Biomedical subjects
Publications and source records attributed to K Ichihara.
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Glibenclamide, an ATP-sensitive K (K ATP) channel blocker, worsens the ischemia-induced metabolic derangement in the heart through inhibition of K ATP channels. We examined whether the hypoglycemic effect of glibenclamide was involved in the worsening of myocardial energy metabolism during ischemia. Pentobarbital-anesthetized dogs were subjected to 15-min ligation of the left anterior descending coronary artery. Either vehicle (dimethyl sulfoxide, DMSO) or glibenclamide (1 mg/kg) was injected i.v. 10 min before the ligation. In half of the animals given glibenclamide, glucose was continuously infused at 3 mg/kg per min immediately after glibenclamide injection. Glibenclamide increased the serum insulin level and decreased the blood glucose level. Glucose infusion completely abolished the hypoglycemia due to glibenclamide. Glibenclamide enhanced the decrease in ATP and total adenine nucleotides and increase in tissue lactate caused by ischemia. Glucose infusion did not cancel the augmentation of ischemia-induced alterations of myocardial energy metabolism caused by glibenclamide. These results suggest that K ATP channels directly play an important role in endogenous mechanisms of myocardial protection against ischemic damage.
Recently, the importance of achieving a balance in terms of length of life (LL), quality of life (QOL) and medical costs has been emphasized in the evaluation of cancer treatment, and it is also said that the cost should be seen from the viewpoints of both the society and the patient. Few studies, however, have been performed to investigate how the patients bear the cost and the influence of this factor. Therefore, in the present study we examined the perception of medical care cost (PMC) in 83 non-recurrent post-surgical breast cancer patients. The factors that influence the PMC were analyzed by univariate and multivariate analyses using the variables representing QOL, sociodemographic and clinical characteristics, types of therapy, and various types of medical cost. First, the results of the relationship between the variables and the PMC revealed that the patients with better QOL, especially those with better social category QOL, tended to have a lower PMC. However, no other variable had any significant associations with the PMC. Second, the results of multiple regression analyses revealed that patients with better QOL, especially those with better social category QOL, in the elderly, and/or those with higher level of education tended to show a lower PMC. In conclusion, the results of the present study suggest that, when we consider evaluating the cost of cancer treatment for postsurgical breast cancer patients, we should take into account the patients' QOL, age, and their level of education.
The effects of transfection of phosphorothioate antisense oligonucleotides (ASOs) into BALB/c 3T3 mouse fibroblasts on procollagen type III production were examined. Immunohistochemistry and Western blots showed that the expression of procollagen type III decreased. Semi-quantitative reverse transcription polymerase chain reaction revealed that the expression of procollagen type III mRNA was inhibited. ASOs were effective for inhibiting procollagen type III production at the gene level, although the effect was transient.
The quality of life (QOL) in 55 early-stage breast cancer patients after surgery was prospectively assessed using a newly developed Japanese QOL questionnaire: The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The impacts of breast conserving treatment (BCT) (22 cases) and modified radical mastectomy (MRM) (33 cases) on the QOL in those subjects were compared. The overallQOL scores were evaluated during four periods (before surgery, 0-2, 3-12, and 13-24 months after surgery). The mean scores of the four categories of the QOL-ACD (activity, physical condition, psychological condition, and social relationships) were also compared. The results demonstrated that a significant improvement was observed in the overall QOL scores among the three periods after surgery (0-2, 3-12, and 13-24 months) only in the BCT group (p<0.05). There were no significant differences between the two groups in the overall QOL scores during any of the three periods after surgery, and the mean score of the 'psychological condition' during 0-2 months period in the BCT group was significantly lower than that in the MRM group (p<0.05). These results suggest that BCT does not always improve the patients' QOL more than MRM does, and that the patients receiving BCT require more psychological support than those receiving MRM during the early postoperative period.
The aim of the present study was to examine the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on mitochondrial respiration in ischemic rat hearts, and to compare the effects between water-soluble pravastatin and lipid-soluble simvastatin. Either vehicle (0.5% carboxymethyl cellulose), pravastatin (2 or 4 mg/kg per day), or simvastatin (1 or 2 mg/kg per day) was orally administered for 3 weeks. Ischemia was induced by ligating the aorta for 60 min in anesthetized open chest rats under artificial respiration. The hearts were removed, mitochondria were isolated, and the respiration was determined by polarography using glutamate and succinate as substrates. When succinate was used as a substrate, the ADP-stimulated respiration (QO3) and ATP production per unit oxygen (ADP/O ratio) were decreased by ischemia. The decreases in QO3 and ADP/O ratio in the pravastatin- and simvastatin-treated groups appeared to be more prominent than those in the vehicle-treated group. This was especially true in the simvastatin-treated group. The ADP-limited respiration (QO4) with succinate in the vehicle-treated heart was slightly increased by ischemia, while that in the pravastatin- or simvastatin-treated hearts was decreased. In conclusion, HMG-CoA reductase inhibitors may result in worsening of myocardial mitochondrial respiration during ischemia.
The inhibitory effect of fluvastatin sodium (fluvastatin), a new type of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A inhibitor, on de novo cholesterol synthesis was investigated and compared with that of pravastatin. Fluvastatin at a concentration of 12.5 mg/kg inhibited sterol synthesis ex vivo from [14C]acetate in rat liver and ileum by 97-99% with respect to the control, while the inhibition in kidney was 55%. The inhibition by fluvastatin in the liver and ileum persisted for approximately 9 h after administration. Significant differences between fluvastatin also had an inhibitory effect on cholesterol synthesis in vivo in various tissues of rats given [14C]acetate intraperitoneally. Sterol synthesis in the liver, ileum and kidney was inhibited by over 95% 3 h after administration of 6.25 mg/kg of fluvastatin. Significant differences between fluvastatin and pravastatin were found in the liver and ileum. Fluvastatin was more potent than pravastatin in inhibiting both ex vivo and in vivo sterol synthesis in the ileum (but not in kidney) and liver.
To investigate the factors influencing the quality of life (QOL) of Japanese patients with advanced or recurrent breast cancer, a newly developed QOL questionnaire, "The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs" (QOL-ACD), was answered by 23 patients, and a multiple regression analysis was performed. The demographic and medical factors relating to the overall QOL score and to the four categories of the QOL-ACD, namely (1) activity, (2) physical condition, (3) psychological condition, and (4) social relationships, were analyzed. The results indicated that skin metastasis, a heavier body weight, and bone metastasis had a strong negative influence on the overall QOL scroe, whereas endocrine therapy, the existence of a primary lesion, and more extensive first surgery had a strong positive influence on it. With regard to the analysis of the four categories, endocrine therapy was found to be positively related to all four categories. The multiple correlation coefficient (R) between the estimated overall QOL score and the observed overall QOL score was about 0.77. The results of this analysis showed that endocrine therapy can improve the QOL of patients with advanced or recurrent breast cancer, and that the QOL-ACD questionnaire could prove extremely useful for predicting the QOL of individual patients and for aiding clinicians in deciding on the most appropriate type of therapy for each patient.
A new ELISA for anti-HCV antibody was developed employing a shorter synthetic N-terminal peptide, 2-62aa, within the core region of 1-191aa. The basic performance of the assay was comparable to three other second-generation assays using longer HCV core antigens. To evaluate assay performance at the borderline level, 25 samples with indeterminate results were selected from 3000 routine serum samples. Only 5 of the 25 sera were found to be HCV-RNA-positive by a nested PCR assay and with apparent clinical evidence of HCV infection. The results of the new ELISA agreed with those of the PCR-RNA test in 23/25 (kappa statistics 0.75), whereas C22-3 of the RIBA II test using 2-120aa of the core agreed in 9/25 (0.09), the Abbott pHCV-34 EIA test using 1-150aa agreed in 10/25 (-0.12), and a neutralization inhibition assay for Abbott EIA II using 2-120aa agreed in 6/25 (0.02). These results indicate that the UBI CORE ELISA has greatly improved specificity and can be a useful indication of viremia in HCV infection.
BACKGROUND: OG-VI is a solution composed of 30 mmol/l inosine, 30 mmol/l sodium 5'-guanylate, 30 mmol/l cytidine, 22.5 mmol/l uridine and 7.4 mmol/l thymidine, and has a protective effect on stunned myocardium. We examined the effects of the constituents of OG-VI on stunned myocardium in dogs, and compared them with that of acadesine (5-amino-4-imidazole carboxamide riboside; AlCAr) to try to elucidate the mechanism of the effect of OG-VI. METHODS: Dogs anesthetized with pentobarbital were subjected to left anterior descending coronary artery ligation for 20 min followed by reperfusion for 30 min. Saline, OG-VI, its purine component (inosine and sodium 5'-guanylate; IG), its pyrimidine component (cytidine, uridine and thymidine; CUT) or AlCAr (30 mmol/l) was infused at 0.1 ml/kg/min, starting 30 min before the ischemia. Myocardial segment shortening function was determined by sonomicrometry. The tissue level of adenosine triphosphate (ATP) was determined in the hearts reperfused for 30 min. RESULTS: Following reperfusion, the group treated with saline showed an incomplete recovery of segment shortening function, which had been decreased by ischemia, to the pre-ischemic level. The segment shortening function was almost completely recovered in the groups treated with OG-VI and IG, to a lesser extent in the AlCAr-treated group, and CUT was found to be ineffective. The levels of ATP in the OG-VI- and AlCAr-treated groups were significantly higher than that in the saline-treated group. In contrast to saline, IG and CUT were both ineffective at increasing ATP during reperfusion. CONCLUSION: Of the compounds tested, only OG-VI improves both ATP levels and segment shortening recovery in stunned dog myocardium. The increase in ATP levels is not the only factor responsible for contractile recovery.
We studied the effect of sevoflurane on ischaemic myocardium in terms of myocardial energy and carbohydrate metabolism. Mongrel dogs were anaesthetized initially with sodium pentobarbitone, and then inhaled sevoflurane at 0% (0 MAC), 2.4% (1.0 MAC) or 4.7% (2.0 MAC) of inspired concentration for 60 min. Ischaemia was then induced for 3 min by ligating the left anterior descending coronary artery. The tissue levels of energy and carbohydrate metabolites were determined before and after sevoflurane inhalation, and after 3 min of ischaemia. Sevoflurane significantly decreased systolic and diastolic blood pressures, heart rate, and rate-pressure product in a dose dependent manner. When the animals did not inhale sevoflurane (0 MAC), ischaemia significantly decreased adenosine triphosphate and creatine phosphate levels, and produced alterations of carbohydrate metabolism. These metabolic changes induced by ischaemia were lessened by inhalation of sevoflurane. To exclude the influence of haemodynamic changes, blood pressure and heart rate were maintained during 1.0 MAC sevoflurane inhalation. Significant attenuation of ischaemia-induced metabolic changes caused by sevoflurane was still observed in some metabolites. These results indicate that the ischaemic influences on the myocardium may be reduced by sevoflurane, and this protective effect can be explained not only by its haemodynamic effect.
1. Effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Q10, and on mitochondrial respiration were examined in dogs. 2. Either vehicle (control), pravastatin (4 mg kg-1 day-1), or simvastatin (2 mg kg-1 day-1) was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Q10 was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates. 3. Simvastatin significantly decreased the myocardial level of coenzyme Q10, but pravastatin did not. 4. Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin-treated groups. 5. Only in the simvastatin-treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate. 6. The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Q10 level.
Three-dimensional structures of the nerves of the guinea-pig gallbladder, after histochemical demonstration of the acetylcholinesterase activity and HCl hydrolysis-collagenase digestion, were examined by scanning electron microscope. HCl-collagenase digestion facilitated easy identification of silver- and gold-intensified acetylcholinesterase-positive nerve fibers at a high accelerating voltage (25 kV), due to their strong reflection image. Ganglia were either triangular or ovoidal in shape. Dense para- and peri-vascular nerve fibers occurred around the cystic artery. There were a few intramuscular nerve fibers with varicosity-like structures among smooth muscle bundles. Dense branched and tapering nerve fibers with varicosities in the lamina propria mucosae were closely attached to epithelial cells. The acetylcholinesterase-positive fibers in the lamina propria and peri- and para-vascular nerves, and fewer positive fibers in the smooth muscle layer probably represent cholinergic nerves involved in the concentration of biliary compounds and lesser in the motor function of the smooth muscle.
It is generally difficult to determine reference interval in enzyme immunoassay (EIA) at an individual laboratory because of many sources of variations for analytes measured by EIA, low analytical precision and high reagent cost of EIA. Large within-kit variations can be reduced by strict control of assay procedures so that the reference interval can be determined jointly and transferred among users of the same kit. To set clinical decision limits (CDL) it is necessary to consider low frequency of abnormality in tumor markers and hormones when they are measured for case finding. The CDL which minimize an expected cost can be determined when costs for false positive/negative results are given together with pretest probability, sensitivity and specificity.
The vasoactive intestinal peptide (VIP) immunoreactive nerve fibres in the gallbladder from 14 human patients with cholelithiasis was examined by immunohistochemical method. In the chronic cholecystitis, hyperplastic VIP immunoreactive nerves were observed around the hypertrophied muscle bundles, Rokitansky Aschoff Sinus and in the mucosal layer. However, in the acute cholecystitis and gangrenous cholecystitis, reduction or disappearance of VIP nerve fibres was observed. These reductions or disappearances of VIP immunoreactive nerves may secondly result from severe tissue damage. These results suggest that hyperplastic VIP nerves cause gallbladder relaxation, stasis and mucosal fluid unbalance, which may closely correlate to gallstone formation.
The quality of life (QOL) of 21 patients with advanced or recurrent breast cancer was assessed using a QOL measure developed by the Ministry of Welfare in Japan: The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The factors that improve the QOL were analyzed by multiple regression analysis. The difference of the QOL score between pre- and post-treatment was set as a dependent variable, and sociodemographic and therapeutic characteristics were set as independent variables. The results revealed that the improvement of the QOL score had close associations with therapeutic efficacy (TE) and shorter disease-free interval (DFI). In the analysis using the mean scores of the four categories of the QOL (activity, physical, psychological and social aspects) as dependent variables, activity had a close association with shorter DFI; physical aspect had close associations with TE and shorter DFI; and the psychological aspect had close associations with chemoendocrine therapy and less lines of previous therapies. The results suggest that, to improve the QOL of patients with advanced or recurrent breast cancer, we should attempt to obtain higher efficacy of treatments such as endocrine therapy for patients with shorter DFI in the earlier period of their clinical course.