Population pharmacokinetic analysis of pirmenol in healthy volunteers and patients with arrhythmia.
Explore the source record for details and available documents.
Age Factors↗
Biomedical subjects
H Kasai
Publications and source records attributed to H Kasai.
Pericecal appendiceal abscess with drainage during colonoscopy.
Explore the source record for details and available documents.
Abdominal Abscess↗
Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function.
The application of caged-Ca2+ compounds to the study of Ca2+-dependent exocytosis has begun to reveal kinetic intermediates in this important process. The time course of exocytosis varies greatly among different cell and vesicle types, even in response to Ca2+ 'jumps' of identical amplitude. The kinetics of the binding of Ca2+ to the putative Ca2+ sensor for exocytosis also vary. Theoretical analysis reveals that the kinetic diversity of exocytotic and Ca2+-binding reactions has distinct roles in determining the probability of exocytosis occurring. It is proposed that both of these reactions are optimized for the secretory function of specific cell types and that the exocytotic reaction includes vesicle translocation in addition to the fusion of vesicles with the plasma membrane.
Animals↗
Immunochemical detection of glyoxal DNA damage.
The relevance of reactive oxygen species (ROS) in the pathogenesis of inflammatory diseases is widely documented. Immunochemical detection of ROS DNA adducts has been developed, however, recognition of glyoxal-DNA adducts has not previously been described. We have generated a polyclonal antibody that has shown increased antibody binding to ROS-modified DNA in comparison to native DNA. In addition, dose-dependent antibody binding to DNA modified with ascorbate alone was shown, with significant inhibition by desferrioxamine, catalase, and ethanol. Minimal inhibition was observed with uric acid, 1,10-phenanthroline and DMSO. However, antibody binding in the presence of EDTA increased 3500-fold. The involvement of hydrogen peroxide and hydroxyl radical in ascorbate-mediated DNA damage is consistent with ascorbate acting as a reducing agent for DNA-bound metal ions. Glyoxal is known to be formed during oxidation of ascorbate. Glyoxylated DNA, that previously had been proposed as a marker of oxidative damage, was recognised in a dose dependent manner using the antibody. We describe the potential use of our anti-ROS DNA antibody, that detects predominantly Fenton-type mediated damage to DNA and report on its specificity for the recognition of glyoxal-DNA adducts.
Animals↗
Supralinear Ca2+ signaling by cooperative and mobile Ca2+ buffering in Purkinje neurons.
Endogenous high-affinity Ca2+ buffering and its roles were investigated in mouse cerebellar Purkinje cells with the use of a low-affinity Ca2+ indicator and a high-affinity caged Ca2+ compound. Increases in the cytosolic Ca2+ concentration ([Ca2+]i) were markedly facilitated during repetitive depolarization, resulting in the generation of steep micromolar Ca2+ gradients along dendrites. Such supralinear Ca2+ responses were attributed to the saturation of a large concentration (0.36 mM) of a mobile, high-affinity (dissociation constant, 0.37 microM) Ca2+ buffer with cooperative Ca2+ binding sites, resembling calbindin-D28K, and to an immobile, low-affinity Ca2+ buffer. These data suggest that the high-affinity Ca2+ buffer operates as the neuronal computational element that enables efficient coincidence detection of the Ca2+ signal and that facilitates spatiotemporal integration of the Ca2+ signal at submicromolar [Ca2+]i.
Algorithms↗
Analysis of 8-hydroxyguanine in rat kidney genomic DNA after administration of a renal carcinogen, ferric nitrilotriacetate.
The frequency of oxidative base damage, such as 8-hydroxyguanine (8-OH-Gua), was determined at the nucleotide level of resolution using the ligation-mediated PCR technique. Administration of a renal carcinogen, ferric nitrilotriacetate (Fe-NTA), is known to induce oxidative stress and subsequent formation of 8-OH-Gua in the rat kidney. Whole genomic DNA was isolated from the rat kidney after or without Fe-NTA treatment and then cleaved with hot piperidine. In order to assess the frequency of 8-OH-Gua formation, we chose three genes, the tumor suppressor gene p53, the heat shock protein 70 (HSP70-1) gene and the Na,K-ATPase alpha1 subunit gene. No alteration in the cleavage profile was observed in the p53 and HSP70 genes after Fe-NTA treatment. In the case of the p53 gene, a low incidence of point mutations has been observed in this carcinogenesis system. On the other hand, time-dependent alterations, corresponding to the time course of overall 8-OH-Gua formation and repair, were detected in the promoter region of the Na,K-ATPase alpha1 subunit gene. GpG and GpGpG in specific regions seem to be hotspots for the formation of 8-OH-Gua. These results were confirmed by formamidopyrimidine-DNA glycosylase-dependent DNA cleavage patterns. Thus, oxidative base damage, such as 8-OH-Gua, was not distributed uniformly along the whole genome, but seemed to be restricted to particular genes and regions.
Animals↗
Changes in levels of 8-hydroxyguanine in DNA, its repair and OGG1 mRNA in rat lungs after intratracheal administration of diesel exhaust particles.
Diesel exhaust particles (DEP), an environmental pollutant, are known to induce lung cancer in experimental animals. To clarify whether reactive oxygen species (ROS) are involved in its carcinogenic mechanism, we examined the levels of 8-hydroxyguanine (8-OH-Gua), its total repair and the repair enzyme OGG1 mRNA in female Fischer 344 rat lungs, as markers of the response to ROS, after DEP was intratracheally instilled. The 8-OH-Gua levels in both DEP-treated groups (2 and 4 mg) were increased during the 2-8 h following exposure to DEP. The 8-OH-Gua repair activities in the DEP-treated groups decreased during the period from 2 h to 2 days following DEP exposure and then recovered to the level of the control group at 5 days after exposure. OGG1 mRNA was induced in rats treated with 4 mg DEP for 5-7 days after administration. In conclusion, the 8-OH-Gua level in rat lung DNA increases markedly at an early phase after DEP exposure, by the generation of ROS and the inhibition of 8-OH-Gua repair activity, and induction of OGG1 mRNA is also a good marker of cellular oxidative stress during carcinogenesis.
Animals↗
Increased 8-hydroxyguanine in DNA and its repair activity in hamster and rat lung after intratracheal instillation of crocidolite asbestos.
Asbestos and man-made-mineral fibers are known to increase one type of oxidative DNA damage, 8-hydroxyguanine (8-OH-(Gua), in vitro. In this study, we analyzed the 8-OH-Gua level in DNA and its repair activity after a single intratracheal instillation of fibers (crocidolite or glass) or saline to Syrian hamsters or Wistar rats. The 8-OH-Gua level was measured with a high-performance liquid chromatography-electrochemical detector (HPLC-ECD) system. The 8-OH-Gua repair enzyme activity was determined with an endonuclease nicking assay using a 32P-labeled or fluorescently labeled 22mer DNA that contains 8-OH-Gua at a specific position. A significant increase in the 8-OH-Gua level in the lung DNA was observed 1 day after the exposure to crocidolite, as compared to the saline control. The repair activity was increased significantly at 7 days. On the other hand, after exposure to glass fibers, little or no increase of these carcinogenicity indicators was detected. These assays of 8-OH-Gua and its repair activity in short-term animal experiments will be useful for evaluating the carcinogenicity of fibers. This is the first report of the increase of 8-OH-Gua and its repair activity in the animal lung after the instillation of asbestos fibers.
Animals↗
Development of ventricular fibrillations with different characteristics in the local electrocardiogram: large and small amplitude of activation, and its implication for implantable cardioverter defibrillator treatment.
An implantable cardioverter defibrillator (ICD) was implanted in 2 patients with ventricular tachyarrhythmia related to old myocardial infarction, and defibrillation tests were attempted at the time of ICD implantation and at 2 or 4 weeks after the operation. Ventricular fibrillation (VF) was induced by T-wave shocks, but the amplitude of the ventricular electrogram was different in each VF. In most of the VFs with large ventricular electrograms, the local activity was appropriately detected. However, many undersensed beats were observed in other VFs that had fine ventricular electrograms and a longer time was needed before delivering the shock. The amplitude of the ventricular electrogram might be small in some cases of VF and this might result in undersensing and/or unsuccessful defibrillation. Close attention must be paid to the amplitude of ventricular activation in each VF to avoid possible difficulty in ICD therapy.
Aged↗
Both low and high energy cardioversion induced accelerated ventricular tachycardia in a patient treated with an implantable cardioverter defibrillator.
A 72-year old male with an old myocardial infarction who had drug-refractory ventricular tachyarrhythmias received an implantable cardioverter-defibrillator (ICD). The patient did not take his prescribed beta-blocking agent for two days, following which he experienced six discrete shocks for spontaneous VT while riding his bicycle. Both 5J and 30J cardioversions were ineffective at terminating the VT and accelerated VT developed following the shocks. After admission, an electrophysiological study was performed while he was taking the beta-blocking agent, both low and high energy cardioversions reproducibly terminated the clinical VT without showing any accelerated rhythm. These findings suggest that the increase in sympathetic discharge may enhance the proarrhythmic potential of ICDs.
Adrenergic beta-Antagonists↗
Ventricular fibrillation with small amplitude of activation and its implications for implantable cardioverter defibrillator treatment.
An implantable cardioverter defibrillator (ICD) was implanted in a patient with ventricular fibrillation (VF) related to old myocardial infarction. During VF, amplitude of ventricular activation was small, and the ventricular sensitivity at 1.2 mV failed to detect several small ventricular activations. When the sensitivity was changed to 0.3 mV, both under- and oversensed beats occurred during VF, and at the ventricular sensitivity of 0.15 mV, the undersensed beats disappeared while oversensed beats markedly increased. Defibrillation test was repeated one and four weeks after the implantation, and these inappropriate beats were minimized at the ventricular sensitivity of 0.3 mV. We should pay attention to the amplitude of ventricular activation to avoid possible trouble in ICD therapy.
Aged↗
[Public health nurses' disaster responses for intractable neurological patients at home].
OBJECTIVE: This paper describes the 1995 Hanshin-Awaji Earthquake experience of the local public health nurses. The purpose of the study was to identify problems regarding assistance of intractable neurological patients at home during and after the earthquake and to discuss ways to improve future local disaster responses by public health nurses for those patients. METHODS: Approximately 2 hours of a group interview of public health nurses from 2 public health centers in Kobe City was conducted in August, 1996. Interview data was collected via audio-tape and transcribed. The data was organized according to phases of the earthquake. The acute phase of the earthquake disaster ended within 72 hours. The data was then analyzed to identify problems in assisting intractable neurological home patients in order to discuss disaster responses by public health nurses. RESULTS: There was a delay in confirming the safety of and providing needed assistance for intractable neurological patients at home by public health nurses. During the first 3 days after the earthquake, the majority of public health nurses were unable to commute to work due to the shutdown of transportation systems. In addition, nurses, who were able to come to work, were preoccupied with treating earthquake casualties and distributing medical supplies. Other factors associated with the delay included the following: lack of a registration list for intractable neurological patients at home; lack of close contacts between public health nurses and patients, and between public health nurses and patient support groups; and sparing nurses for guiding volunteers and for coordinating between shelters and hospitals. CONCLUSION: Measures to improve future disaster responses are as follows: a) teaching patients and their families how to safeguard against disaster; b) preparing registration lists; c) establishing support networks and cooperating with network members; and d) upon disaster, assigning some nurses to assess the needs of patients.
Disaster Planning↗
[Antiangiogenic and antitumor effect of BPHA, an orally-active matrix metalloproteinase inhibitor, in in vivo murine and human tumor model].
We examined the antiangiogenic and antitumor efficacy of a newly-developed matrix metalloproteinase (MMP) inhibitor, BPHA (N-biphenyl sulfonyl-phenylalanine hydroxiamic acid). BPHA potently inhibits MMP-2, 9 and 14 but not MMP-1, 3 or 7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMP tested. Daily oral administration of BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth and liver metastasis, whereas (-)BPHA did not. These results demonstrate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential without hematotoxic effect or loss of body weight.
Animals↗
[Problems of cancer patient home therapy in our clinic].
We studied the problems of cancer patient home therapy in our clinic over the last 4 years. Cancer patients tend to be younger than other home patients, and their home therapy period is shorter than others. Therefore, hospital doctors should decide the local home doctor of the patients at an early stage. The frequency of emergency calls is higher than with other patients, so cooperation between hospital and clinic is very important.
Adult↗
The choleretic effects of N-acetylglucosaminides, major urinary metabolites of ursodeoxycholic acid, in bile fistula rats.
We investigated the effects of three bile acids conjugated with N-acetylglucosamine, ursodeoxycholate N-acetylglucosaminide, tauroursodeoxycholate N-acetylglucosaminide and glycoursodeoxycholate N-acetylglucosaminide, on bile flow and biliary excretion of various markers in comparison with ursodeoxycholic acid, tauroursodeoxycholic acid and glycoursodeoxycholic acid in bile fistula rats. These bile acids were infused intravenously at a constant rate of 0.3 or 0.6 micromol/min/100 g b.w. for 2 h. All bile acids examined increased bile flow in a dose-dependent manner. In particular, ursodeoxycholate N-acetylglucosaminide has a longer-lasting effect after its infusion on bile flow than the other bile acids. Furthermore, these bile acids markedly increased biliary total bile acid excretion. At a higher dose level, the coefficient of determination (r2) between the biliary total bile acid excretion and bile flow for ursodeoxycholate N-acetylglucosaminide (r2 = 0.39) was lower than that for the other bile acids (r2 = 0.75-0.92). The ursodeoxycholate N-acetylglucosaminide, as well as tauroursodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholate N-acetylglucosaminide and glycoursodeoxycholate N-acetylglucosaminide, was mostly excreted in an unchanged form in bile, whereas ursodeoxycholic acid was excreted as a conjugate with taurine. The three N-acetylglucosaminides as well as ursodeoxycholic acid, tauroursodeoxycholic acid and glycoursodeoxycholic acid significantly increased the biliary excretion of cholesterol, phospholipid, bilirubin and total Ca2+. In contrast, the N-acetylglucosaminides significantly decreased in biliary bicarbonate concentration, whereas ursodeoxycholic acid significantly increased biliary bicarbonate concentration. However, tauroursodeoxycholic acid and glycoursodeoxycholic acid did not significantly change the biliary bicarbonate concentration. The results indicate that N-acetylglucosaminides have a choleretic effect in bile fistula rats. Our present study also demonstrates that N-acetylglucosaminides, but not ursodeoxycholic acid, tauroursodeoxycholic acid or glycoursodeoxycholic acid, can significantly reduce the biliary bicarbonate concentration. Furthermore, our findings suggest that ursodeoxycholate N-acetylglucosaminide may partly exert a choleretic effect via mechanisms different from those of the other bile acids.
Animals↗
Alcohol consumption enhances liver metastasis in colorectal carcinoma patients.
BACKGROUND: It is important to identify risk factors for liver metastasis in patients with colorectal carcinoma because the liver is the most common site of recurrence. Alcohol consumption reportedly is associated with hematogenous metastasis in certain animal models. Furthermore, some studies have shown that carmofur, a derivative of 5-fluorouracil, is particularly effective as adjuvant chemotherapy for colorectal carcinoma, and may even suppress liver metastasis, although the mechanism by which this occurs remains unknown. In addition, carmofur is known to inhibit alcohol metabolism. To the authors' knowledge, the relation between liver metastasis in colorectal carcinoma and alcohol consumption has not been examined previously. Therefore, the authors studied the relations between liver metastasis in colorectal carcinoma and various clinicopathologic factors including alcohol consumption status. METHODS: This study was comprised of 133 colorectal carcinoma patients with invasion beyond the submucosal layer who had undergone surgical resection. The subjects were examined and divided into two groups according to the occurrence or absence of liver metastasis. The relations between liver metastasis and other clinicopathologic factors were analyzed by univariate and multivariate statistical methods. RESULTS: Univariate analysis showed alcohol consumption (P=0.0021) and blood vessel invasion (P=0.0045) were correlated with liver metastasis. Multivariate analysis showed both to be independent risk factors for liver metastasis. CONCLUSIONS: Alcohol consumption is an independent risk factor for liver metastasis in colorectal carcinoma patients. Therefore, patients with colorectal carcinoma who drink alcohol require intensive examination and follow-up with respect to liver metastasis. Further study is necessary to confirm the effect of adjuvant chemotherapy using carmofur in colorectal carcinoma patients.
Adult↗
The mutations induced by oxidatively damaged nucleotides, 5-formyl-dUTP and 5-hydroxy-dCTP,in Escherichia coli.
The mutational properties of 5-formyl-2'-deoxyuridine 5'-triphosphate (5-CHO-dUTP) and 5-hydroxy-2'-deoxycytidine 5'-triphosphate (5-OH-dCTP), the major oxidatively damaged pyrimidine nucleotides derived from dTTP and dCTP, respectively, were analyzed by an in vivo assay. 5-CHO-dUTP and 5-OH-dCTP were directly incorporated into Escherichia coli , and their mutagenicities were evaluated by the chromosomal lacI forward mutation assay. The mutation frequencies increased, depending on the dose of these damaged nucleotides, indicating that these nucleotides were incorporated into E.coli and acted as mutagens in vivo . The mutagenicities of 5-CHO-dUTP and 5-OH-dCTP were comparable to that of 8-hydroxy-2'-deoxyguanosine 5'-triphosphate, a major form of dGTP oxidative damage. 5-CHO-dUTP induced G.C to A.T, A.T to G.C and G.C to T.A mutations, and 5-OH-dCTP elicited G.C to A.T, A.T to C.G and G.C to T.A mutations.
Bacterial Proteins↗
2-Hydroxyadenine, a mutagenic form of oxidative DNA damage, is not repaired by a glycosylase type mechanism in rat organs.
Oxygen radicals are known to play a role in causing cellular DNA damage, which is involved in carcinogenesis. 8-Hydroxyguanine (8-OH-Gua) is a major form of oxidative DNA damage and is known as a useful marker of DNA oxidation. Recently, we found another type of oxidative DNA damage, 2-hydroxyadenine (2-OH-Ade), which has a mutation frequency comparable to that of 8-OH-Gua. We compared the repair activities for two types of oxidative DNA damage, 8-OH-Gua and 2-OH-Ade, in 7-week-old male Sprague-Dawley (SD) rat organs. The repair activities were measured by an endonuclease nicking assay using 22 mer [32P]-end-labeled double-stranded DNA substrates, which contained either 8-OH-Gua (opposite C) or 2-OH-Ade (opposite T or C). In all of the SD rat organs we studied, the nicking activity for 2-OH-Ade was not detected, while that for 8-OH-Gua was clearly detected with the same conditions. Moreover, the 2-OH-Ade nicking activity was not induced in Wistar rat kidney extracts prepared after ferric nitrilotriacetate (Fe-NTA) treatment, which is known to increase 8-OH-Gua repair activity. These results suggest that 2-OH-Ade might not be repaired by the glycosylase type mechanism in mammalian cells.
Animals↗