Biomedical subjects
Publications and source records attributed to Y Murakami.
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To clarify whether levofolinate calcium (1-LV) enhances 5-fluorouracil (5-FU) toxicity, a 4-week toxicity study of 5-FU (10 mg/kg/day) in combination with 1-LV (6, 20 or 60 mg/kg/day) was conducted in rats. In the 5-FU alone group, a decrease in body weight gain, food consumption, RBC parameter and WBC counts were detected. Histopathologically, lymphoid depletion of lymphatic organs, hematopoiesis enhancement of the spleen and myelosuppression were observed. In the group for which 5-FU was combined with 1-LV, the RBC counts decreased, extramedullary hematopoiesis increased and the suppression of lymphatic organs was enhanced. Changes in the lymphatic organs were observed at 20 mg/kg/day of 1-LV and above. In monitoring of blood drug concentrations of 1-LV, 5-methyl tetrahydrofolic acid, a metabolite of 1-LV, and 5-FU after the 1st and 14th dosings, there was no apparent difference between 5-FU alone and 5-FU combined with 1-LV in Cmax and AUC0-infinity. The potentiation induced by 1-LV in the toxicity of 5-FU appeared to be mainly immuno-suppression and myelosuppression, which were related to the anti-tumor activity of 5-FU. Plasma concentrations of 5-FU and 1-LV in this study overwhelmed the concentrations that enhancement of thymidylate synthetase (TS) inhibition due to 5-FU was observed by addition of 1-LV in vitro. Therefore toxic potentiation of 5-FU due to simultaneous 1-LV dosing is presumed to be concerned with an increased ternary complex (FdUMP-TS-5,10-methylenetetrahydrofolate) formation and a greater extent of TS inhibition.
A repeated oral dose toxicity study of methotrexate (MTX) was conducted in order to examine whether the enhancement of MTX toxicity would occur in unilaterally nephrectomized (UNX) rats. UNX rats or sham-treated (SHAM) rats received dosages of 0, 0.06, 0.2 or 0.6 mg/kg/day (control animals received physiological saline). Toxic effects of MTX observed in this study were not different from studies already conducted, i.e., myelo- and lympho-toxicity, gastrointestinal toxicity, hepatotoxicity, pulmonary toxicity and renal toxicity were evident in the animals given MTX. Toxic effects of MTX in the UNX rats were more severe than those in the SHAM rats; a higher number of dead and moribund animals was observed among the UNX rats, and abnormal clinical signs appeared a few days earlier in the UNX rats. In the hematological examination, a decreased number of the blood cells in the UNX rats was observed at the lower dose level as compared to SHAM rats. The nontoxic dose of MTX in SHAM rats and UNX rats was 0.06 mg/kg/day and below 0.06 mg/kg/day, respectively. According to the results of a toxicokinetic examination conducted in the animals receiving 0.2 mg/kg/day, AUC and T 1/2terminal of MTX in the UNX rats were higher than those of SHAM rats. It was considered that the enhancement of the MTX toxicity in UNX rats was caused by the longer exposure of MTX in UNX rats. Serum UN and Cr of the UNX rats receiving physiological saline were higher than those of the corresponding SHAM rats, which suggested a slightly decreased GFR had been induced in UNX rats in this study. However, decreased PSP excretion was not observed in the UNX rats and urine volume of the UNX rats was equivalent to that of SHAM rats. Thus, it was considered that vicarious hypertrophy occurred in the residual kidney and decreased renal function was not evident in the UNX rats. This study demonstrated that the enhancement of toxicity of MTX had occurred even though a decreased renal function was not evident.
We investigated the effect of a two-way exchange transfusion on cerebral hemodynamics and oxygenation in 3 neonates using near infrared spectroscopy (NIRS). A total of 4 exchange transfusions (ET) for the treatment of sepsis were performed. Cerebral oxyhemoglobin concentrations (HbO2) increased immediately after commencing with ET by 8.82 +/- 3.46 (mean +/- SD) micromol/l, which persisted throughout the ET. Total hemoglobin concentrations (HbT) simultaneously increased by 8.92 +/- 3.81 (mean +/- SD) micromol/l. No changes in cerebral deoxyhemoglobin concentrations (HbR) and cytochrome aa3 (Cytaa3) were observed. In one occasion, however, HbR increased markedly and HbO2 decreased immediately after ET had begun, thus HbT remained slightly increased compared to the 3 other occasions. The extension of periventricular echogenecity was observed after ET by cranial ultrasound scan in this patient and periventricular leukomalacia was confirmed by autopsy. We conclude that a two-way exchange transfusion increases cerebral blood volume and improves cerebral oxygen delivery. Furthermore NIRS was useful in monitoring changes in cerebral hemodynamics and oxygenation in unstable septic neonates.
Rats were fed 20 or 70% casein diets with varying amounts of vitamin B6 (B6), and the B6 content and B6-dependent enzymatic activity in their tissues were examined to determine the minimum requirement of B6 for animals subjected to different levels of dietary protein (i.e., 20%: 0, 1.45, 2.90, 5.80 mg pyridoxine (PN)/kg diet; 70%: 0, 2.90, 5.80, 8.70 mg PN/kg diet). B6 requirements for the rats were almost met in the 1.45 mg PN/kg 20% casein diet and the 2.90 mg PN/kg 70% casein diet when judged from the hepatic B6 content. However, almost twice the PN was required in both 20 and 70% casein diets when judged from PLP-enzymatic activity. The content of B6 vitamers in plasma appeared to be most sensitive to B6 status, though the satisfactory level is not known. It was confirmed that, in any case tested, a high-protein diet increased the requirement of B6.
Human CD46 was identified as a complement regulator and was later shown to be a measles virus receptor. The ubiquitous distribution profile of CD46 accounted for systemic measles infection and general protection of host tissue/organs from autologous complement. A similar ubiquitous distribution was observed for swine and simian CD46 homologues based upon subsequent cDNA cloning and Northern analysis, reinforcing the roles of CD46. In contrast, recent cDNA cloning and distribution analyses of murine and guinea-pig CD46 revealed the predominant expression of these rodent CD46 homologues in the testis, especially in mature testicular germ cells. These results do not support the established functions of human CD46 but support the hypothesis that CD46 on sperm serves as a fertilization-related adhesion molecule toward eggs. Here, we review the structure, function and distribution of human CD46 and discuss the possible differences between human CD46 and its homologues recently cloned from a variety of non-human primates and other animals.
We investigated the time courses of histopathological changes in various brain regions following permanent occlusion of the bilateral common carotid arteries (2VO) in rats. 2VO rats exhibited rarefaction in the white matter, shrinkage of neurons in the cerebral cortex and hippocampus CA1-3 and dentate gyrus areas 1-3 days after the operation. These histological changes in the cortex and hippocampus were accompanied by a decrease in immunoreactivity for microtubule-associated protein 2 (MAP2), a marker protein of neuronal dendrites. Immunoreactivity for glial fibrillary acid protein (GFAP) was observed at 3-7 days after the 2VO operation. A marked increase in GFAP staining of the astrocytes in the cerebral cortex and hippocampus was found 30 days after ligation. Eight-arm radial maze performance was tested from 14 days to 60 days after the operation. The 2VO rats showed fewer initial correct responses than sham-operated control rats during a repeated training period. These findings suggested that the loss in dendritic MAP2 immunoreactivity and an increase in astroglial staining and/or rarefaction of the white matter may cause neuronal death, infarction and learning impairment under conditions of chronic hypoperfusion.
To study the probability of leaving metastatic lymph nodes or intralobar metastasis unresected by limited surgery, we reviewed histopathologically 189 patients who had major pulmonary resection and complete lymph adenectomy for peripheral, p-T 1 or T 2 non-small cell lung cancer from 1975 to 1997 at our hospital. Lymph node involvements and or intralobar metastasis were found in 25 (26.0%) of 96 cases with tumor smaller than 3.0 cm and 44 (47.3%) of 93 cases with tumor larger than 3.0 cm. There was no difference between histological types of lung cancer. From this result, it was suggested that the risk of leaving cancer by limited operation would not be low. In conclusion, we believe that limited operation is not an alternative to the standard resection in patients with peripheral, stage I non-small cell lung cancer.
The mechanisms and pathophysiology of sleep disturbances in patients with endocrine diseases are reviewed. Abnormalities in sleep regulations were demonstrated in patients with thyrotoxicosis and hypothyroidism in a use of electroencephalogram during sleep. Mental disorders are one of the causes of sleep disturbance, for example insomnia due to depression in Cushing's syndrome. Metabolic abnormalities such as hyponatremia and hypoglycemia due to adrenal insufficiency could also contribute to sleep disturbance. Obstructive, central and mixed types of sleep apnea syndrome are known to occur in hypothyroidism, acromegaly and diabetic neuropathy with autonomic dysfunction. Thus, multiple factors are involved in sleep disturbance in patients with endocrine disorders.
The purpose of this study was to assess the point at which the postoperative infection has occurred in order to decide upon the proper duration of prophylactic antibiotic use. Another goal of this study was to determine whether prediction for the development of postoperative infections in major surgery such as esophagectomy should be the same as that in routine gastroenterological surgery. Twenty-five patients who underwent transthoracic esophagectomy and 127 patients who underwent gastrectomy were studied. On the third day after gastric surgery, the body temperature of patients who developed an infection was higher than that of the patients who did not develop an infection. The relative changes in peripheral white blood count (WBC), and C-reactive protein (CRP) concentration on the third and fourth days were more predictive of the development of infection than the absolute values. Almost all patients with systemic inflammatory response syndrome (SIRS) on the third day after gastric surgery developed an infection. On the other hand, the incidence of SIRS in patients who did not develop an infection was high on both the third and fourth days after esophageal surgery. It was nearly impossible to predict who would develop an infection in esophageal surgery. The high incidence of postoperative infections, and their significant consequences justify planned successive postoperative antibiotic use in esophageal surgery.
The cytotoxic effects of a toxic preparation from Clostridium novyi type A were demonstrated on tissue-cultured bovine kidney cells. The cytotoxic response was dose-dependent and could be neutralized by homologous antiserum. Scanning electron microscopy revealed damaged kidney cell surfaces. These findings indicated that the cytotoxicity may contribute to the formation of the foci in bovine tissue during an infection with C. novyi.
Cardiomyopathy (CM) is a primary degenerative disease of myocardium and is traditionally categorized into hypertrophic and dilated CMs (HCM and DCM) according to its gross appearance. Cardiomyopathic hamster (CM hamster), a representative model of human hereditary CM, has HCM and DCM inbred sublines, both of which descend from the same ancestor. Herein we show that both HCM and DCM hamsters share a common defect in a gene for delta-sarcoglycan (delta-SG), the functional role of which is yet to be characterized. A breakpoint causing genomic deletion was found to be located at 6.1 kb 5' upstream of the second exon of delta-SG gene, and its 5' upstream region of more than 27.4 kb, including the authentic first exon of delta-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of delta-SG transcripts with the consequent loss of delta-SG protein in all the CM hamsters, despite the fact that the protein coding region of delta-SG starting from the second exon was conserved in all the CM hamsters. We elucidated the molecular interaction of dystrophin-associated glycoproteins including delta-SG, by using an in vitro pull-down study and ligand overlay assay, which indicates the functional role of delta-SG in stabilizing sarcolemma. The present study not only identifies CM hamster as a valuable animal model for studying the function of delta-SG in vivo but also provides a genetic target for diagnosis and treatment of human CM.
Orc5p is a subunit of the origin recognition complex in the budding yeast Saccharomyces cerevisiae, which has been shown to play a critical role in both chromosomal DNA replication and transcriptional silencing. We have cloned cDNAs from both human and fission yeast Schizosaccharomyces pombe that encode proteins homologous to the budding yeast and Drosophila Orc5p. Human Orc5p showed 35.1, 22.3, and 19.4% identity to the Drosophila, S. pombe, and S. cerevisiae Orc5p, respectively. We have localized the human ORC5 gene (ORC5L) to chromosome 7 using Southern and PCR analysis of DNA isolated from a panel of human/rodent somatic cell hybrids and mapped the gene locus to 7q22 using fluorescence in situ hybridization. We have identified a YAC clone that contains human ORC5L and maps to chromosome band 7q22.1. We have identified the S. pombe ORC5 gene and located it in a cosmid mapped on chromosome II.
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Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to have trophic effects on neurons. Apoptosis of PC12 cells was induced by depletion of serum and nerve growth factor (NGF) from culture medium. Not only high potassium-induced Ca2+ channel activation but PACAP-38 at physiological concentrations (10[-10] to 10[-8] M) protected PC12 cells from apoptosis. PACAP-38 increased Ca2+ uptake and intracellular Ca2+ concentrations in PC12 cells. The effects of PACAP-38 on cell survival and Ca2+ channels were eliminated by inhibitors for Ca2+ channels and protein kinase A, and mimicked by 8-bromo-cAMP. Mitogen-activated protein (MAP) kinase activity was stimulated by PACAP-38. These findings implicate that PACAP protects PC12 cells from apoptosis by activating Ca2+ channels via the cAMP-protein kinase A pathway to stimulate MAP kinase cascade.
A scanning near-field optical/atomic force microscope (SNOAM) system was applied for simultaneous topographic and fluorescence imaging of biological samples in air and liquid. The SNOAM uses a bent optical fiber simultaneously as a dynamic mode atomic force microscopy cantilever and as a scanning near-field optical microscopy probe. Optical resolution of this system was about 50-100 nm in fluorescence mode for fluorescent latex beads on a quartz glass plate. Green fluorescent protein (GFP) is a convenient indicator of transformation and should allow cells to be separated by fluorescence-activated cell sorting. The gene coding to GFP was cloned in recombinant Escherichia coli. The SNOAM system used 458- or 488-nm irradiation from a multiline Ar ion laser for excitation of GFP, since a native GFP has been known to give a maximum at 395 nm and a broad absorption spectrum until 500 nm. Topographic and fluorescence images of recombinant E. coli were obtained simultaneously with a high spatial resolution which was apparently better than that of a conventional confocal microscope. A nanoscopic GFP fluorescence spectrum was obtained by positioning the optical fiber probe above the bright area of the E. coli cells. Comparing topographic and fluorescence images, it can be seen that individual E. coli cells expressed different fluorescence intensities. Fluorescence obtained by SNOAM indicated that GFP oxidation possibly occurred near the cell surface. A SNOAM system also indicated the possibility of precise imaging of native cells in liquid.