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Biomedical subjects

H Ikeda

Publications and source records attributed to H Ikeda.

At least 289 records · Page 16Linked to original sources
PubMed1999

Effects of terfenadine, astemizole and epinastine on electrocardiogram in conscious cynomolgus monkeys.

We examined the effects of non-sedative histamine H1 receptor antagonists on the electrocardiogram (ECG) in conscious cynomolgus monkeys. Terfenadine (3 mg kg(-1) h(-1), i.v.) and astemizole (0.3 and 1 mg kg(-1) h(-1), i.v.) caused significant time-dependent increases in the QT interval and QTc Bazett (QTc). However, normal ECG forms were found during a 60-min infusion of epinastine (3 mg kg(-1) h(-1) i.v.). A higher dose of epinastine (10 mg kg(-1) h(-1), i.v.) increased the QTc and PR interval only 5 min after the start of the infusion. The minimum plasma concentrations of terfenadine, astemizole and epinastine which caused QTc prolongation were 85, 35 and over than 3600 ng/ml, respectively. These drugs did not alter the PQ and QRS intervals and did not cause arrhythmia or atrioventricular block. Our results are consistent with the clinical observation that prolongation of QTc is caused by terfenadine and astemizole but not by epinastine. Thus, measurement of QTc in cynomolgus monkey appears to be a useful approach for evaluating the potential cardiotoxicity of histamine H1 receptor antagonists.

Animals↗
PubMed1999

Mechanism of DNA gyrase-mediated illegitimate recombination: characterization of Escherichia coli gyrA mutations that confer hyper-recombination phenotype.

To study the mechanism of DNA gyrase-mediated illegitimate recombination in Escherichia coli, we isolated temperature-sensitive gyrA mutants that confer spontaneous illegitimate recombination and spontaneous induction of lambda prophage at higher frequencies than that in the wild-type. After reconstruction of single mutations by targeted mutagenesis, we confirmed that two single mutations, gyrAL492P and gyrAL488P, and a double mutation, gyrAI203V+gyrAI205V, show the same properties as those described above. With respect to the phenotypes of hyper-recombination and higher induction of lambda prophage, these mutations were dominant over the wild-type. Analysis of recombination junctions of lambdabio transducing phages formed spontaneously in these mutants showed that the parental E. coli bio and lambda recombination sites have a homologous sequence of only 0. 7 base-pair on average, indicating that homology is not required for this illegitimate recombination. Analysis of nucleotide sequences of mutant gyrA genes revealed that the gyrAL492P and gyrAL488P mutations contain amino acid substitutions of Leu492-->Pro and Leu488-->Pro, respectively, which correspond to the alpha18 helix in the breakage-reunion domain of DNA gyrase A subunit. The gyrAI203V and gyrAI205V mutations contain Ile203-->Val and Ile205-->Val, respectively, which correspond to the alpha10' helix, also in the breakage-reunion domain of DNA gyrase A subunit. Biochemical analysis indicated that the GyrA63 protein that contains the L492P mutation has an apparently normal supercoiling activity, but it also produces a small amount of linear DNA in the absence of DNA gyrase inhibitor during the supercoiling reaction, suggesting that the mutant DNA gyrase may have a defect at the step of religation or a defect in the subunit interaction. These results suggest that the recombination is induced by defects of religation and/or dimer formation in the mutant DNA gyrases, implying that two alpha helices, alpha10' and alpha18, of DNA gyrase A subunit have crucial roles in subunit interaction and/or resealing of DNA.

Alleles↗
PubMed1999

Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with upregulation of FLT tyrosine kinase receptor family, FLT-1.

Activated hepatic stellate cells produce vascular endothelial growth factor (VEGF). VEGF has been shown to act on mesenchymal cells as well. If hepatic stellate cells can express FLT tyrosine receptor family, flt-1 and KDR/flk-1, their function might be regulated by VEGF in an autocrine manner. This hypothesis was tested using hepatic stellate cells isolated from normal rats. Northern blot analysis and immunocytochemical study revealed that hepatic stellate cells cultured for 3 days on plastic dishes expressed both flt-1 and KDR/flk-1. When the culture was prolonged to 10 days, the flt-1 mRNA expression was increased, whereas both KDR/flk-1 mRNA and protein expressions diminished. DNA and collagen syntheses were minimal in the cells cultured for 3 days, but marked in those cultured for 10 days. Addition of recombinant human VEGF to the culture medium did not change both syntheses but attenuated an increase of smooth muscle alpha-actin expression in the cells during culture on plastic dishes and also contraction of collagen gels on which the cells were cultured. We conclude that VEGF may inhibit contraction of hepatic stellate cells appearing during activation by culture, probably through attenuation of smooth muscle alpha-actin expression via upregulated VEGF receptor, flt-1.

Animals↗
PubMed1999

Predictors of death from congestive heart failure in hypertrophic cardiomyopathy.

In 309 patients with hypertrophic cardiomyopathy during long-term follow-up (mean 9.4 years), independent predictors of death from congestive heart failure (n = 15) were smaller electrocardiographic SV1 + RV5 and smaller echocardiographic fractional shortening at the initial evaluation. Our data may contribute to the construction of therapeutic strategies for the prevention of heart failure death in patients with hypertrophic cardiomyopathy.

Adolescent↗
PubMed1999

Enhanced neural regeneration from transected vagus nerve terminal in diabetic mice in vitro.

This study examined the effect of diabetes on neural regeneration in vitro. Nodose ganglia (NG) with vagal nerve fibers, dissected from streptozotocin-induced diabetic and normal C57BL/6J mice were embedded in collagen gel. After 3 and 7 days in culture, the numbers of regenerating neurites from transected nerve terminals of NG in diabetic mice were significantly greater than those in controls. Although many studies have revealed diabetes-associated impairment in neural regeneration, the results in the present study suggest that experimental diabetes could induce the potential to enhance regenerative capability of vagal sensory nerves after axotomy.

Animals↗
PubMed1999

Expression of osteopontin in Kupffer cells and hepatic macrophages and Stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas.

Activated Kupffer cells and macrophages accumulate in necrotic areas in the liver. Osteopontin, an extracellular matrix with RGD sequence, has been shown to act as a chemokine that can induce monocyte migration. The possibility that osteopontin can play a role in infiltration of both cells into hepatic necrotic areas was investigated in rats. Northern blot analysis revealed that osteopontin mRNA expression was minimal in Kupffer cells and hepatocytes immediately after isolation from normal rats, but slight in hepatic stellate cells assumed nearly quiescent in function after 3 days of culture on plastic dishes. When rat received carbon tetrachloride, liver necrosis developed between 1 and 3 days following the intoxication. In these rats, osteopontin mRNA expression assessed by quantitative competitive RT-PCR was increased in the liver later than 1 day with its peak at 2 days following the intoxication. Kupffer cells and hepatic macrophages and hepatic stellate cells isolated from such liver showed marked expression of osteopontin mRNA on Northern blotting. Immunohistochemical examination disclosed that osteopontin was stained in macrophages including Kupffer cells and stellate cells in the necrotic areas. On electron microscopy, osteopontin stains were present in the Golgi apparatus in these cells. Recombinant human osteopontin promoted migration of Kupffer cells isolated from normal rats and cultured in a Transwell cell culture chamber in a dose-related manner. We conclude that activated Kupffer cells and hepatic macrophages and stellate cells express osteopontin. These cells might contribute to the infiltration of Kupffer cells and macrophages into hepatic necrotic areas by expressing osteopontin.

Animals↗
PubMed1999

Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system.

We identified a novel member of the Ikaros gene family, which has critical roles in the development of lymphoid lineages. This gene, which we named Eos, was expressed predominantly in the developing central and peripheral nervous system. Eos protein could interact with itself and Ikaros protein through its C-terminal portion in the yeast two hybrid assay. These findings suggested that Eos may have important roles in neural development similarly to the Ikaros family in the development of hemolymphoid tissue.

Amino Acid Sequence↗
PubMed1999

Endothelial injuries of coronary arteries distal to thrombotic sites: role of adhesive interaction between endothelial P-selectin and leukocyte sialyl LewisX.

Intracoronary thrombus formation is associated with epicardial vasoconstriction distal to the thrombotic site. To investigate the mechanisms of abnormal vasomotor function of the artery distal to the thrombotic site, we studied coronary vessels in dogs with cyclic flow variations (CFVs) of the left anterior descending coronary artery (LAD) stenosis with endothelial injury. Coronary rings isolated from the LAD (proximal, stenotic, and distal sites) and control circumflex coronary arteries were tested for responsiveness to endothelium-dependent (acetylcholine and A23187) and endothelium-independent vasodilators (NaNO2). Endothelium-independent relaxation was intact in all 4 sites. Endothelium-dependent relaxation was intact in the control and proximal sites and impaired in the stenotic sites. Relaxations not only to acetylcholine and A23187 but also to serotonin, ADP, and thrombin were impaired in the distal sites after observing CFVs for 80 minutes. Electron microscopy revealed the loss of endothelial integrity with leukocyte adherence to the endothelium in the distal sites. Immunohistochemical expression of P-selectin on the endothelial cells was more upregulated in the distal site than in the proximal site, and P-selectin mRNA expression was significantly greater in the ischemic region distal to the thrombotic site than in the proximal nonischemic region. PB1.3, a neutralizing monoclonal antibody against P-selectin, and sialyl LewisX (SLeX)-containing oligosaccharide SLeX, a carbohydrate analogue of selectin ligand, preserved endothelial function without affecting CFVs. SLeX-containing oligosaccharide preserved endothelial integrity of the distal site and inhibited P-selectin expression of the distal site. Thus, the adhesive interaction between endothelial P-selectin and leukocyte SLeX may play an important role in endothelial injuries of the coronary artery distal to the thrombotic site.

Animals↗
PubMed1999

SK&F 83959 and non-cyclase-coupled dopamine D1-like receptors in jaw movements via dopamine D1-like/D2-like receptor synergism.

This study compared the effects of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro- 1 H-3-benzazepine), which inhibits the stimulation of adenylyl cyclase, and A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman), a full efficacy agonist, in regulating jaw movements in the rat by synergism with dopamine D2-like receptor agonism. When SK&F 83959 and A 68930 were given in combination with quinpirole, there was a synergistic induction of jaw movements. Responsivity to SK&F 83959 + quinpirole was antagonised by the dopamine D1-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-ben zaz epine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline); synergism was antagonised also by the dopamine D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-++ +methyl-aminobenzamide). Responsivity to A 68930 + quinpirole was enhanced by low doses of SCH 23390, BW 737C and YM 09151-2, and antagonised by higher doses of SCH 23390 and YM 09151-2. These results implicate a novel, dopamine D1-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and suggest that its functional role extends to the regulation of jaw movements by synergistic interactions with dopamine D2-like receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1999

Activating mutation in the catalytic domain of c-kit elicits hematopoietic transformation by receptor self-association not at the ligand-induced dimerization site.

The c-kit receptor tyrosine kinase (KIT) is constitutively activated by naturally occurring mutations in either the juxtamembrane domain or the kinase domain. Although the juxtamembrane domain mutations led to ligand-independent KIT dimerization, the kinase domain mutations (Asp814 --> Val or Tyr) did not. In an effort to determine if the kinase domain mutant could transfer oncogenic signaling without receptor dimerization, we have constructed the truncated types of c-kitWild and c-kitTyr814 cDNAs (c-kitDel-Wild and c-kitDel-Tyr814 cDNAs, respectively), in which ligand-binding and ligand-induced dimerization domains were deleted. When c-kitDel-Wild and c-kitDel-Tyr814 genes were introduced into a murine interleukin-3 (IL-3)-dependent cell line Ba/F3, KITDel-Tyr814 was constitutively phosphorylated on tyrosine and activated, whereas KITDel-Wild was not. In addition, Ba/F3 cells expressing KITDel-Tyr814 (Ba/F3(Del-Tyr814)) grew in suspension culture without the addition of exogenous growth factor, whereas Ba/F3 cells expressing KITDel-Wild (Ba/F3(Del-Wild)) required IL-3 for growth. The factor-independent growth of Ba/F3(Del-Tyr814) cells was virtually abrogated by coexpression of KITW42 that is a dominant-negative form of KIT, but not by that of KITWild, suggesting that KITDel-Tyr814 may not function as a monomer but may require receptor dimerization for inducing factor-independent growth. Furthermore, KITDel-Tyr814 was found to be coimmunoprecipitated with KITWild or KITW42 by an ACK2 monoclonal antibody directed against the extracellular domain of KIT. Moreover, KITW42 was constitutively associated with a chimeric FMS/KITTyr814 receptor containing the ligand-binding and receptor dimerization domain of c-fms receptor (FMS) fused to the transmembrane and cytoplasmic domain of KITTyr814, but not with a chimeric FMS/KITWild receptor even after stimulation with FMS-ligand. These results suggest that constitutively activating mutation of c-kit at the Asp814 codon may cause a conformation change that leads to receptor self-association not in the extracellular domain and that the receptor self-association of the Asp814 mutant may be important for activation of downstream effectors that are required for factor-independent growth and tumorigenicity.

Animals↗
PubMed1999

Expressions of vascular endothelial growth factor in nonparenchymal as well as parenchymal cells in rat liver after necrosis.

Vascular endothelial growth factor (VEGF) can induce proliferation of sinusoidal endothelial cells. Its mRNA expression was increased in proliferating rat hepatocytes in primary culture. To clarify a role of VEGF in liver after necrosis, expressions of VEGF and its receptors were measured in the liver or liver cells isolated from rats after carbon tetrachloride intoxication. Hepatic VEGF mRNA expression increased later than 24 h after the intoxication and became prominent at 168 h when liver necrosis disappeared, while hepatic mRNA expressions of its receptors increased between 24 and 72 h. VEGF mRNA expression was increased in Kupffer cells, hepatic macrophages and stellate cells isolated from rats between 24 and 72 h after the intoxication and in hepatocytes at 168 h compared to those cells from normal rats. Immunohistochemical VEGF stains were comparable to such results. Vascular endothelial cells existed abundantly in the necrotic areas, and sinusoidal endothelial cells appeared following disappearance of the necrotic areas. VEGF mRNA expression in hepatocytes isolated from 70% resected liver was increased at 12 h after the operation and became marked between 72 and 168 h. Similar increase of hepatic VEGF expression was immunohistochemically seen. In conclusion, VEGF derives from nonparenchymal as well as parenchymal cells in rat liver after necrosis. The former might contribute to vascular endothelial cell proliferation and the latter to sinusoidal endothelial cell regeneration.

Animals↗
PubMed1999

Cell-specific targeting of a thymidine kinase/ganciclovir gene therapy system using a recombinant Sindbis virus vector.

Transfer of the herpes simplex virus type I thymidine kinase (HSV-TK) gene into tumor cells using virus-based vectors in conjunction with ganciclovir (GCV) exposure provides a potential gene therapy strategy for the treatment of cancer. The possibility of using a novel targetable Sindbis virus expression vector containing the HSV-TK gene was examined. Baby hamster kidney (BHK) cells and several human tumor cells infected with a Sindbis virus containing the HSV-TK gene showed strong expression of HSV-TK protein. Cells transduced with the HSV-TK gene exhibited increased TK activity, ranging from 3- to 20-fold over an average baseline level. The human HeLa-CD4+ cells infected with recombinant Sindbis virus containing the HSV-TK gene were sensitive to low concentrations of GCV (0.1-1 microg/ml) and the 50% growth inhibitory concentration (IC50) was 0.6 microg/ml. We also demonstrated applications of cell type-specific Sindbis virus-mediated antigen-antibody targeting of the HSV-TK/GCV system in vitro. Sindbis virus containing the HSV-TK gene packaged in a helper virus displaying the IgG-binding domain of protein A on its envelope could infect various tumor cell lines in the presence of specific antibodies that recognize antigens on their surfaces. HSV-TK-transduced tumor cell lines exhibited sensitivity to GCV. Our data suggest the potential for targeted gene therapy of the HSV-TK/GCV system using a cell type-specific recombinant Sindbis virus vector-antibody system.

Animals↗
PubMed1999

Promotional effects of CO(2) laser and scalpel incision on 4-NQO-induced premalignant lesions of mouse tongue.

BACKGROUND AND OBJECTIVES: CO(2) laser and scalpel incision have been demonstrated to have promotional effects on oral neoplastic lesions. However, a precise understanding has not been achieved as to which modality has a more significant effect on cancer promotion. The purpose of this study was to determine the histological and biological changes after CO(2) laser surgery and scalpel incision in oral premalignant lesions. STUDY DESIGN/MATERIALS AND METHODS: Premalignant lesions of mouse tongue induced by 4-nitroquinoline-1-oxide (4NQO) in drinking water for 4 months were used in this study. A 2-mm incision was made on the right margin of each mouse tongue, using either a CO(2) laser (group A) or a scalpel (group B). Mice without incisional treatment were used as controls (group C). Seven months after laser and scalpel treatments, hematoxylin-eosin staining and proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), and p53 immunostaining were performed for tongue specimens. RESULTS: The epithelia of right tongue margins showed more severe dysplasia than those of left tongue margins in both group A and group B. The PCNA labeling indices (LIs) and EGFR expression for right tongue margins were also higher than for left margins in both group A and group B. There was no obvious difference between these two groups. Almost no p53-positive staining was found in either group. CONCLUSION: CO(2) laser surgery and scalpel incision seem to have similar promotional effects on oral premalignant lesions.

4-Nitroquinoline-1-oxide↗
PubMed1999

Spi(-) selection: An efficient method to detect gamma-ray-induced deletions in transgenic mice.

Despite the importance of genome rearrangement in the etiology of cancer and human genetic disease, deletion mutations are poorly detectable by transgenic rodent mutagenicity tests. To facilitate the detection and molecular analysis of deletion mutations in vivo, we established a transgenic mouse model harboring a lambdaEG10 shuttle vector that includes the red and gam genes for Spi(-) (sensitive to P2 interference) selection [Nohmi et al. (1996] Environ. Mol. Mutagen. 28:465-470]. This selection has a great advantage over other genetic systems, because phage deletion mutants can be preferentially selected as Spi(-) plaques, which can then be subjected to molecular analysis. Here, we show nucleotide sequences of 41 junctions of deletion mutations induced by gamma-irradiation. Unlike spontaneous deletion mutants, more than half of the large deletions occurred between short homologous sequences from one to eight bp. The remaining junctions had no such homologous sequences. Intriguingly, two Spi(-) mutants had P (palindrome)-like nucleotide additions at the breakpoints, which are frequently observed in the coding junctions of V(D)J recombination, suggesting that broken DNA molecules with hairpin structures can be intermediates in the repair of radiation-induced double-strand breaks. We conclude that Spi(-) selection is useful for the efficient detection of deletion mutations in vivo and that most rearrangements induced by gamma-rays in mice are mediated by illegitimate recombination through DNA end-joining.

Animals↗
PubMed1999

Autoimmune diseases developed in athymic nude mice grafted with embryonic thymus of xenogeneic origin.

Reconstitution of T cell functions in athymic BALB / c nude mice was investigated after transplantation of embryonic thymus grafts under the renal capsule (TG nude mice). Thymi were obtained from mice, rats, rabbits, hamsters, guinea pigs, swine and cows. All of the grafted thymi grew and formed proper thymic structures with host CD90(+) cells. The TCRalpha beta expression pattern of the lymphocytes in the grafted thymi was quite similar to that of normal mouse thymocytes. Sufficient CD4(+) populations were observed in the peripheral lymphoid organs of all groups of TG nude mice. Plaque-forming cell assay revealed that the TG nude mice had acquired considerable helper T cell functions. Histological and serological studies, however, showed multiple organ-localized inflammatory diseases in TG nude mice of all xenogeneic thymus groups, but not with syngeneic or allogeneic thymi. The organs affected were the thyroid, the lacrimal, submandibular and sublingual glands, the eyes, stomach and ovaries. The incidence of lesions was variable depending on the species of origin of the grafted thymus. Lesions from TG nude mice were successfully transferred into naive nude mice by host CD4(+) cells. These results together suggested that the microenvironment of grafted thymi, even if xenogeneic, is able to educate host T cell precursors. However, this reconstitution of functions does not always induce tolerance to certain autoantigens, resulting in development of multiple autoimmune lesions.

Animals↗
PubMed1999

Coronary stent deployment in a young adult with Kawasaki disease and recurrent myocardial infarction.

A 19-year-old man developed a huge coronary aneurysm and stenosis in the right coronary artery as a sequela of Kawasaki disease (KD) that resulted in recurrent episodes of myocardial infarction. Coronary ischemic events were successfully prevented after balloon angioplasty followed by coronary stent implantation into the stenotic lesion. The stent deployment may have an advantage compared with balloon angioplasty and other new devices for the treatment for patients with KD showing stenotic lesions without dense calcification.

Adult↗
PubMed1999

Cytokine regulation of env gene expression of human endogenous retrovirus-R in human vascular endothelial cells.

To determine whether human endogenous retroviruses are implicated in the pathogenesis of inflammatory vascular diseases of unknown etiology, we examined mRNA expression of a human endogenous retrovirus, HERV-R, which has a long open reading frame in the env region, in cultured human vascular endothelial and smooth muscle cells stimulated in the presence of various cytokines. mRNA of HERV-R was always evident in these cells but not in fibroblastic cells. Levels of expression in vascular endothelial cells were significantly regulated by treatment with tumor necrosis factor-alpha, interleukin (IL)-1alpha, and IL-1beta as up-regulators and interferon-gamma as a down-regulator. These observations are interpreted to mean that HERV-R expression may be up- or down-regulated at sites of inflammation in vessels in vivo and hence may play a pathogenetic role in inflammatory vascular diseases in humans, perhaps similar to endogenous retroviruses in mouse models of polyarteritis nodosa in humans.

Cells, Cultured↗