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Biomedical subjects

T Miki

Publications and source records attributed to T Miki.

At least 307 records · Page 17Linked to original sources
PubMed1998

[ACE inhibitors use in patients with acute coronary syndrome].

Angiotensin converting enzyme (ACE) inhibitors (ACE-I) reduce the incidence of re-infarction in patients with myocardial infarction (MI), and the DD genotype for the ACE gene is an independent risk factor of MI. These findings suggest involvement of ACE in the natural history of coronary plaques and in the pathogenesis of acute coronary syndrome (ACS). ACE-I potentially prevent coronary plaque rupture by suppressing angiotensin II-induced vasoconstriction and sympathetic nerve activity. Actions of ACE-I on risk factors, including insulin resistance, may retard the progression of atheromatous changes in the coronary artery. Furthermore, ACE-I attenuate contractile dysfunction due to myocardial stunning and hibernation, while it augments anti-infarct tolerance of the myocytes afforded by preconditioning. These actions on the myocardium may also be beneficial in ACS. Although favorable effects of ACE-I on the mortality rate of MI patients has been established, the benefit of chronic therapy with ACE-I for patients who have coronary artery disease without MI remains to be clarified.

Acute Disease↗
PubMed1998

Different patterns of p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of microdissected specimens.

Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and can be divided into high-grade (HGPIN) and low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic carcinoma (PCA). Microdissected DNA selectively extracted from paraffin-embedded sections of 29 cases of PCA and 1 benign prostatic hypertrophy were analyzed for p53 mutation by single-strand conformation polymorphism (SSCP) of polymerase chain reaction (PCR)-amplified DNA fragments followed by direct sequencing. These patients had received total prostatectomy (27 cases) or transurethral resection (3 cases). Under direct microscopic observation, DNA was microdissected from 108 lesions: 67 lesions from 22 cases of PIN (55 HGPIN and 12 LGPIN), 29 from 22 cases of PCA, and 12 from 11 cases of adjoining benign glands. Analysis revealed 13 mutations in 10 lesions from six cases. All 13 were point mutations: 7 missense, 5 silent, and 1 nonsense. Mutations were detected in 3 cases (14%) of PIN and 5 cases (25%) of PCA. PIN lesions with p53 mutations were all categorized as HGPIN. Neither LGPIN nor benign glands adjoining PIN and/or PCA had mutations. Two PIN and one PCA lesion in each of two cases had mutations that were different from each other. G-to-A transition was the commonest mutation pattern. The current findings showed that HGPIN, but not LGPIN, and PCA are similar with regard to p53 mutation. The diverse patterns of p53 mutation among HGPIN and PCA lesions suggested multiclonal development of prostatic precancerous lesions.

Amino Acid Substitution↗
PubMed1998

[Progress of the molecular genetic analysis for Alzheimer's disease].

The pathogenesis of Alzheimer's disease (AD) remains unclear. We ascertained 57 Japanese families with early onset familial Alzheimer's disease (EOFAD; mean onset age < 65 years). Screening the known beta/A4 amyloid precursor protein (APP) mutations in familial AD by a simplified PCR product detection system disclosed only one EOFAD with the APP717Val-Ile mutation (AD1 locus). Four of 6 families showing a positive linkage to AD3 locus had four different mutations on the presenilin 1 gene. These mutations were Val 96 Phe, Ile223Thr, His163Arg and splicing mutation with an AG-AA substitution at the acceptor site of intron 9. The allele frequency of APOE-e4 of late-onset and early-onset AD was significantly higher than that of age-matched controls (p < 0.0001). These results suggest that APOE-e4 (AD2 locus) is a susceptibility gene for AD in the Japanese population, regardless of the age at onset. It is probable that the risk for AD in most subjects is likely to arise from the cumulative effects of environmental factors along with various genetic factors. Advances in molecular biology and molecular genetics have enabled us to more easily understand these genetic factors.

Adult↗
PubMed1998

Inhibition of DMBA-initiated rat mammary tumour development by 1-O-hexyl-2,3,5-trimethylhydroquinone, phenylethyl isothiocyanate, and novel synthetic ascorbic acid derivatives.

The effects of a synthetic phenolic antioxidant, 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), two novel synthetic ascorbic acid derivatives, 3-O-ethyl ascorbic acid (EAsA) and 3-O-dodecylcarbomethylascorbic acid (DAsA), and phenylethyl isothiocyanate (PEITC) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis were examined in female Sprague-Dawley rats. Groups of 20, 7 week-old rats received an intra-gastric dose (50 mg/kg, b.w.) of DMBA, and starting one week thereafter received powdered diet containing 1.0% HTHQ, 1.0% EAsA, 1.0% DAsA, 0.1% PEITC or a basal diet alone for 35 weeks. Although the final incidences of mammary adenocarcinomas did not significantly differ among the DMBA-treated groups, multiplicities were significantly lowered in the EAsA (1.6+/-1.6 per rat, P < 0.01) and HTHQ (2.6+/-1.9, P < 0.05) animals as compared with the basal diet case (4.1+/-2.9). The average carcinoma volumes were also significantly smaller in rats given EAsA (2.1+/-3.8 cm3, P < 0.05), DAsA (2.5+/-5.3, P < 0.05) or PEITC (2.4+/-5.9, P < 0.05) than in those receiving DMBA alone (4.9+/-9.2). The results indicate that HTHQ, EAsA and PEITC all exert chemopreventive influence on the promotion/progression stage of DMBA-induced rat mammary carcinogenesis, with EAsA being particularly effective. To our knowledge this is the first documented example of an ascorbic acid derivative possessing chemopreventive potential against mammary cancer in vivo.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

[Accumulation of a photosensitizer ATX-S 10 Na (II) to experimental corneal neovascularization].

In order to determine the most appropriate time point for laser irradiation in photodynamic therapy with a new photosensitizer, ATX-S 10 Na (II), which produces selective occlusion of new vessels, we investigated the time course of plasma levels of ATX-S 10 Na (II) after intravenous administration and degree of dye accumulation in the corneal neovascularization in rabbit eyes. Plasma ATX-S 10 Na (II) concentration decreased rapidly after injection and become virtually undetectable at 24 h, indicating rapid excretion from the body. Nitrogen-pulsed laser spectrofluorometry demonstrated that the amount of ATX-S 10 Na (II) in new corneal vessels increased and reached a maximal level 2 to 4 hours after dye injection. Under a fluorescence microscope, ATX-S 10 Na (II) was localized in the wall new corneal vessels and in extravascular tissue 2 to 4 hours after dye injection. These results indicate that the appropriate time for laser irradiation in selective PDT is between 2 and 4 hours after dye injection, when a larger amount of dye is accumulated in neovasculature tissue compared to normal tissue.

Animals↗
PubMed1998

Glenohumeral osteoarthritis following a "color test" during rotator cuff repair. A case report and a review of the literature.

A case of glenohumeral osteoarthritis in a 35-year-old female following a color test during rotator cuff repair is described. The patients had a tear in the rotator cuff involving the supraspinatus muscle and rotator interval. A color test with a 0.4% aqueous solution of gentian violet was performed during the operation and the ruptured cuff was not tightly sutured. The patient developed glenohumeral osteoarthritis 25 months postoperatively. Plain film radiographs showed joint space narrowing and bone sclerosis of the humeral head, but there was no evidence of osteophytes. This pathology was thought to have been caused by the aqueous gentian violet solution.

Adult↗
PubMed1997

Incidence of prostatic intra-epithelial neoplasia in Osaka, Japan.

High-grade prostatic intra-epithelial neoplasia (HGPIN) is the most likely precancerous lesion for prostatic carcinoma. A high incidence of its association with cancer has been reported in Western countries. On the other hand, information regarding its incidence is limited in Japan, where the mortality due to prostate cancer is much lower. We reviewed 53 clinical stage T2 or T3 prostatic cancers of Japanese patients living in Osaka, Japan (mean age, 67.2 years). These cases were subdivided into a pre-operatively non-castrated group (34 cases) and a medically or surgically castrated group (19 cases). HGPIN was found in 27 cases. The incidence of HGPIN was significantly lower in the castrated group (21.0%) compared with the non-castrated group (67.6%). In the non-castrated group, patient age, pathological stage, Gleason score, tumor size and serum prostate-specific antigen showed no significant correlation with HGPIN. Advanced pathological stage and tumor size tended to decrease the incidence of HGPIN, although this was not statistically significant. When the study group was limited to stage T2 tumors of the non-castrated group, the incidence of HGPIN was 81.0%. HGPIN in Japan may also be clinically and etiologically significant as a precursor of clinical cancer.

Aged↗
PubMed1997

Estimation of the numerical densities of neurons and synapses in cerebral cortex.

In this paper we discuss a stereological technique, 'the unfolding method', for a quantitative study of the nervous system [1,31]. Stereology implies a geometric analysis of structures and textures, and is a method to derive directly metric properties of structures from two-dimensional sections on the basis of geometrico-statistical reasoning [36,37]. Recent advances in the stereological method allow quantitative analysis [8,19,27,32]. Images on sections provide only two-dimensional information, but the stereological method can offer three-dimensional and quantitative information [19]. The need for quantitative analysis is more important and useful in the central nervous system (CNS) than in other organs. Two functional units, neurons and synapses, are of particular interest in evaluating CNS function. Numerical densities of neurons and synapses in rat visual cortex were estimated using the unfolding method at light and electron microscopic levels, respectively. Once the numerical densities of neurons and synapses were obtained, synapse-to-neuron ratios could be calculated. The ratios are interpreted as a means to obtain an index of interneuronal connectivity [9]. The unfolding method may become a powerful strategy in neuroscience research when numerical estimates are performed in restricted areas such as cortical layers II-IV, because this method is less time-consuming than other stereological methods [6,21,22].

Animals↗
PubMed1997

Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.

ATP-sensitive K+ (KATP) channels are known to play important roles in various cellular functions, but the direct consequences of disruption of KATP channel function are largely unknown. We have generated transgenic mice expressing a dominant-negative form of the KATP channel subunit Kir6.2 (Kir6.2G132S, substitution of glycine with serine at position 132) in pancreatic beta cells. Kir6.2G132S transgenic mice develop hypoglycemia with hyperinsulinemia in neonates and hyperglycemia with hypoinsulinemia and decreased beta cell population in adults. KATP channel function is found to be impaired in the beta cells of transgenic mice with hyperglycemia. In addition, both resting membrane potential and basal calcium concentrations are shown to be significantly elevated in the beta cells of transgenic mice. We also found a high frequency of apoptotic beta cells before the appearance of hyperglycemia in the transgenic mice, suggesting that the KATP channel might play a significant role in beta cell survival in addition to its role in the regulation of insulin secretion.

Adenosine Triphosphate↗
PubMed1997

Heat shock-induced excessive relaxation of DNA in Escherichia coli mutants lacking the histone-like protein HU.

Plasmid DNA in exponentially growing Escherichia coli immediately relaxes after heat shock but the relaxed DNA re-supercoils rapidly, the despite continued presence of the heat shock conditions. We have now obtained genetic evidence indicating that the histone-like protein HU of E. coli is required for this re-supercoiling of DNA. Plasmid DNA in a hupA-hupB double gene-disruption mutant relaxed excessively after heat shock, while the relaxation of DNA in a himA-himD double gene-disruption mutant and in an hns insertion mutant was transient, thereby indicating that HU protein, but not IHF or H-NS proteins, is required for the re-supercoiling of DNA. Exposure of the hupA-hupB double mutant to a temperature of 50 degrees C led to both excessive relaxation of DNA and to a decrease in viable cell number but temperatures lower than 46 degrees C did not lead to these events. Based on these results, we propose that HU protein maintains the negative supercoiling of DNA during thermal stress and contributes to cellular thermotolerance in E. coli.

Bacterial Proteins↗
PubMed1997

Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations.

To assess the effect(s) of the C-terminal domain on FGFR2 function, we engineered a series of mutant FGFR2 cDNAs encoding deletions in the C-terminus of the receptor and compared their growth properties in NIH3T3 fibroblasts. In contrast to FGFR2-WT, receptors with C-terminal truncations induced ligand-independent transformation of NIH3T3 cells and transfectants expressing these mutant receptors efficiently formed colonies in semisolid medium. Introduction of point mutations (Y to F) into the C-terminus of FGFR2 at positions 813, 784 or 780 revealed that these mutant receptors also displayed activities similar to that of C-terminally truncated receptors. C-terminally altered FGF receptors did not show an increase in the basal level of receptor phosphorylation compared to that of FGFR2-WT suggesting that elevated receptor phosphorylation does not underlie the transforming activity of these receptors. Interestingly, expression of transforming FGFR2 derivatives, unlike H-Ras transformed cells, did not result in the activation of the mitogen-activated protein kinases (MAPKs), p42/ERK2 and p44/ERK1, indicating that this pathway is not constitutively active in FGFR2-transformed cells. Finally, we report the overexpression of FGFR2 mRNA and protein in several human tumor cell lines suggesting activation of the receptor in these tumors.

3T3 Cells↗
PubMed1997

Disruption of the Bcl6 gene results in an impaired germinal center formation.

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6(-/-)RM). Lymphogenesis in primary lymphoid tissues of Bcl6(-/-)RM is normal, and Bcl6(-/-)RM produced control levels of primary IgG1 antibodies specific to T cell-dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.

Animals↗
PubMed1997

Oxidation process of bovine heart ubiquinol-cytochrome c reductase as studied by stopped-flow rapid-scan spectrophotometry and simulations based on the mechanistic Q cycle model.

Stopped-flow rapid-scan spectrophotometry was employed to study complicated oxidation processes of ubiquinol-cytochrome c reductase (QCR) that was purified from bovine heart mitochondria and maximally contained 0.36 mol of ubiquinone-10/mol of heme c1. When fully reduced QCR was allowed to react with dioxygen in the presence of cytochrome c plus cytochrome c oxidase, the oxidation of b-type hemes accompanied an initial lag, apparently low potential heme bL was oxidized first, followed by high potential heme bH. Antimycin A inhibited the oxidation of both b-type hemes. The oxidation of heme c1 was triphasic and became biphasic in the presence of antimycin A. On the other hand, starting from partially reduced QCR that was poised at a higher redox potential with succinate and succinate-cytochrome c reductase, the b-type hemes were oxidized immediately without a lag. When the ubiquinone content in QCR was as low as 0.1 mol/mol heme c1 the oxidation of the b-type hemes was almost suppressed. As the Q-deficient QCR was supplemented with ubiquinol-2, the rapid oxidation of b-type hemes was restored to some extent. These results indicate that a limited amount of ubiquinone-10 found in purified preparations of QCR is obligatory for electron transfer from the b-type hemes to iron-sulfur protein (ISP) and heme c1. The characteristic oxidation profiles of heme bL, heme bH, and heme c1 were simulated successfully based on a mechanistic Q cycle model. According to the simulations the two-electron oxidation of ubiquinol-10 via the ISP and heme c1 pathway, which is more favorable thermodynamically than the bifurcation of electron flow into both ISP and heme bL, does really occur as long as heme bL is in the reduced state and provides ubiquinone-10 at center i. Mechanistically this process takes time, thus explaining the initial lag in the oxidation of the b-type hemes. With the partially reduced QCR, inherent ubisemiquinone at center i immediately oxidizes reduced heme bH thus eliminating the lag. The mechanistic Q cycle model consists of 56 reaction species, which are interconnected by the reaction paths specified with microscopic rate constants. The simulations further indicate that the rate constants for electron transfer between the redox centers can be from 10(5) to 10(3) s-1 and are rarely rate-limiting. On the other hand, a shuttle of ubiquinone or ubiquinol between center o and center i and the oxidation of heme c1 can be rate-limiting. The interplay of the microscopic rate constants determines the actual reaction pathway that is shown schematically by the "reaction map." Most significantly, the simulations support the consecutive oxidation of ubiquinol in center o as long as both heme bL and heme bH are in the reduced state. Only when heme bL is oxidized and ISP is reduced can SQo donate an electron to heme bL. Thus, we propose that a kinetic control mechanism, or "a kinetic switch," is significant for the bifurcation of electron flow.

Animals↗
PubMed1997

Loss of imprinting of the insulin-like growth factor II gene in renal cell carcinoma.

Loss of imprinting (LOI) has been implicated in the pathogenesis of embryonal malignancies as well as adult cancers. Insulin-like growth factor II (IGF2) gene is an imprinted gene, normally transcribed only from the paternal allele. We investigated allele-specific expression of the IGF2 gene in 22 cases of renal cell carcinoma (RCC), a common adult-onset renal tumor. Sixteen cases (72%) were informative for IGF2 gene expression, and 9 (56%) of these cases showed biallelic expression of the IGF2 gene. Additionally, in four cases with biallelic expression from which uninvolved kidney tissue was available, LOI of the IGF2 gene was also demonstrated in the normal tissue. All cases with LOI of IGF2 were low-grade and low-stage tumors. LOI of the IGF2 gene in RCC was not associated with overexpression of IGF2 mRNA, whereas IGF2 overexpression was frequently observed in high-stage tumors. These results suggest that LOI of IGF2 predisposes to low-grade and low-stage tumors, whereas IGF2 overexpression may have a role in RCC tumor progression.

Adult↗
PubMed1997

Negative control of DNA replication by hydrolysis of ATP bound to DnaA protein, the initiator of chromosomal DNA replication in Escherichia coli.

DnaA protein, the initiation factor for chromosomal DNA replication in Escherichia coli, is activated by ATP. ATP bound to DnaA protein is slowly hydrolyzed to ADP, but the physiological role of ATP hydrolysis is unclear. We constructed, by site-directed mutagenesis, mutated DnaA protein with lower ATPase activity, and we examined its function in vitro and in vivo. The ATPase activity of purified mutated DnaA protein (Glu204-->Gln) decreased to one-third that of the wild-type DnaA protein. The mutation did not significantly affect the affinity of DnaA protein for ATP or ADP. The mutant dnaA gene showed lethality in wild-type cells but not in cells growing independently of the function of oriC. Induction of the mutated DnaA protein in wild-type cells caused an overinitiation of DNA replication. Our results lead to the thesis that the intrinsic ATPase activity of DnaA protein negatively regulates chromosomal DNA replication in E. coli cells.

Adenosine Diphosphate↗