astroglial cells.
Eight patients with squamous cell carcinoma in situ of the vagina were treated with monthly 5 day courses of 20% 5-fluorouracil cream applied to the vagina. Seven (87.5%) of the women had an initial complete response; however, three subsequently developed recurrence after the treatment was stopped. They were retreated, and two of these three patients achieved a subsequent complete response. The overall response to therapy was 75% (6/8) with six women off therapy from 1.1 to 6.9 years. Total follow-up of all patients was 3.1 to 6.9 years with no patients having developed invasive carcinoma. Because of the high success rate with no associated serous sequelae, this is believed to be a satisfactory method of therapy for women with squamous cell carcinoma in situ of the vagina occurring after pelvic irradiation.
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