Biomedical subjects
Publications and source records attributed to T Takano.
Cardiac troponin T, measured by second-generation assay, is a highly sensitive and specific marker of minor myocardial damage. Cardiac troponin T was elevated in patients with severe chronic heart failure; it identifies those with latent and progressive myocardial damage and those who are at increased risk of cardiac events.
A novel monoclonal antibody (ASH1a/256C) that recognizes atherosclerotic lesions in human and Watanabe heritable hyperlipidemic (WHHL) rabbit aortae is described. When (123)I-labeled ASH1a/256C antibody is injected intravenously into WHHL rabbits, it associates specifically with fatty streaks on the aorta. The antigen recognized by the antibody is lipid, based on extraction with chloroform and methanol from WHHL rabbit tissues. The antigen, purified by high performance liquid chromatography, was shown to be phosphatidylcholine (PC), which contains unsaturated fatty acyl groups based on analyses utilizing (1)H and (13)C nuclear magnetic resonance, Fourier transfer-infrared spectrum, and mass spectrometry. The antibody did not react with other classes of phospholipids or neutral lipids when tested using an enzyme-linked immunosorbent assay. When PC was mixed with either cholesterol, cholesteryl ester, or triacylglycerol, however, the reactivity of the antibody to PC increased up to 8-fold. Homogenates of aorta tissue obtained from normal and WHHL rabbits were fractionated using sucrose density gradient ultracentrifugation in which neutral lipid droplets, cellular membranes, and proteins are separated. The phospholipid content in cellular membrane fractions from WHHL rabbits was twice as high as that of normal rabbits, and there was an enormous difference in the antigenic activity in these fractions. The content of cholesterol in the cellular membrane fraction of WHHL rabbits was approximately 50 times higher than that of normal rabbits. Addition of neutral lipids to the cellular membrane fraction of normal rabbit markedly increased the antigenic activity. Atheromatous lesions in thickened WHHL rabbit aortic intima that were rich in lipid droplets were stained positively with ASH1a/256C immunohistochemically. These results strongly suggest that PC-neutral lipid complex domains are formed in atherosclerotic lesions.
Syk has been shown to be activated by osmotic stress, however, the mechanisms involved are largely unknown. In this study, we demonstrated that cell shrinkage, rather than osmolarity, was responsible for osmotic stress-induced Syk activation. Osmotic stress-induced Syk activation depended partly upon aggregation of surface receptors. Moreover, intracellular reactive oxygen species were involved in mediating osmotic stress-induced Syk activation, with osmotic stress-induced Syk activation being inhibited by the pretreatment of cells with N-acetyl-cysteine and reduced glutathione. When cells were treated with the combination of sodium chloride and hydrogen peroxide, there was a synergistic activation of Syk. In conclusion, osmotic stress-induced Syk activation required suramin-inhibitable surface receptor aggregation and accumulation of intracellular reactive oxygen species.
In order to elucidate the relationship between virus neurotropism and neuronal maturity, two experiments were performed. First, mumps virus infectivity was compared among the different developmental stages of hamster brains inoculated with mumps virus by examining the immunohistochemical distribution of mumps virus antigen. Second, brain lesions resulting from mumps virus infection during the period of neuronal migration were histologically and ultrastructurally analyzed. Three groups of Syrian hamsters, Group E12 (fetuses on the 12th day of gestation), and Groups P2 and P30 (2 and 30 days old, respectively), were injected with mumps virus intraplacentally or intracerebrally. In Group P30, mumps virus antigen was observed specifically in ependymal cells and the choroid plexus. In addition to these areas, in Group P2, some neurons in layers II and III of the cerebral cortex also showed virus antigen immunoreactivity. In Group E12, mumps virus antigen accumulated primarily in the neuroepithelial cells within the ventricular zone. Neither specific intranuclear changes related to viral replication nor the formation of complete virions and nucleocapsids was observed. We conclude that mumps virus neurotropism to hamster brains is dependent on the degree of neuronal maturity and that mumps virus can induce an abortive infection and resultant neuronal cell necrosis in the immature developing hamster brain.
Sequence specific-differential display (SS-DD) is a powerful method for screening significant changes in gene expression between normal and malignant tissues. Using this method, we detected 3 genes for which the expression is much decreased in thyroid tumors. After sub-cloning and sequencing analysis, one of the genes was revealed to be acid ceramidase (AC). The expression of AC in normal thyroids and thyroid tumors was examined by semi-quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR). Obvious decreases in the expression of AC mRNA were observed in 5/6 follicular adenomas, 2/2 adenomatous goiters, 3/6 papillary carcinomas and 1/2 follicular carcinomas. To confirm this result, real-time quantitative PCR analysis (TaqMan PCR) was carried out. The relative expression level of AC mRNA compared with that of GAPDH mRNA was reduced in follicular adenomas, follicular carcinomas, and papillary carcinomas. Further, the expression of AC mRNA was extremely reduced in 2 anaplastic carcinomas. These results suggest a possible relationship between thyroid tumorigenesis and the expression of AC mRNA. Moreover, the increased expression of AC mRNA in normal thyroid tissues suggests some fundamental roles of AC in thyroid function.
The 70-kDa peroxisomal membrane protein (PMP70) is one of the major components of rat liver peroxisomal membranes and belongs to a superfamily of proteins known as ATP binding cassette transporters. PMP70 is markedly induced by administration of hypolipidemic agents in parallel with peroxisome proliferation and induction of peroxisomal fatty acid beta-oxidation enzymes. To characterize the role of PMP70 in biogenesis and function of peroxisomes, we transfected the cDNA of rat PMP70 into Chinese hamster ovary cells and established cell lines stably expressing PMP70. The content of PMP70 in the transfectants increased about 5-fold when compared with the control cells. A subcellular fractionation study showed that overexpressed PMP70 was enriched in peroxisomes. This peroxisomal localization was confirmed by immunofluorescence and immunoelectron microscopy. The number of immuno-gold particles corresponding to PMP70 on peroxisomes increased markedly in the transfectants, but the size and the number of peroxisomes were essentially the same in both the transfectants and the control cells. beta-Oxidation of palmitic acid increased about 2-3-fold in the transfectants, whereas the oxidation of lignoceric acid decreased about 30-40%. When intact peroxisomes prepared from both the cell lines were incubated with palmitoyl-CoA, oxidation was stimulated with ATP, but the degree of the stimulation was higher in the transfectants than in the control cells. Furthermore, we established three Chinese hamster ovary cell lines stably expressing mutant PMP70. In these cells, beta-oxidation of palmitic acid decreased markedly. These results suggest that PMP70 is involved in metabolic transport of long chain acyl-CoA across peroxisomal membranes and that increase of PMP70 is not associated with proliferation of peroxisomes.
This paper reviews the angiotensin I-converting enzyme inhibitory peptides originated from milk proteins. Focus was put on the peptides derived from milk casein by the action of some proteolytic enzymes and fermented products by lactic acid bacteria. Some of the angiotensin I-converting enzyme inhibitory peptides exhibit significant antihypertensive effects in spontaneously hypertensive rats. However, there were some antihypertensive peptides with low inhibitory activity of this enzyme. Key factors needed for the peptide to demonstrate the antihypertensive effects are discussed. Fermented milk, which has inhibitory activity of the enzyme, showed the reduction of blood pressure of hypertensive subjects. The possibility of the bioactive peptides for functional foods are also discussed.
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In recent years, homelessness has been recognized as a growing urban social problem in various countries throughout the world. The health problems of the homeless are considerable. The purpose of this study was to elicit, with sociodemographic profiles, the disease patterns among Tokyo's homeless. The subjects were 1,938 men who stayed at a welfare institution from 1992 to 1996. Diagnosed diseases/injuries and sociodemographic profiles were analyzed. The disease patterns of the homeless were compared to those of the male general population. Of the subjects, 8.3% were admitted to the hospital; 64.0% received outpatient care. Their observed morbidity rates by disease category were greater than those of the male general population in both Japan and Tokyo. Comorbidity of alcoholic psychosis/alcohol-dependent syndrome to both liver disease and pulmonary tuberculosis were greater than the average (P < .01). Construction work brought a higher risk of pulmonary tuberculosis (odds ratio = 2.0) and dorsopathies (odds ratio = 1.4) than did other jobs (P < .05). Disease patterns among the homeless in Tokyo were characterized by alcoholic psychosis/alcohol-dependence syndrome; liver disease; pulmonary tuberculosis; diabetes mellitus; fractures, dislocations, sprains, strains; hypertension; and cerebrovascular disease. Although the sociodemographic backgrounds of Tokyo's homeless have become more diverse, the principal occupation of the homeless was unskilled daily construction work, which underlay the characteristics of their disease patterns.
The expression levels of each splice variant of the fibronectin gene in the normal thyroid and in thyroid tumors were examined by reverse transcription-polymerase chain reaction (RT-PCR). In thyroid papillary carcinomas, insertion of a variant exon in the ED-A and ED-B domains, and three of five types of splice variants in the IIICS domain were observed. In spite of the marked increase in the expression of oncofetal fibronectin mRNA with the IIICS sequence in papillary and anaplastic carcinomas in the previous reports, the relative expression levels of each splice variant with or without the IIICS sequence showed no difference among all the tumor types. Therefore, the much increased expression of oncofetal fibronectin mRNA in these carcinomas is not caused by the alternation in splicing, but may be caused by an increase in promoter activity or stability of mRNA of the fibronectin gene.
OBJECTIVE: The aim of this study was to examine the hypothesis that long-term treatment with antipsychotic drugs in conventional doses prolongs QTc dispersion and increases ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease. METHODS: We measured QTc and QTc dispersion and ventricular tachyarrhythmias in 64 patients with schizophrenia, including 59 patients who received psychiatric medications, and five patients who did not receive psychiatric medications, and 45 healthy volunteers. None of the subjects had a history of cardiac disease or showed any abnormality in chest radiograph and transthoracic echocardiographic studies. None of the subjects had electrolyte abnormality. None of the subjects were taking drugs known to influence the QT interval, other than psychiatric medications. RESULTS: QTc and QTc dispersion were significantly (P < 0.017) increased in patients who received psychiatric medications compared with patients who did not receive psychiatric medications, or with healthy volunteers [QTc: 0.442 (0.029), 0.418 (0.029), 0.417 (0.028) s, QTc dispersion: 0.054 (0.013), 0.038 (0.017), 0.038 (0.009) s]. Daily ventricular premature beats were 183 (689), 77 (23), and 86 (149), respectively. No ventricular tachycardia was observed. There were no correlation between QTc and QTc dispersion and ventricular premature beats. CONCLUSION: Long-term treatment with antipsychotic drugs in conventional doses prolonged both QTc and QTc dispersion in patients with schizophrenia, but did not increase ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease. However, despite the negative findings, ventricular tachyarrhythmias may occur as a rare side-effect of antipsychotic drugs, particularly if a patient has additional risk factors.
Signals from extracellular matrix (ECM) to growth factor receptors regulate glomerular epithelial cell (GEC) proliferation. Epidermal growth factor (EGF), basic fibroblast growth factor, hepatocyte growth factor (HGF), or thrombin stimulated proliferation of GECs when the cells were adherent to collagen matrices, but not plastic substratum. Furthermore, EGF, HGF, or thrombin activated p42 mitogen-activated protein (MAP) kinase in collagen-adherent GECs, whereas activation was weak in GECs on plastic. To further examine the interaction of ECM with the Ras-MAP kinase cascade, GECs were stably transfected with a constitutively active Ras mutant (V12Ras). Low or moderate levels of V12Ras expression did not affect basal MAP kinase activity but, unlike parental GECs, in clones that express V12Ras, EGF was able to induce proliferation and activate MAP kinase when these cells were adherent to plastic. In parental and V12Ras-transfected GECs, MAP kinase activation was inhibited by cytochalasin D. Thus, adhesion of GECs to ECM facilitates proliferation and MAP kinase activation by mitogens acting via tyrosine kinase or non-tyrosine kinase receptors. Activation of pathway(s) downstream of V12Ras supplants signals from ECM that enable proliferation. These signals may involve the actin cytoskeleton.
In the passive Heymann nephritis (PHN) model of membranous nephropathy, C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated via production of eicosanoids. Using rat GEC in culture, we demonstrated that sublytic C5b-9 induced tyrosine phosphorylation of the epidermal growth factor receptor (EGF-R), Neu, fibroblast growth factor receptor-2, and hepatocyte growth factor receptor. In addition, C5b-9 stimulated increases in tyrosine(204) phosphorylation of extracellular signal-regulated kinase-2 (ERK2), as well as free [(3)H]arachidonic acid (AA) and prostaglandin E(2) (PGE(2)). Phosphorylated EGF-R bound the adaptor protein, Grb2, and the EGF-R-selective tyrphostin, AG1478, blocked the C5b-9-induced ERK2 phosphorylation, [(3)H]AA release, and PGE(2) production by 45 to 65%, supporting a functional role for EGF-R kinase in mediating the activation of these pathways. Glomeruli isolated from rats with PHN demonstrated increases in ERK2 tyrosine(204) phosphorylation and PGE(2) production, as compared with glomeruli from control rats, and these increases were partially inhibited with AG1478. Thus, C5b-9 induces transactivation of receptor tyrosine kinases, in association with ERK2 activation, AA release, and PGE(2) production in cultured GEC and glomerulonephritis in vivo. Transactivated tyrosine kinases may serve as scaffolds for assembly and/or activation of proteins, which then lead to activation of the ERK2 cascade and AA metabolism.
A child is presented who displayed hypointense multiple sclerotic lesions on fluid-attenuated inversion recovery sequences by magnetic resonance imaging, with the possible pathologic tissue changes of these hypointense lesions evaluated. The magnetic resonance imaging results in this patient demonstrated the disappearance of low-signal lesions on fluid-attenuated inversion recovery in multiple sclerosis, and the improvement of this patient's condition was likely compatible with sequential magnetic resonance imaging findings. Some hypointense lesions in the supratentorial white matter that appear on fluid-attenuated inversion recovery images in multiple sclerosis patients may include reversible brain lesions, suggesting extracellular fluid collection not accompanied by axonal loss or gliosis.
There exists limited information about the usefulness of hemopoietic stem cell transplantation (HSCT) for the treatment of patients with refractory Langerhans cell histiocytosis (LCH). We report here four Japanese pediatric patients with multisystem LCH disease who underwent HSCT between 1994 and 1997. Two of the four patients are doing well without any relapse. However, neither of them shows improved sequelae 3 to 4 years after allogeneic HSCT, although the graft was rejected in one of the cases. The remaining two patients died of septic shock. A review of the literature of 11 patients revealed four fatalities after the use of HSCT in the treatment of LCH. Three of these were due to active LCH and three deaths occurred within 2 months after HSCT. To establish the usefulness of HSCT for refractory LCH, further studies are required.
BACKGROUND: Orthotopic penetrating keratoplasty in the sheep was developed as an outbred preclinical model to allow correlation of the cellular infiltrate during graft rejection with local production of cytokine mRNA. METHODS: Penetrating corneal autografts and allografts were performed in Merino sheep. Graft outcome was followed at the slit-lamp. Corneal infiltrates were examined by immunoperoxidase staining on postmortem specimens. Cytokine mRNA was detected by polymerase chain reaction. RESULTS: Corneal autografts survived indefinitely. Allografts became vascularized and underwent rejection at a median of 20 days postgraft. Both endothelial and epithelial rejection lines were observed. Immunohistochemical staining of rejecting grafts showed up-regulation of major histocompatibility complex class I molecules on corneal graft epithelium, damaged or absent graft endothelium and a marked, predominantly mononuclear cell infiltrate. CD4-positive T cells were observed in the graft within 2 days of the onset of rejection, followed several days later by CD8-positive T cells. Messenger RNA transcripts for interleukin (IL)-2, tumour necrosis factor (TNF)-alpha and IL-10 (but not for interferon (IFN)-gamma or IL-4) were found in autografted corneas. Proportionately, more allografts than autografts contained transcripts for IL-2 and TNF-alpha, and IFN-gamma was detected in three of four allografts. CONCLUSIONS: Corneal graft rejection in the sheep is macroscopically and histologically similar to human corneal graft rejection. Allografts become infiltrated by both CD4- and CD8-positive T cells and local production of pro-inflammatory cytokines occurs during graft rejection.
A totally implantable centrifugal artificial heart has been developed. The plastic prototype, the Gyro PI 601, passed 2 day hemodynamic tests as a functional total artificial heart (TAH), 2 week screening tests for anti-thrombogenecity, and a 1 month system feasibility study. Based upon these results, a metallic prototype, the Gyro PI 700 series, was subjected to long-term in vivo left ventricular assist device (LVAD) studies of over 1 month. The Gyro PI 700 series has the same inner dimension and same characteristics of the Gyro PI 601 such as an eccentric inlet port, a double pivot bearing system, and a magnet coupling system. The PI metallic pump is also driven with the Vienna DC brushless motor actuator like the PI 601. The pump-actuator package was implanted in 3 calves in the preperitoneal space, bypassing from the left ventricular (LV) apex to the descending aorta. Case 1 achieved a 284 day survival. Case 2 was euthanized early at 72 postoperative days as a result of the functional obstruction of the inlet port due to the excessive growth of the calf. There was no blood clot inside the pumps of either case. Case 3 is on-going (22 days on July 24, 1998). During these periods, all cases showed no physiological abnormalities. In conclusion, the PI 700 series pump has excellent results as a long-term implantable LVAD.