Biomedical subjects
Publications and source records attributed to K Morikawa.
The radiologic and pathologic features of three cases of adenomyotic cysts are presented. Two cases were subserosal and one was intramyometrial. All three cases had cystic spaces filled with hyperintense fluid on T1-weighted images, which were surrounded by hypointense tissue on T2-weighted images.
In order to elucidate the relationship between plasma dehydroepiandrosterone (DHA) and sulpiride-induced hyperprolactinemia (of 60 day duration) in normal men, five normal men (aged 27-46) were administered daily 300 mg of sulpiride orally for 60 days to induce hyperprolactinemia. Plasma levels of prolactin, DHA and cortisol were measured by radioimmunoassay before sulpiride treatment, at day 14 and day 60 after initiation of the treatment. Plasma levels of prolactin after the administration rose significantly (P less than 0.001) to 71.6-95.3 ng/ml in four out of the five subjects compared with those of the controls. In the same four subjects the mean DHA values in plasma were elevated significantly (P less than 0.05) to 877 +/- 160 ng/dl from the mean baseline values (669 +/- 91 ng/dl). The elevated values remained during sulpiride treatment. Plasma levels of cortisol did not change significantly during sulpiride administration in all subjects. Our results suggest that sulpiride-induced hyperprolactinemia sustained at least 14-60 days in normal men stimulates the adrenal cortex to secrete DHA.
Sleep EEG and nocturnal penile tumescence (NPT) were investigated in 6 healthy men during placebo and mianserin administration and after mianserin withdrawal. The results were assessed in a historical comparison with those previously obtained with clomipramine. With mianserin, REM sleep was suppressed slightly. However, the suppressive effect of mianserin on REM sleep--based on the historical comparison--was significantly weaker than that of clomipramine throughout all the drug nights. Accordingly, a rebound increase in REM sleep was not observed after withdrawal. Less suppressive effects on NPT and disturbance of sexual function with mianserin than with clomipramine were observed. We suggest that a correlation between the prolonging effect on REM latency and the clinical antidepressant effect is limited to some antidepressants.
Sixty-eight patients with various malignancy was examined for their natural killer (NK) cell activity against 14 target cell lines. The group consisted of 10 patients with gastric cancer, 10 patients with lung cancer, 8 patients with hepatoma, 11 patients with cancer of female genital organs, 14 patients with malignant lymphoma and 15 patients with acute myelogenous leukemia (AML). The target cells from a variety of lineage were selected to examine the disease-related specificity in NK cell activity. The peripheral mononuclear cells from patients with gastric cancer did not show a decrease in NK activity against 14 targets including gastric cancer cell lines. Other patients except for AML demonstrated low NK activity against one or two target cells out of 14 targets. Whereas, NK activity in patients with AML was remarkably depressed against 10 target cells out of 14. At single cell assay, killing ability rather than binding activity to target was markedly impaired in AML. Comprehensively, the data demonstrated the marked difference in the NK level between the patients with solid tumor and the patients with hematopoietic malignancy. There existed neither disease-related specificity in NK cytolysis, nor correlation in NK levels and clinical severity in the patients with malignancy. These results suggested that it was very difficult to evaluate the anti-cancer capacity in patients with malignancy by NK activity alone.
The natural killer (NK) cell activity of the blood and marrow was studied in patients with acute myelogenous leukemia (AML). NK activity of the cells from blood and marrow was significantly decreased in AML to three target cell lines. Both binding and killing capacities of the effector cells were deeply depressed in the blood as well as in the marrow at single cell assay. Surface phenotypic analysis showed a significant decrease in CD 11+ cell subsets, but not in CD 16+ or Leu-7+ cells, in both blood and marrow cells from AML. A significant decrease of large granular lymphocytes (LGL) was also displayed in these samples at morphological examination. The effector cells from AML patients poorly responded to interferon stimulation in NK cytolysis. Taken together, a decrease in CD 11+ cell population with LGL morphology appeared to be responsible for the impaired NK activity in patients with AML.
The mechanism which produces marrow failure in idiopathic aplastic anemia is still unknown. Recent investigations have suggested the crucial role of NK cells in the regulation of normal hematopoiesis. In this study, the cytotoxic activity of mononuclear cells from human bone marrow and peripheral blood was examined against three NK-sensitive target cell lines in 15 patients with aplastic anemia as well as 21 normal subjects. Marrow mononuclear cells from aplastic anemia demonstrated a high cytotoxicity comparable to peripheral blood NK cells to these target cells. Neither large granular lymphocytes nor the cells expressing known NK cell surface phenotypes increased in aplastic marrow cell elements. The aplastic marrow cells showed strong killing activity rather than binding at single cell assay. They consisted of non-adherent and adherent cell population in plastic adherence and were unresponsive to IFN treatment. The existence of cytotoxic cells with high NK-like activity may be responsible for the mechanism of marrow failure in aplastic anemia.
In order to study regional differences in the dietary intake of environmental pollutants in Japan, we measured the daily intake ingested via food (the main route for pollutant intake) and analyzed the data by multivariate analysis. Daily mean samples were collected by the duplicate method from 25 women per area in 5 cities in both northern and southern Japan in July, 1987. Cadmium, lead, benzo(a)pyrene, hexachlorobenzene, DDT, chlordane isomers, and the total amount of the isomers were determined for typical pollutants. The data were statistically analyzed by multivariate analysis. Regional differences in the daily intake of environmental pollutants were studied by discriminant analysis. The eigenvalues of the functions 1 and 2, which accounted for 84.8% of variance, were 0.647 and 0.221, respectively. The function 1 was related to regional differences in the intake of environmental pollutants in the northern and southern regions of Japan. The statistical distance calculated from the intake of environmental pollutants correlated well with the geographical distance. The coefficients of the canonical discriminant function 1 were large in the order of lead (Pb) and the total amount of chlordane isomers (T-CLD). The regional difference was assumed to be due to the intake of Pb in the north and the intake of T-CLD in the south. Other pollutants, however, did not contribute to the observed regional difference. The study shows that performing multivariate analysis by computer provides a useful means for processing a large amount of data and can provide important information for data analysis in environmental health.
(-)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R), cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP) were compared for their antitumor effects and nephrotoxicity-inducing activities at the same dosage (1/8, 1/4, 1/3, 1/2, 2/3 or 3/4 of the LD10 or LD10) on the basis of their intravenous lethal doses in mice. DWA2114R was effective against murine tumor lines, Colon 26 and Colon 38 carcinomas, M5076 ovarian sarcoma and P388 L1210 leukemias, implanted subcutaneously (s.c.). Triple injection every other day of DWA2114R was more effective than a single injection at each sublethal dose. The antitumor effects of DWA2114R against these tumors were more effective than or were similar to those of CBDCA and CDDP. The antitumor effect against CDDP-resistant L1210 leukemia implanted s.c. was only observed in the treatment of DWA2114R, but not in CBDCA and CDDP. No excellent antitumor effects of three platinum complexes were observed against Lewis lung carcinoma and B16 melanoma implanted s.c. even at triple injection every other day, and no effect was obtained against Meth-A fibrosarcoma under similar conditions. While the treatment of CDDP showed marked increases in levels of blood urea nitrogen and of urinary protein and sugar at effective doses in the antitumor evaluations, the treatment of DWA2114R as well as CBDCA showed no increase in these parameters. These results indicate that DWA2114R represents a desirable second generation antitumor platinum complex.
The antitumor mechanism of (-)-(R)-2- aminomethylpyrrolidine (1.1-cyclobutanedicarboxylato)platinum(II) (DWA2114R) was examined using cultured murine L1210 leukemia cells by estimating its effects on parameters such as proliferation, macromolecular synthesis, morphology and cell cycle progression. Each parameter was estimated in cells concomitantly exposed to the drug for 24-48 hr. More than 0.1 microM of DWA2114R markedly inhibited cell proliferation as well as DNA synthesis, and it decreased in mitotic index in a concentration-dependent manner. One microM of DWA2114R decreased DNA synthesis by 80% in the cells treated for 24 hr, while the inhibition of RNA synthesis was less than 40%. A significant inhibition of protein synthesis was caused only by treatment with a high concentration (100 microM) of the drug. Under complete cytostatic conditions (10 microM of DWA2114R), cell volume markedly increased and about 40% of the total cells were polynucleate. In addition, flow cytometrical analysis revealed that most of these cells were accumulated in the G2/M phase of the cell cycle, and a new peak located in the G2/M phase of tetraploid cells emerged. On the other hand, the cells treated with 100 microM of the drug did not increase in volume and their progress in the cell cycle was almost completely blocked.
One hundred cis-diamminedichloroplatinum (II) (CDDP) analogs have been evaluated for antitumor activity in male CDF1 mice subcutaneously (s.c.) implanted with tumor fragments of Colon 26 carcinoma. Among the complexes tested, 2-aminomethyl-pyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) (DWA 2114) had the best antitumor effect. The mice intraperitoneally (i.p.) injected with DWA 2114 at a dose of 40 mg/kg/day on days 4, 6 and 8 after inoculation showed a 97% growth inhibitory ratio (GIR) on day 14 compared to the non-treated control mice. We evaluated the inhibitory effects of DWA 2114 on other tumors, such as Colon 38 carcinoma, Ca 755 mammary adenocarcinoma and L1210 leukemia, and found that it also had antitumor effects on various kinds of tumors. The nephrotoxicity-inducing activity of DWA 2114 and CDDP was evaluated in normal BDF1 mice, as indicated by changes in blood urea nitrogen (BUN) at almost the maximum tolerated dose (MTD) (DWA 2114: 100 mg/kg, CDDP: 12 mg/kg). DWA 2114 had no effect on BUN levels, while CDDP elevated BUN levels. These results indicate that DWA 2114 represents a second generation platinum antitumor complex.
The first attempt to study crystal structures of tRNA by electron microscopy is described. Sufficiently thin crystals were prepared from yeast tRNAphe. The thickness of the thinnest was estimated at 130 A corresponding to a bilayer of the molecules. The L-shaped structure seemed to be maintained even after the negative staining with uranyl acetate. Optically filtered images from electron micrographs were compared with those simulated from the drawing of the molecular model by optical transform. The results suggest that the observed images reflect the real molecular arrangements within the crystal lattice although the shape of tRNA molecules seems to be somewhat modified by the uneven staining.
An autopsied case of Ramsay Hunt syndrome with progressive dementia was reported. The clinical symptoms included progressive intellectual decline, myoclonus, generalized convulsive seizure, cerebellar ataxia and positive pyramidal signs. Neuropathological examination disclosed cerebral white matter demyelination marked in the frontal lobe and fibrillary gliosis predominantly in the subcortical U-fibers, grumose degeneration in the dentate nucleus and inferior olivary nucleus lesion. The skeletal muscle showed no ragged-red fiber. The present case can be included in Ramsay Hunt syndrome because of the absence of pathological hallmark of mitochondrial encephalomyopathy and of the presence of the degenerative lesions in the olivary and dentate nucleus without cerebellar Purkinje cell loss. The intellectual decline is a result of extensive frontal white matter change, and myoclonus and ataxia are closely associated with dentate grumose degeneration. The cerebral white matter change is an unusual finding and the present case might be a variant in Ramsay Hunt syndrome.
The in vitro antitumor activities of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R), against various human tumor lines (23 solid tumor lines and 6 hematopoietic malignant lines) were examined in comparison with those of cis-diammine (1,1-cyclobutanedicarboxylato) platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP). The growth inhibitory activities of the compounds were estimated by MTT assay after the incubation of cells under continuous exposure to the drug. The mean concentrations (microM) of DWA2114R, CBDCA and CDDP needed to inhibit the proliferation of cells by 50% (IC50) were 64.0, 55.1 and 6.8 against solid tumor lines and 8.5, 7.4 and 1.7 against hematopoietic malignant lines, respectively. Comparing the drug sensitivity of the solid tumor lines by type, ovarian cancer was found to be the most susceptible to all three compounds. The susceptibilities of other tumors were in the order prostate, breast and colon cancers for DWA2114R and CBDCA but colon, prostate and breast cancers for CDDP. The correlations of the mean IC50 values for all three combinations of the two compounds were statistically evaluated. A significant correlation was shown between DWA2114R and CBDCA, or CBDCA and CDDP, but not between DWA2114R and CDDP. These results suggest that DWA2114R is almost equivalent in effect to CBDCA which is several times less potent than CDDP, but also that the in vitro cell line subpanel specificity of DWA2114R is in certain respects different from CDDP, in contrast with CBDCA.