Fluorometric studies on the role of calcium in substrate binding to 3-ketovalidoxylamine A C-N lyase.
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Biomedical subjects
Publications and source records attributed to K Matsui.
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Spontaneous movement and ataxic gait in ataxic mice showing various pathological changes in the cerebellum were investigated according to developmental stage by the open-field method of comparison with normal mice. As the cerebellum contains relatively high levels of cyclic nucleotide, its concentrations was measured by radioimmunoassay to elucidate the correlation between spontaneous movement and ataxic gait and the neurological changes. The movements of Rolling Mouse Nagoya (RMN), Weaver and Reeler mice without Purkinje Cell Degeneration (PCD) were found to decrease at 4 and 12 weeks of age. The degree of ataxic gait worsen in RMN, was unchanged in Reeler and improved in Weaver and PCD mice. The cerebellar c-GMP concentration of ataxic mice was decreased, while no significant changes in c-AMP concentration were found in comparison with normal mice. With development, the level of cerebellar c-GMP in Weaver mice increased, but this was not apparent in RMN, Reeler or PCD mice. The results of this investigation indicated that there may be some relation between the degree of ataxic gait and the level of cerebellar c-GMP in Weaver mice.
Immunoreactive-somatostatin (IR-SRIF) levels were investigated in the brain of 4 types of ataxic mice (Rolling Mouse Nagoya, Weaver, PCD, Staggerer) with different cerebellar pathologies. IR-SRIF concentrations (ng/mg) were found to be significantly elevated in both cerebellum and cerebrum of all ataxic mutant mice, IR-SRIF (ng/organ) was found to be increased in the cerebellum and cerebrum in Rolling Mouse Nagoya and PCD compared with control mice. The gel-filtration profile (Sephadex G-50) in the cerebellar extracts of Rolling Mouse Nagoya proved to be identical to that of control mice. Three peaks of IR-SRIF were found to be uniformly elevated in Rolling Mouse Nagoya, with the highest peak coinciding with authentic somatostatin-14. The present results suggest that elevated levels of IR-SRIF in the brain may play a role in the mechanism underlying the manifestation of ataxia in ataxic mutant mice, especially in Rolling Mouse Nagoya and PCD.
To evaluate the role of cyclic guanosine monophosphate (cGMP) in the vascular and renal action of atrial natriuretic peptide (ANP), we compared the effects of atriopeptins (APs) on cGMP accumulation in cultured cells from rat mesenteric vascular smooth muscle (VSM), glomerular mesangium (GM) and renal papillary collecting tubule (RPCT), and also evaluated the relationship between renal sodium or water excretion and urinary cGMP in AP-infused rats. Both AP I and AP III increased intracellular cGMP levels dose-dependently in all types of cells, while they did not affect intracellular cAMP levels or prostaglandin synthesis. AP III was 100 times more potent than AP I. The magnitude change in cGMP levels was largest in GM cells. The sensitivity of VSM and GM cells to AP III were greater than that of RPCT cells. There were significant positive relationships between urinary excretion of sodium or water and that of cGMP levels in AP-infused rats. These results may suggest that GM and VSM cells are the principal targets for ANP to stimulate cGMP synthesis and, possibly, to exert the renal sodium and water excretion, and also support the hypothesis that cGMP mediates the cellular action of ANP.
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Ablation of renal arteriovenous malformations with absolute alcohol was performed in seven patients with massive hematuria. In three patients, total occlusion of the malformations was accomplished by ablation of two arterial branches. In the remaining four patients, the malformations were partially occluded by ablation of one or two arterial branches. In addition to ablation with alcohol, two of the four patients underwent subselective embolization with Gelfoam (absorbable gelatin sponge) under epinephrine pharmacoangiography, which resulted in the disappearance of the remaining malformations. None of the patients had serious complications from ablation with alcohol, although dyspnea and headache occurred in one patient with marked arteriovenous shunting. During long-term follow-ups, hematuria disappeared in six patients. In the remaining patient hematuria recurred but did not require treatment. These data suggest that alcohol ablation is useful and safe in the treatment of renal arteriovenous malformations.
The intestinal absorption of riboflavin was studied using radioactive riboflavin and its analogues 8-demethylriboflavin, 3-methylriboflavin, 5'-deoxyriboflavin, 2'-deoxyriboflavin, 7,8-dimethyl-10-hydroxyethylisoalloxazine, lumiflavin, lumichrome, and riboflavin-5'-monosulfate, which were synthesized with high specific radioactivity. A specific absorption of riboflavin at dietary concentrations was confirmed using an in situ circulation system. The relation between the chemical structure of flavins and the absorption mechanism was studied using this system. The 8-demethylriboflavin, an analogue modified at benzene moiety of the isoalloxazine ring, was absorbed in a similar way to riboflavin, by dual kinetics: by a process specific for riboflavin at dietary concentrations and by simple diffusion (nonspecific absorption) predominating at higher concentrations (over 100 microM). However, 3-methylriboflavin and analogues modified at the ribityl group, including 5'-deoxyriboflavin, were absorbed only via simple diffusion even at dietary concentrations. Many flavins examined, except for 3-isobutylriboflavin, 3-carboxymethylriboflavin, lumichrome, and riboflavin-5'-monosulfate, interfered with the specific absorption of riboflavin. It was concluded from these results that one of the specific absorption processes for riboflavin is a phosphorylation-dephosphorylation process. Four water-soluble vitamins did not interfere with the specific absorption of riboflavin, indicating that these vitamins do not share a common specific absorption pathway with riboflavin.
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Phase II studies of single agent and CDDP-based two drug combination were performed in 189 patients with inoperable non-small cell lung cancer. Six drug regimens were performed: CDDP alone, VDS alone, Epi-ADM alone, CDDP + VDS, CDDP + CPA, CDDP + ADM. The response rates were 15.4% (6/39) with CDDP alone, 8.0% (2/25) with VDS alone, 6.1% (2/33) with Epi-ADM alone, 26.7% (8/30) with CDDP + VDS, 14.3% (4/28) with CDDP + CPA, 17.6% (6/34) with CDDP + ADM and one CR was performed with CDDP + ADM. In patients with no prior chemotherapy, the response rates were 20.0% (6/30), 11.8% (2/17), 12.5% (2/16), 26.7% (8/30), 16.0% (4/25) and 25.0% (3/12), respectively. The median survival times were 25, 27, 23, 33, 25, and 45 weeks, respectively. The efficacy of CDDP in non-small cell lung cancer patients was re-confirmed, and that of CDDP + VDS, CDDP + ADM was suggested. No death due to toxicity occurred and toxicity was generally tolerable.
The recent results of chemotherapy for SCLC were reviewed in this paper. The combination chemotherapy with some highly active drugs can be summarized as follows: response rate 74-94% in limited disease (LD) and 63-90% in extensive disease (ED), complete response 39-57% in LD and 20-48% in ED, median survival 10-21 months in LD and 7-12 months in ED. To overcome drug resistance in the treatment of SCLC, non-cross resistant alternating chemotherapy has been explored. In our institute, a randomized study of continuous vs alternating regimen for SCLC was carried out from August 1982 to March 1985. This resulted in the acknowledged superiority of the alternating regimen in CR rate and the overall response rate, but no differences in survival. A current study comparing the standard chemotherapy with cyclophosphamide, adriamycin and vincristine (CAV) to alternating CAV with etoposide (E) and cisplatin (P) has suggested an advantage for alternating chemotherapy, with a statistically superior response rate and survival. The high-dose (HD) chemotherapy for SCLC is also a new strategy to improve the current treatment results. We are now studying the efficacy of HD-E (1.0-1.5 g/m2) with or without P (80-120 mg/m2) for relapsed SCLC. The result suggested that HD-E and P is an effective treatment modality as a salvage therapy. The search for new active drugs is another important way to improve the treatment results. Since 1986, a phase II study of Carboplatin has been performed in Japan. The ongoing data suggest that Carboplatin is a highly active agent against SCLC. Finally, further research will be necessary to investigate novel modalities in order to achieve a breakthrough in the current status.
Rats immunized with an emulsion of Engelbreth-Holm-Swarm (EHS) tumour and Freund's complete adjuvant (FCA) excreted large amounts of urinary protein from the 14th week after the initial immunization. The amount of urinary protein increased progressively and, after 1 year, reached over 1 g/day. Kidneys removed from immunized rats at 10 weeks, 24 weeks and 1 year after the initial immunization were examined by immunofluorescence, light and electron microscopy. By immunofluorescence microscopy, granular deposits of rat immunoglobulins (Igs) were observed along the glomerular capillary walls from the 10th week until the end of the observation period. Glomerular membranous transformation was observed from the 24th week by light microscopy. The glomerular capillary walls were thickened and argyrophilic spikes and vacuolations were detected. At 1 year the severity of these changes was increased. Electron microscopic examination showed only a few electron-dense deposits after 10 weeks, but after 24 weeks numerous electron-dense deposits were detected in all glomeruli, the glomerular basement membrane was thickened and irregular and podocyte foot processes were effaced. At 1 year, dense deposits were located intramembranously and their density decreased from the circumference to the centre. Lesions characteristic of human membranous nephritis were observed in this model, the appearances at 10 weeks, 24 weeks and 1 year corresponding to stages I, II and III, respectively, of the classification of Ehrenreich and Churg (1968). Comparison of the immunohistochemical abnormalities in this model and in Heymann nephritis revealed antigenic cross-reactivity; there appears to be common antigenicity between the immune deposits in the glomeruli in both models, cell surface antigens in the EHS tumour and those located in the cell surface antigens in the brush borders of proximal convoluted tubules. Although the antigens responsible have not yet been clearly identified, in this paper I describe a new model of membranous nephritis, tentatively termed EHS nephropathy.
Muroctasin, a derivative of MDP, is known to augment the number of WBC via colony-stimulating factor. Muroctasin has been expected to be promising for application to leukopenia caused by anticancer chemotherapy. When WBC decreased to less than or equal to 3,000/mm3 after the 1st course of chemotherapy, 131 patients with lung cancer, who were previously classified by chemotherapy combination, were enrolled in the study and randomized into 3 groups, 200 micrograms (H), 100 micrograms (L) and untreated control (C) groups. The patients were then subcutaneously treated once daily for 6 consecutive days. WBC and its differential count were measured on days 4, 7 and 15 after commencement of the study. WBCs in H and L groups showed greater recovery than in C group. In WBC differential count, the recovery of neutrophil was prominent in muroctasin-treated groups. A portion of immature neutrophil in bone marrow was also increased by muroctasin treatment. In the present study, the usefulness of muroctasin in leukopenia was indicated when administered at dosages of 200 micrograms for 6 days.
Twenty-eight patients with malignant pleural effusion received instillation of cisplatin (CDDP) into the pleural cavity to examine the pharmacokinetics and side effects of CDDP Thirteen patients received high-dose CDDP (120 mg/m2-160 mg/m2) in combination with sodium thiosulfate (STS), while 15 others received CDDP alone (80 mg/m2). Total Pt and non-protein-bound Pt (free Pt) concentrations in the pleural effusion and plasma were determined by flameless atomic absorption spectrometry. In one patient, Pt concentrations of intact CDDP and STS-bound CDDP were determined using high performance liquid chromatography and flameless atomic absorption spectrometry. Instillation of CDDP at 160 mg/m2 into the pleural cavity was achieved by concurrent use of STS in the large dose (STS 20 g/m2 1 hr later, totalling 625-fold molar ratio to CDDP). When CDDP was combined with STS, there was alleviation in hematological, renal and auditory toxicity but not in nausea, vomiting or anorexia. When CDDP was instillated into the pleural cavity at 150 mg/m2 (in combination with STS equivalent to 200-fold molar ratio to CDDP), a high Pt concentration of intact CDDP could be maintained in the pleural effusion over a prolonged period of time, recording 8.80 micrograms/ml even as late as 12 hr after instillation. On the other hand nearly all of the free Pt concentration for the first 2 hr was considered to be due to intact CDDP. Once systemically administered, STS quickly moved into the pleural effusion, binding with CDDP in the pleural cavity and thus probably reducing its anti-tumor effect. STS did not greatly affect the plasma concentration of total Pt when it was administered at a 100-fold molar ratio to CDDP, yielding only p poor effect. Our findings suggest that malignant pleural effusion could be effectively treated by the instillation of CDDP 80 mg/m2 into the pleural cavity.
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To elucidate the ataxic mechanism of Wriggle mouse Sagami (WMS), a behavioural pharmacological investigation was carried out by open-field study. The dysfunction of DA receptor, alpha-receptor, beta-receptor, 5-HT receptor and Ach-receptor appeared in WMS. Further examination will be necessary to investigate WMS with receptor dysfunction.
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Agarose gel isoelectric focusing (pH 5--6.5) in the study of plasma factor XIII (FXIII) polymorphism revealed heterogeneity characterized by a narrow or broad type of the electrophoretic band of the A subunit (FXIIIA). Isoelectric focusing in polyacrylamide gels supplemented with 2 M urea could clearly discriminate three different patterns in each of the two homomeric dimers, FXIIIA 1 and FXIIIA 2. These patterns can be explained by the existence of two codominant subtypes in each of the two common alleles, FXIIIA*1 and FXIIIA*2. These subtypes are termed FXIIIA*1A, 1B, 2A, and 2B, respectively. In random population samples of Japanese, all the possible phenotypes deduced from the four codominant alleles were observed except for the FXIIIA 2A homozygote with the least frequency. This hypothesis is compatible with the segregation study on 35 family samples. The frequencies of the four alleles were calculated in 433 unrelated Japanese as being .2748 for FXIIIA*1A, .6201 for FXIIIA*1B, .0069 for FXIIIA*2A, and .0982 for FXIIIA*2B. The data obtained in this study will contribute much more to disputed paternity cases and to anthropological surveys than will the former FXIIIA system with two common alleles.