Attempts to reveal the mechanism of CD95-ligand-mediated inflammation.
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Animals↗
Biomedical subjects
M Otsuka
Publications and source records attributed to M Otsuka.
Screening for inducers of apoptosis in apoptosis-resistant human carcinoma cells.
Many anticancer agents are known to induce apoptosis in cultured cells, but human solid tumor cells are often resistant to apoptosis induction. Human pancreatic adenocarcinoma AsPC-1 cells were found to be resistant to apoptosis. So, we screened microbial culture filtrates and synthetic chemicals for their ability to induce apoptosis in AsPC-1 cells. Polyoxypeptin A was isolated from a Streptomyces culture broth as a potent inducer of apoptosis. Its cyclic hexadepsipeptide structure contains a simple but hitherto unreported amino acid, (2S,3R)-3-hydroxy-3-methylproline. Polyoxypeptin A induced early cell death, apoptotic morphology, and internucleosomal DNA fragmentation in AsPC-1 cells at low concentrations. Polyoxypeptin A can induce caspase 3 activation in human T cell leukemia Jurkat cells but not in AsPC-1 cells. The mechanism of apoptosis in AsPC-1 cells has not been elucidated yet. Less toxic derivatives of polyoxypeptin A are being prepared. A macrocyclic lactam called BE-14106 was also isolated from Streptomyces as an inducer of apoptosis in AsPC-1 cells. Histidine-pyridine-histidine-3 (HPH-3) is an oxygen-activating ligand derived from the structure of bleomycin, and it also induced apoptosis in AsPC-1 cells. Induction of apoptosis by HPH-3 was inhibited by zinc and copper ions, indicating that chelation with ferrous ion is responsible for induction of apoptosis, as is chelation by bleomycin to cleave DNA. Bleomycin A2 and its portion having no DNA-binding region, glycopeptide-3(GP-3), did not induce apoptosis in AsPC-1 cells. Thus, among the actions of bleomycin-related compounds, the induction of apoptosis is a unique characteristic of HPH-3.
Anti-Bacterial Agents↗
Blood and urinary levels of ethanol, acetaldehyde, and C4 compounds such as diacetyl, acetoin, and 2,3-butanediol in normal male students after ethanol ingestion.
Aldehyde dehydrogenase (ALDH) isozyme 2 genes were determined in 15 students. Of these subjects, five healthy male students were administered 0.4 kg/kg ethanol. One subject was defective in aldehyde dehydrogenase 2 (ALDH2), two had normal ALDH2, and the other two were hetero type. After the intake of alcohol, the concentration of ethanol, acetaldehyde, and C4 compounds in blood and urine were determined. The student with the inactive form of ALDH2 was flushed and his levels of 2,3-butanediol and acetaldehyde in blood and urine were found to be the highest.
Acetaldehyde↗
Fluorescence property of oxazole yellow-linked oligonucleotide. Triple helix formation and photocleavage of double-stranded DNA in the presence of spermine.
Oxazole yellow is an intercalator that shows enhanced fluorescence upon binding to DNA. We prepared an oxazole yellow-linked oligonucleotide that can form triple helix with interleukin 2 receptor alpha chain promoter. The oxazole yellow-linked oligonucleotide showed linear increase of fluorescence by the triple helix formation with double-stranded DNA and also induced photocleavage of the targeted DNA in the presence of spermine upon visible illumination. Cleavage site of one strand was 7 or 8 bases away from the site of intercalation whereas the other strand was cleaved at the intercalated site.
Benzoxazoles↗
Effects of water-soluble component content on cephalexin release from bioactive bone cement consisting of bis-GMA/TEGDMA resin and bioactive glass ceramics.
The effect of the amount of a water-soluble, lactose, on cephalexin (CEX) release from bioactive bone cement consisting of bisphenol-alpha-glycidyl methacrylate (bis-GMA), triethylene-glycol dimethacrylate (TEGDMA) resin and apatite- and wollastonite-containing glass-ceramic (A-W GC) powder was investigated. A-W GC powder containing 5% CEX and lactose powders hardened within 5 min after mixing with bis-GMA/TEGDMA resin, and furthermore its compressive strength was expected to be higher than that of polymethylmethacrylate cement. In vitro CEX release from bioactive bone cement pellets in a simulated body fluid at pH 7.25 and 37 degrees C continued for more than 2 wk. The drug-release rate increased with increasing amount of lactose powder in the mixture. CEX release profiles followed the Higuchi equation in the initial stage, but not in later stages. As hydroxyapatite was precipitated out on the cement surface, the CEX release rate decreased. The micropore distribution of the cements measured by mercury porosimetry also supported the variation in drug release due to cement porosity being mainly a result of the dissolution of lactose in the cements. These results suggest that the rate of CEX release from bioactive bone cement could be controlled by varying the amount of lactose in the cement system.
Journal Article↗
Treatment of gallbladder cancer by radical resection.
BACKGROUND: The use of radical resection for gallbladder cancer is controversial. This study evaluated results of resection for gallbladder cancer and analysed prognostic factors. METHODS: A retrospective review of 135 patients who underwent surgical resection for gallbladder cancer between 1976 and 1998 was performed. Of these, 123 patients underwent radical resection and the remaining 12 had palliative resection. The resections included 32 hepatopancreatoduodenectomies and 57 with adjuvant radiotherapy. Twelve prognostic factors were analysed. A subset of 96 patients with stage IV disease was analysed separately with respect to residual tumour level and adjuvant radiotherapy. RESULTS: Surgical resection was associated with a 5-year survival rate of 36 per cent, with a mean follow-up time of 870 days. Twenty-two patients have survived more than 5 years including three with stage IV disease. Overall operative morbidity and mortality rates were 13 and 4 per cent respectively. The 5-year survival rate decreased with disease stage: 100, 78, 69 and 11 per cent for stages I (n = 13), II (n = 19), III (n = 7) and IV (n = 96) respectively. Performance status, jaundice, histopathological type and grade, primary tumour, lymph node, distant metastasis, stage grouping, residual tumour level and adjuvant radiotherapy were significant prognostic factors. CONCLUSION: With careful patient selection, radical resection for gallbladder cancer improves the prognosis with acceptable operative mortality and morbidity rates, even for stage IV disease, provided that complete gross tumour resection is combined with radiotherapy.
Adult↗
Negative C-reactive protein in children with bacterial infection.
PURPOSE: To evaluate the practical value of initial C-reactive protein (CRP) in the diagnosis of bacterial infection in children. METHODS: The subjects comprised 11 children, six boys and five girls, aged 3 months through to 3 years (median age 16 months), whose initial CRP levels were < 1.0 mg/dL despite bacterial infection. C-reactive protein was quantitated at the first medical examination by nephelometry. RESULTS: The diagnosis was urinary tract infection (n = 4), bacterial meningitis (n = 2), sepsis (n = 2), pneumonia (n = 2) and arthritis of the hip joint (n = 1). The CRP levels were significantly elevated during the course of infection, ranging from 7.6 to 28.5 mg/dL. The bacterial etiology was non-specific. Eight patients were examined within 12 h of onset, three exhibited negative CRP values despite the duration of the insult over 12 h. Six patients were tentatively diagnosed as having a bacterial infection, but the other five were not. Each patient was treated, leading to a favorable outcome without any serious complications. CONCLUSIONS: Low levels of CRP do not rule out the possibility of bacterial infection in children. The initial value of CRP may be negative, even in patients with severe bacterial infection or even after 12 h from onset. The data suggest that pediatricians should consistently be aware of the possibility of bacterial infection even if the initial CRP test result is negative and that serial CRP measurements appear to be practical.
Bacterial Infections↗
Physicochemical characterization of glybuzole polymorphs and their pharmaceutical properties.
Systematic polymorphic screening tests were performed using 11 kinds of solvents and 6 kinds of preparation methods, and the three specific modifications of glybuzole (forms I and II and amorphous form) were identified by X-ray diffractometry and differential thermal analysis (DTA). The physicochemical properties of forms I and II and amorphous forms were measured using X-ray diffractometry, differential scanning calorimetry (DSC), thermogravimetry (TG), scanning electron microscopy (SEM), solubility tests, and others. The solubilities of all modifications in JP XII, first and second fluid (pH 1.2 and 6.8, respectively) were evaluated at 37 degrees C. Forms I and II and the amorphous form showed almost equivalent solubilities. Forms I and II were stable polymorphic forms at 0% and 75% relative humidity (RH), respectively, at 40 degrees C for 2 months, but the amorphous form was not stable. The crystallization rates of the amorphous form at 0% and 75% RH at 40 degrees C were estimated by X-ray diffraction analysis based on the Jander equation, and the rate at 0% RH was 364 times slower than that at 75% RH.
Chemical Phenomena↗
Effects of crystalline form on the tableting compression mechanism of phenobarbital polymorphs.
The effects of the polymorphic form on the compression mechanism of forms A, B, and F of phenobarbital were investigated using a compression simulator, mercury porosimetry, X-ray diffraction analysis, BET gas absorption method, and scanning electron microscopic (SEM) photography. The order of tablet hardness obtained from all phenobarbital polymorphs was form A > form B > form F in accordance with that of the specific surface area. The Cooper and Eaton method was applied to evaluate two individual compression processes: particle rearrangement (phase I) and fragmentation and/or deformation (phase II). The parameters for compression processes were calculated using a nonlinear regression analyses program, and the compression energies of phases I and II were calculated from these parameters. The relationship between specific surface area after compression and compression energy at phase I showed a good linear correlation, but their ratio did not. In contrast, the specific surface area ratio showed a linear relationship with the compression energy on phase II, but again the ratio of these two parameters did not. The tablet hardness showed a linear relationship with the specific surface area ratio, but not with the specific surface area. Again, the ratio of these two parameters did not show a linear relationship.
Anticonvulsants↗
Strict temperature control has no effect on injection pain with propofol.
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Anesthetics, Intravenous↗
Effect of plasma-calcium-level-responsive oestradiol release from apatitic bone cement on bone mineral density in ovariectomized rats.
The effects of plasma calcium levels on oestradiol release from apatite bone cement and on the bone mineral density of ovariectomized rats have been investigated. Apatite cement was prepared from an equimolar mixture of tetracalcium phosphate, dicalcium phosphate dihydrate and 0.5% beta-oestradiol bulk powder. After subcutaneous implantation of the cement, oestradiol release in diseased rats (ovariectomized rats on a low-calcium diet) was significantly higher than in normal rats. The drug levels of recovery-model rats (ovariectomized, but on a high-calcium diet) were significantly lower than those of the diseased rats. Calcium levels in diseased rats remained low during drug release but the plasma calcium levels of the recovery-model rats increased. The areas under the plasma calcium concentration-time curves (Ca-AUCs) for the recovery-model rats were higher than those for the diseased-model rats. The plasma oestradiol concentration AUCs and the Ca-AUCs were linearly related. The body weight of the recovery-model rats increased after five days, but that of the diseased-model rats did not. The bone mass of the recovery-model rats was greater after the experiment than before. The relationship between the bone mineral density and Ca-AUC of the diseased rats suggested that bone mineral density increased with increasing Ca-AUC. The results suggest that the severity of osteoporosis in this animal model is reduced by implantation of the oestradiol-loaded apatite cement.
Animals↗
Contribution of a high dose of L-ascorbic acid to carnitine synthesis in guinea pigs fed high-fat diets.
Ascorbate is a cofactor of two-enzyme hydroxylation in the pathway of carnitine biosynthesis. The purpose of this study was to investigate the contribution of ascorbate to endogenous carnitine in guinea pigs fed high-fat diets. The contents of carnitine in plasma, urine and tissues of guinea pigs supplemented with L-ascorbic acid were determined and compared with those supplemented with carnitine. Albino-Hartley guinea pigs were fed vitamin C-deficient diets containing lard throughout the experiment. They were administered orally with 5 mg L-ascorbic acid/d/animal for 14 d, and then divided into three groups and administered orally with the following supplements (/d/animal) for 14 d; L (5 mg L-ascorbic acid), LASA (100 mg L-ascorbic acid), and LCAR (10 mg carnitine plus 5 mg L-ascorbic acid). As a control, a normal group was fed vitamin C-deficient diets and administered orally with 5 mg L-ascorbic acid/d/animal for 28 d. The animals fed high-fat diets (L group) had higher free-carnitine contents in the muscle and urine than the normal group. The groups of LCAR and LASA had significantly higher contents of acid-soluble carnitine (p < 0.05) in plasma than the L group. Urinary excretion of carnitine in the LASA group was decreased to the same level as that in the normal group, although no significant difference between the groups of L and LCAR was observed. Moreover, the supplement of ascorbic acid, but not of carnitine, induced a significantly lower content of triacylglycerol in the plasma of the LASA group as compared to the L group (p < 0.05). These data suggest that high doses of ascorbic acid in guinea pigs fed high-fat diets contribute to the enhancement of carnitine synthesis and improvement of the triacylglycerol content in the plasma.
Animals↗
Hepatic branched-chain alpha-keto acid dehydrogenase complex in female rats: activation by exercise and starvation.
The effects of acute exercise and starvation on hepatic branched-chain alpha-keto acid dehydrogenase (BCKDH) complex activity were examined in female rats fed high (30%)- or low (8%)-protein diets. The total activity of the complex was significantly higher in the high protein-fed rats than in the low protein-fed rats but was not affected by acute exercise and starvation in either diet group. The proportion of the active form of BCKDH complex was less than 10% in both diet groups. Acute exercise and starvation markedly increased the active form of the complex in both diet groups. The activity of BCKDH kinase, which is responsible for inactivation of the BCKDH complex by phosphorylation, tended to be decreased by acute exercise and starvation in both diet groups. These results suggest that the activity of the BCKDH kinase is an important factor determining the proportion of the active form of BCKDH complex in exercise and starvation, and that the female rat is a useful model for studying the regulation of hepatic BCKDH complex activity.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
[Clinical significance of improved persistent defect by thallium-201 reinjection imaging in the subacute phase of myocardial infarction].
The clinical significance of new fill-in observed by thallium-201 (201Tl) reinjection in myocardial segments with persistent defect in the subacute phase of myocardial infarction was investigated. Seventy-five patients with subacute phase (mean 20th day) of first myocardial infarction underwent stress-redistribution-reinjection 201Tl single photon emission computed tomography (SPECT) imaging. Percentage 201Tl uptake was calculated and classified as persistent defect without fill-in even after reinjection (PD group, n = 26, 35%), persistent defect with new fill-in after reinjection [REINJ (+) group, n = 19, 25%] and reversible defect [RD (+) group, n = 24, 32%]. The clinical features and angiographic findings were assessed in the same phase in each group. Diameter stenosis of the infarction-related arteries by coronary angiography was 68 +/- 34% in the PD group, 31 +/- 23% in the REINJ (+) group and 83 +/- 27% in the RD (+) group [p < 0.01, REINJ (+) group vs PD group and RD (+) group]. Wall motion of the infarcted myocardial segments significantly improved and the mean left ventricular ejection fraction (EF) was higher in the REINJ (+) group than in the PD group (mean EF 51% vs 43%, p < 0.01). Post infarction angina was more frequent in the RD (+) group than in the REINJ (+) group (38% vs 5%, p < 0.05). Although new fill-in-after 201Tl reinjection has been considered to indicate severe myocardial ischemia in chronic coronary disease, these results indicate that this phenomenon in viable myocardium in patients with subacute phase of myocardial infarction is not always related to residual ischemia in the infarcted myocardial area.
Female↗
[Functional imaging for disorders of basal ganglia].
The nigrostriatal dopaminergic function and regional glucose metabolism were evaluated in patients suffering from various disorders of basal ganglia by using positron emission tomography with 18F-dopa and 18F-FDG, respectively. The 18F-dopa uptake in the striatum (the caudate head and the putamen) decreased in patients with Parkinson's disease but was relatively unaffected in the caudate. The cerebral glucose metabolism was normal in patients with Parkinson's disease. The 18F-dopa uptake in the striatum also decreased in cases of multiple system atrophy and progressive supranuclear palsy, but there was no difference in the uptake between the caudate and the putamen. The glucose metabolism decreased in the cerebral cortices and the striatum: this finding was also different from those of Parkinson's disease. A normal 18F-dopa uptake with a markedly decreased striatal glucose metabolism was observed in cases of Huntington's disease. The 18F-dopa uptake increased and the glucose metabolism was normal in cases of idiopathic dystonia. Various patterns of 18F-dopa uptake and glucose metabolism were thus observed in the various disorders of basal ganglia. These results suggest that the measurements of the 18F-dopa uptake and glucose metabolism would be useful for evaluating the function of the basal ganglia in various disorders of basal ganglia.
Basal Ganglia↗
[Prognosis for patients with angina pectoris accompanied by chronic renal failure].
Chronic renal failure (CRF) is one of the risk factors of a worse outcome for patients with coronary artery disease. However, few studies have assessed the outcome in such patients. This study investigated the clinical characteristics, treatment modalities, and prognosis for patients with angina pectoris accompanied by CRF and evaluated the validity of current treatment strategy for these patients. A total of 593 patients (248 with stable angina and 345 with unstable angina) admitted to our institution were studied. Renal failure was defined as serum creatinine of > or = 2.0 mg/dl. Patients were divided into 2 groups, with renal failure (46 patients) and without renal failure (547 patients), and the former group was further divided into 2 groups with hemodialysis (26 patients) and without hemodialysis (20 patients). The mean follow-up period was 2.5 +/- 1.2 years and the follow-up rate was 99%. The prevalences of congestive heart failure (26% vs 3%, p < 0.001), hypertension (72% vs 45%, p < 0.005), and multivessel coronary artery disease (65% vs 33%, p < 0.001) were higher in patients with CRF. The left ventricular end-diastolic volume was greater in patients with CRF than in patients without CRF (114 +/- 36 vs 85 +/- 24 ml/m2, p < 0.001). The calcification score of both coronary arteries and abdominal aorta evaluated by electron-beam computed tomography was higher in patients with CRF (2,187 +/- 2,727 vs 631 +/- 841, p = 0.03; 4,091 +/- 3,068 vs 2,191 +/- 2,249, p = 0.02, respectively). In-hospital cardiac mortality was higher in patients with CRF than in patients without CRF (8.7% vs 0.7%, p < 0.001). The cumulative survival was 88% at 1 year and 65% at 3 years in patients with CRF and 99% and 97% in patients without CRF, respectively (p < 0.001). The incidence of re-hospitalization due to congestive heart failure was higher in patients with CRF (19% vs 1.3%, p < 0.0001). The cumulative survival in CRF was 93% at 1 year, 57% at 3 years in the medical treatment group and 87% and 75% in the invasive therapy group, respectively (p = 0.1). Patients with angina pectoris and CRF had a poor prognosis under the current treatment strategy. Newly developed therapeutic strategies, such as rotational atherectomy, minimally invasive direct coronary artery bypass surgery and combinations, will be necessary to improve the long-term prognosis for these patients.
Aged↗
[Efficacy of hemostatic puncture closing device for hemostasis and early ambulation after coronary angiography and angioplasty: results of a multicenter trial].
To assess the efficacy and safety of a hemostatic puncture closing device for reducing patient immobilization after cardiac catheterization from a percutaneous femoral artery approach, we conducted a prospective, randomized trial at 4 participating centers. A total of 240 patients (183 men, 57 women, mean age 61 +/- 10 yr; 157 patients underwent diagnostic angiography, 83 patients underwent coronary angioplasty) were randomized to either the device group (n = 120) or the manual compression group (n = 120). There were no statistical differences in age, gender, weight or sheath size between the 2 groups. A 7, 8F sheath was used in 53 patients of the device group and in 43 patients of the manual compression group. One hundred and two patients (85%) in the device group and 96 patients (80%) in the manual compression group received heparin. Protamine was used in one patient of the device group and 23 patients of the manual compression group. Activated clotting time just prior to sheath removal was 206 +/- 64 sec in the device group and 170 +/- 47 sec in the manual compression group (p < 0.01). Successful placement of the device was achieved in 118 of 120 patients (98%). Time to hemostasis was significantly shorter in the device group (0.8 +/- 3.2 vs 12.2 +/- 5.3 min, p < 0.01). Time to ambulation could be reduced in the device group (5.3 +/- 3.7 vs 10.9 +/- 5.1 hr, p < 0.01). The following complication rates occurred in the device group as compared with the manual compression group: hematoma, 16% vs 10%; bleeding, 8% vs 3%; pseudoaneurysm, 0% vs 1%, respectively. None of these differences was statistically significant. These results indicate that early ambulation using a hemostatic puncture closing device is feasible without significantly increasing the risk of peripheral vascular complications.
Adult↗
Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver.
Human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (DD) is involved in the metabolism of steroid hormones and polycyclic aromatic hydrocarbons, and is also responsible for the reduction of ketone-containing drugs. To account for the interindividual difference in the activity, we isolated and characterized clones for the human liver enzymes. The sequence of the cDNA clone coding for the variant differed from that coding for the wild-type DD by two nucleotides (substitutions of C with G at positions 434 and 931) which caused two amino acid replacements, Ser145 to Cys (S145C) and Leu311 to Val (L311V). The heterologous expression of the variant mRNA was confirmed in four of 31 liver samples from Japanese by an allele-specific polymerase chain reaction. The effects of the mutations on the catalytic properties were examined with the recombinant enzymes expressed in Escherichia coli. The introduction of S145C/L311V double mutations resulted in three- to five-fold decreased activities for xenobiotic and steroidal substrates, whereas no significant change was observed by an introduction of the S145C mutation alone. The results substantiate the existence of polymorphic forms for human liver DD, and also suggest the importance of the residue at position 311 for substrate binding to the enzyme.
Base Sequence↗