Biomedical subjects
S Takayama
Publications and source records attributed to S Takayama.
[Azygos continuation of the inferior vena cava].
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[Interruption of inferior vena cava].
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Increased muscle sympathetic nerve activity after glucagon administration in man.
Muscle sympathetic nerve activity (MSNA) after glucagon administration was quantitatively measured in five healthy male volunteers (age: 20-28 years old). After an overnight fasting, 1 mg glucagon dissolved in a 1-ml vehicle was injected i.v. as a bolus. MSNA, ECG and blood pressure were simultaneously recorded 15 min before and after the injection. MSNA (bursts/min), heart rate (HR), and systolic and diastolic blood pressures (dBP and sBP) were significantly increased at 2-3 min after glucagon injection. Their means and standard deviations of control for 15 min vs. 3 min after the injection were in the five subjects; MSNA, 10 +/- 6 vs. 30 +/- 10 bursts/min, HR, 61 +/- 10 vs. 76 +/- 8 beats/min, dBP, 66 +/- 9 vs. 91 +/- 9 mmHg and sBP, 122 +/- 12 vs. 152 +/- 11 mmHg. These results suggest that glucagon has a direct facilitatory effect on the central sympathetic nervous system.
Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity.
Using a protein interaction cloning technique, we identified cDNAs that encode a novel Bcl-2-binding protein, termed BAG-1. The BAG-1 protein shares no significant homology with Bcl-2 or other Bcl-2 family proteins, which can form homo- and heterodimers. In gene transfer experiments using a human lymphoid cell line, Jurkat, coexpression of BAG-1 and Bcl-2 provided markedly increased protection from cell death induced by several stimuli, including staurosporine, anti-Fas antibody, and cytolytic T cells, relative to cells that contained gene transfer-mediated elevations in either BAG-1 or Bcl-2 protein alone. BAG-transfected 3T3 fibroblasts also exhibited prolonged cell survival in response to an apoptotic stimulus. The findings indicate that bag-1 represents a new type of anti-cell death gene and suggest that some routes of apoptosis induction previously ascribed to Bcl-2-independent pathways may instead reflect a need for the combination of Bcl-2 and BAG-1.
Cytopathological features of undifferentiated carcinoma of the ovary.
Cytopathological characteristics of undifferentiated carcinoma of the ovary were examined and reviewed. Seven cases of undifferentiated carcinoma were encountered among 202 malignant ovarian neoplasms in the Saitama Cancer Center. Histologically, two cases contained a minor component of usual Müllerian carcinoma and five others were purely of solid architecture without differentiation. Nevertheless, six cases, four of which were totally undifferentiated histologically, showed cytological features characteristic of adenocarcinoma. The results indicate that even carcinomas histologically diagnosed as undifferentiated may have cytological features of glandular differentiation, which may be Müllerian in origin.
Expression of platelet-derived growth factor B-chain in the mature rat brain and pituitary gland.
For better understanding of the role of platelet-derived growth factor (PDGF) B-chain in the brain, the expression of PDGF B-chain was studied in the mature rat brain at both protein and mRNA levels, by assay of PDGF B-chain-related mitogenic activity, Northern blot, in situ hybridization and immunohistochemistry. It was shown that (1) mature rat brain contained substantial PDGF B-chain-related mitogenic activity, (2) significant amounts of two sizes of transcripts (3.5 kb, widely, and 2.6 kb, weakly and in narrower areas) were expressed in the brain, and (3) the transcripts were localized in ubiquitous neurons by in situ hybridization, with the strongest signal in hippocampal pyramidal cells, which distribution almost corresponded with that of the immunoreactive products. The abundant neuronal localization of the transcript and protein, as well as the neuronal expression of the receptor reported elsewhere, suggests the role of the growth factor in neuronal cells as a neuronal regulatory and/or trophic agent acting by autocrine loop or by neuron to neuron interaction. However, there was an apparent discrepancy in part, in the distribution between transcripts and immunoreactivity; that is, transcripts were expressed intensely in the intermediate pituitary lobe with only a scattered immunoreactivity, and the opposite situation was observed in the accessory olfactory nerve and posterior pituitary lobe. This might suggest that PDGF B-chain is transported or secreted in these foci.
Separation of neutrophils from blood in human and laboratory animals and comparison of the chemotaxis.
We separated neutrophils from the peripheral blood of the human, monkey, dog, rabbit, rat, hamster, and mouse and investigated their responses to several chemotactic factors to evaluate the species-dependent difference in responsiveness. Heparinized blood was obtained by venipuncture from human, monkey, dog, and rabbit. In the rat, hamster, and mouse, the hetastarch exchange transfusion method was used to increase the neutrophil recovery. After sedimentation of red blood cells, a leukocyte suspension was layered on 5-step discontinuous Percoll gradients of densities from 1.081 to 1.097. We could routinely obtain the fractions containing neutrophils at more than 90% in all of the seven species tested. Chemotaxis assay was performed using a 48-well modified Boyden chamber. Dog neutrophils did not migrate to N-formylmethionyl-leucyl-phenylalamine (fMLP), and dog and rat neutrophil responses to leukotriene B4 (LTB4) were remarkably modest. However, neutrophils from other species showed a high reactivity to fMLP and LTB4. Although neutrophils of all species responded to human recombinant interleukin 8 (hrIL-8), the sensitivity of human and monkey neutrophils to hrIL-8 were higher as compared with other species. Human, dog, and rat neutrophils reacted most to homologous zymosan-activated serum derived respectively from human, dog, and rat serum. The present results show species-dependent differences of neutrophils in chemotactic responses.
Dynamic light scattering study of the effect of Mg2+ and ATP on synthetic myosin filaments.
The dynamic light scattering (DLS) method provides us with information about the apparent diffusion coefficient, Dapp, as well as the static scattering intensity, Is, of particles in solution. For long but thin rods with length L and diameter d, the dependence on L and d of Dapp is quite different from that of Is. By means of DLS we studied synthetic myosin filaments of rabbit skeletal muscle in solution at pH 8.3 and 10 degrees C. It appeared that Mg2+ ions induced thickening and lengthening of the filaments, whereas ATP (and ADP) induced thinning and shortening (depolymerization) of the filaments. When ATP was added to the filament preparation in the presence of Mg2+ ions, it was clearly observed that thinning of the filament (or splitting into subfilaments) occurred before shortening (or depolymerization).
Toxicity of quinolone antimicrobial agents.
An approach to minimization of toxicity of a new compound is to elucidate the mechanisms of toxicity of analogous compounds and to clarify their structure-toxicity relationships. A problem with this approach, however, is that such elucidation remains difficult. For quinolones, some improvements in this mechanistic approach have been achieved in the central nervous system (CNS), particularly with regard to their interaction with non-steroidal anti-inflammatory drugs (NSAIDs), and in genotoxicity and phototoxicity studies, particularly in comparison with other toxicities, such as to the cardiovascular, gastrointestinal, bone, reproductive, and developmental systems. This review concentrates on a description of the known effects of quinolones on various organ systems in experimental animals and humans. Given the logarithmic increase in the synthesis of new quinolones, it is questionable whether these drugs share similar safety and efficacy. Nevertheless, this mechanistic approach to the investigation and minimization of toxicity has produced satisfactory results to date and deserves to be continued.
Proliferative and apoptotic status in endometrial adenocarcinoma.
The contribution of cell proliferation and apoptosis to growth patterns in endometrial adenocarcinoma were investigated. Immunohistochemical staining was carried out by an antibody for Ki-67 proliferative antigen, Ley apoptotic antigen, and oncogene products bcl-2 and p53. Forty cases of endometrial adenocarcinoma were classified as exophytic, endophytic, and mixed exo- and endophytic in light of their vertical growth pattern, and, in each case, the carcinomatous area was divided into three layers by its vertical axis. In all but one case, no zonal distribution of the antigen expression was observed. In one case, an exophytic tumor, Ki-67 expression was intense in the surface layer and Ley expression in the deep layer was also intense, suggesting a correlation between macroscopic growth pattern and cellular growth and apoptotic potential. However, in general, zonal distribution of cell proliferation and apoptosis could not explain the growth morphology of endometrial adenocarcinoma of the uterus and it was suggested that factor(s) other than cell proliferation and apoptosis determine macroscopic growth patterns.
Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo.
We investigated the toxic effect of levofloxacin (LVFX), a quinolone antibacterial agent, on cartilage by examining aspects of its in vivo toxicokinetics and effect on the function of cultured chondrocytes of the femoral articular cartilage from juvenile New Zealand White rabbits. Repeated administration of LVFX (100 mg/kg) orally for 7 days induced focal necrosis and superficial erosion in the articular cartilage of the femoral condyle, but 30 mg/kg did not. Concentrations of LVFX in the cartilage were highest at the first sampling point (30 min) after a single administration, being 4.93 and 12.2 micrograms/g in the 30- and 100-mg/kg groups, respectively. The arthropathic concentration of LVFX in the cartilage was then shown to be 12.2 micrograms/g or more. For an in vitro study, chondrocytes were separated from the articular cartilage of the rabbit femoral condyle and cultured for 7 days until confluence. 35SO4 uptake by cultured chondrocyte sheets was most susceptible to LVFX, decreasing at drug concentrations of 5 micrograms/ml or more in 24- and 48-h cultures but not in a 72-h culture. Furthermore, 3H-thymidine uptake was decreased at concentrations of 10 micrograms/ml or more in a 48-h culture but not in 24- and 72-h cultures. Rhodamine 123 accumulation was susceptible to inhibition in cultured chondrocytes at an LVFX concentration of 10 micrograms/ml or more. These results suggest that LVFX inhibits glycosaminoglycan synthesis initially and DNA synthesis and mitochondrial function secondarily at actual arthropathic concentrations in cultured rabbit chondrocytes but that these changes are reversible and not enough to kill the cells.
Nitric oxide is important for mouse beta-cell line killing by peritoneal exudate cells obtained from cyclophosphamide treated non-obese diabetic mice.
Macrophages from recent onset non-obese diabetic (NOD) mice showed cytotoxicity against the NOD mouse derived beta-cell line, MIN6N-9a. In this report, we examined whether nitric oxide is associated with beta-cell destruction. Peritoneal exudate cells (PEC), obtained from cyclophosphamide treated NOD mice showed higher cytotoxicity against MIN6N-9a compared to PECs from saline injected NOD mice (P < 0.01). This effect was suppressed in cells incubated with 0.5 mmol/l NG-methyl-L-arginine, a nitric oxide synthase inhibitor (P < 0.001). In addition, the nitrite concentration of the co-culture medium, as an index of nitric oxide production, increased in MIN6N-9a cells co-cultured with peritoneal exudate cells from cyclophosphamide injected NOD mice but not in co-culture with saline injected NOD mice (P < 0.05). Thus, nitric oxide plays an important role in beta-cell line destruction of macrophages obtained from NOD mice.
Studies on the optimal treatment period and parameters for detection of male fertility disorder in rats--introductory summary.
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Male reproductive toxicity study of nefiracetam in rats.
Sprague-Dawley male rats were administered nefiracetam orally at daily doses of 500 and 1500 mg/kg/day for 4 or 9 weeks. Although the copulation index was not affected by nefiracetam treatment, the fertility index was extremely low in the 1500 mg/kg/day group for both treatment periods. This high dose group consistently exhibited decreased testicular weights. Epididymal and prostate weights were also reduced in the 1500 mg/kg/day group after both 4- and 9-week treatments and in the 500 mg/kg/day group after the 9-week treatment. Severe degenerative changes such as degeneration of germ cells, loss of germ cells and atrophy of seminiferous tubules were observed in all rats of the 1500 mg/kg/day groups after both 4 and 9 weeks of treatment. Retention of spermatids in stage IX, X and XI seminiferous tubules was also noted after the 4- and 9-week treatments at 500 mg/kg/day. The testicular sperm head counts were markedly decreased following the 4- and 9-week treatments at 1500 mg/kg/day, and mildly reduced after the 4-weeks treatment at 500 mg/kg/day. From these results it is concluded that histopathological examination and the testicular sperm head count method are highly useful for detecting testicular toxicity and that testicular lesions caused by nefiracetam can be detected after 4 weeks of exposure.
Rotihibins, novel plant growth regulators from Streptomyces graminofaciens.
In the course of screening search for plant growth regulators, a culture filtrate of Streptomyces graminofaciens 3C02 was found to inhibit the growth of lettuce seedlings. The active substances, named rotihibin A (1) and B (2), were revealed to be lipo-peptidal compounds. Rotihibins inhibit growth of various plants at below 1 microgram/ml, but do not show lethal activity even at higher doses.
Inhibition of ceramide-induced apoptosis by Bcl-2.
Ceramide, a long chain sphingolipid that is generated intracellularly upon hydrolysis of membrane-associated sphingomyelin, has recently been implicated as a second messenger-like molecule that is produced distal to ligation of the tumour necrosis factor receptor type 1 (TNFR1), as well as the related Fas (CD95/Apo-1) molecule. It is well established that ligation of TNFR1 or Fas leads to apoptosis in most cases. Furthermore, it has also recently been demonstrated that exposure to cell-permeable synthetic ceramides can result in apoptosis in many cases. These and other observations have led to the hypothesis that accumulation of intracellular ceramide may be a common element of several pathways that result in apoptosis. Here we show that exposure to synthetic ceramides triggers apoptosis in the human T lymphoblastoid cell lines, CEM and Jurkat, and that overexpression of the apoptosis-repressor protein, Bcl-2, renders these cells resistant to the apoptosis-inducing effects of ceramide, as well as to several other stimuli. Since exposure to ceramides can result in either cell proliferation, differentiation, cycle arrest, or death, the level of Bcl-2 expression in a cell may be an important factor in determining the outcome of signals that result in intracellular generation of this sphingolipid.
Different effect of cyclosporin A on arthritides induced by a muramyl dipeptide analogue or the complete adjuvant in rats.
Muramyl dipeptide-Lys(L18) given by daily subcutaneous injection for 14 days induced arthritis in male Lewis, Fischer and nude rats, to a lesser degree in the last two than in the first strain. On the other hand, a single intradermal administration of Freund's complete adjuvant induced arthritis in Lewis and Fischer but not nude rats. Cyclosporin A (CsA) co-administered for 14 days markedly exacerbated the muramyl dipeptide-Lys(L18) induced arthritis (MIA) in rats of all three strains, but completely blocked the development of the adjuvant induced arthritis (AIA) in Lewis rats. Furthermore, AIA was transferred to recipient Lewis rats through spleen cells obtained from the donors with AIA, whereas MIA was not. Antibodies against type II collagen and DNA were not detected in sera from MIA or AIA rats. These data show a clear difference between MIA and AIA in the pattern of development of arthritis and suggest that delayed hypersensitivity reactions may be involved in the pathogenetic mechanisms of AIA, but not in MIA.