Biomedical subjects
Publications and source records attributed to A Mizuno.
A technique is presented that allows intraoperative assessment of mitral valve function with the heart filling and actively beating. This technique secures steady coronary perfusion and avoids possible air embolism of the coronary arteries. Repeated assessment and repair during reparative mitral operations are greatly facilitated when this technique is accompanied by warm blood cardioplegia.
We examined whether a 70% pancreatectomy changes the morphofunctionality of pancreatic A cells in a model rat (Otsuka Long-Evans Tokushima Fatty [OLETF]) with non-insulin-dependent diabetes mellitus. Male OLETF rats aged 6 weeks were assigned to two groups: partial pancreatectomy (Px) and sham pancreatectomy (sham). The Px group was divided into three subgroups based on treatment received after surgery, which included treatment with nicotinamide, phlorhizin, or saline. As a control, their diabetes-resistant counterparts, Long-Evans Tokushima Otsuka (LETO) rats, were similarly treated and grouped. Six weeks after surgery, plasma glucagon responses to arginine- and insulin-induced hypoglycemia were examined. In addition, the glucagon content and morphological features of pancreatic A cells in Px-remnant and remnant-equivalent pancreata were investigated 7 weeks after surgery. A sustained nonfasting hyperglycemia was evident in Px OLETF rats, which was ameliorated by administration of nicotinamide. The glucagon content and A-cell mass were not decreased significantly in the remnant pancreas of saline- and phlorhizin-treated Px animals of either strain but increased in nicotinamide-treated animals compared with those in the remnant equivalent of the respective sham rats. The areas under the response curves of plasma glucagon (zigma IRG) during an arginine infusion test and 90 minutes of insulin-induced hypoglycemia were 1,010.7 +/- 72.9, 1,083.1 +/- 95.3, 1,029.6 +/- 65.0, and 1,779.8 +/- 226.9 pmol.L-1.min-1 versus 1,997.0 +/- 283.1,2,217.0 +/- 395.0, 1,479.6 +/- 78.0, and 3,466.4 +/- 174.0 pmol.L-1.min-1 in phlorhizin-, nicotinamide-, and saline-treated Px OLETF and sham OLETF rats, respectively. A similar trend was observed for differences in the response of pancreatic A cells to both stimuli among various groups of LETO rats. There was no significant difference in sigma IRGs during both tests between OLETF and LETO rats with similar treatments, except during an insulin tolerance test (ITT) in saline-treated Px rats. The magnitude of the plasma glucagon response to both stimuli in the test animals was roughly parallel to the glucagon content in the pancreas. These findings suggest that differences in the proliferation and responsiveness of pancreatic A cells between OLETF and LETO rats after a 70% pancreatectomy are not nearly as significant as compared with B cells.
Exercise training has been shown to be effective in preventing the development of non-insulin-dependent diabetes mellitus (NIDDM) in a model rat (Otsuka-Long-Evans-Tokushima Fatty [OLETF]). For determination of how long a preventive effect of exercise training against the development of NIDDM lasts in this model, six male OLETF rats each were assigned to training (1) for a whole experimental period, from 7 to 28 weeks of age (E-E); (2) for the first half of the period, from 7 to 15 weeks of age (E-S); and (3) for the second half of the period, from 16 to 28 weeks of age (S-E). In addition, eight male OLETF rats were given no exercise during the experimental period (S-S). At 28 weeks of age, E-E, E-S, S-E, and S-S rats, weighed averages of 514, 542, 557, and 669 g and had abdominal fat deposits of 13.9, 21.3, 38.2, and 76.0 g, respectively. At 28 weeks of age, the cumulative incidence of NIDDM in S-S was 100%, while none of the trained rats were diabetic. The glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp test, an index of insulin sensitivity, in the E-E group was significantly greater than that in the S-S group. The values in the E-S and S-E groups were slightly, but not significantly, less than that in the E-E group. Morphologic studies on the pancreas of E-E rats and S-E rats showed minimal changes of islets, whereas sections of islets from E-S rats appeared slightly enlarged and fibrotic, although significantly less than those of islets of S-S rats. These results demonstrate that the preventive effect of excercise training against the development of NIDDM lasts for at least 3 months after the cessation of exercise in this model.
To investigate whether inheritance or obesity plays a more important role in the development of non-insulin-dependent diabetes mellitus (NIDDM), female Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, which possess the diabetogenic gene, ODB-1, and Long-Evans-Tokushima-Otsuka (LETO) rats, which have no ODB-1, were compared. Neither strain becomes obese and diabetic when bred ordinarily. Female OLETF rats and male and female LETO rats were assigned to two groups of 20 rats each. Obesity was induced in one group by feeding a high-energy "cafeteria" diet (group D), and the other group was given standard chow (group C). Twenty male OLETF rats were used as NIDDM positive controls. At 25 weeks of age, the mean body weight of group D male LETO and female OLETF rats increased at a rate similar to that of male OLETF rats; female LETO rats did not show increased body weight. The incidence of diabetes mellitus in obese female OLETF rats in group D and positive control male OLETF rats was the same (80%). Only 30% of obese male LETO rats in group D developed diabetes mellitus. The insulin response to intravenous glucose in group D female OLETF rats was the highest for all groups but not sufficient to decrease blood glucose levels. In female OLETF rats, glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp test in group D was decreased to 50% of the group C value and tissue glucose uptake as determined by 3H-glucose infusion was significantly decreased in muscle. In male LETO rats, group D GIR was mildly decreased (80% of group C value) compared with the GIR of female OLETF rats. For obese group D female OLETF rats, abdominal fat increased more with obesity than in their male LETO counterparts. GIR was inversely correlated with the weight of abdominal fat when the data of all groups of animals were combined. The expression of GLUT4 mRNA and its protein level in adipose and muscle tissues and tumor necrosis factor alpha (TNF-alpha) protein in adipose tissue were not significantly different between group D and group C of both strains. In conclusion, the incidence of diabetes in female OLETF rats that possess the diabetogenic gene was significantly greater than in the LETO strains that do not possess the gene, in the presence of excess adiposity.
MPB70 is secreted in high concentrations by Mycobacterium bovis BCG substrain Tokyo (BCG Tokyo), but little by substrains Pasteur (BCG Pasteur) and M. tuberculosis. The gene encoding a MPB70 homologue secreted by BCG Tokyo was found at the upstream region of the gene encoding MPB70, with approximately 2.3 kilobase pairs (kbp) spacing: the same gene was also found in BCG Pasteur. This gene was cloned and sequenced from BCG Tokyo. The DNA sequence which contained a 663 base pair (bp) open reading frame beginning at position 1 and ending with a TAA codon at position 661 was found. Its theoretical molecular mass was calculated to be 22.068 kDa. This gene was highly homologous to the coding region of mpb70 and the deduced amino acid sequence was very similar to MPB83 reported by Harboe et al. It was speculated that the gene the authors characterized probably corresponded to the mpb83 gene.
To investigate the mechanism(s) of degradation of leptin, the protein product of ob (obese) gene, we measured serum leptin levels in 70 patients with chronic renal failure (CRF). The median of serum leptin concentrations of 36 male and 34 female patients with CRF were 7.3 ng/ml ranging from 0.5 to 39.0 ng/ml and 34.9 ng/ml from 1.1 to 76.1 ng/ml, respectively, while those of 29 male and 29 female healthy subjects were 5.8 ng/ml ranging from 0.5 to 37.7 ng/ml and 12.0 ng/ml from 2.0 to 45.2 ng/ml, respectively. The difference in male and female serum leptin concentrations between CRF group and the normal counterpart was statistically significant (p<0.005 and p<0.05, respectively). However, there was no significant correlation, either between serum creatinine or BUN, and serum leptin concentrations. These findings suggest that leptin is degraded and/or filtered in renal tissue.
1. We investigated the pharmacokinetics and pharmacodynamics of (+/-)-sotalol administered orally to healthy male volunteers in single doses of 40, 80 and 160 mg and in multiple doses of 80 mg twice daily for 7 consecutive days. 2. In the single dose studies, the half-life of (-)-sotalol (7.2-8.5 h) was significantly (P < 0.01) shorter than that of (+)-sotalol (9.1-11.4 h) while the renal clearance of (-)-sotalol (110.6-126.4 ml min-1) was significantly (P < 0.01) faster than that of (+)-sotalol (102.2-110.1 ml min-1). In the multiple dose studies, similar differences in the pharmacokinetics of (+)- and (-)-sotalol were observed. In addition, the pharmacokinetics of both (+)- and (-)-sotalol on day 4 were shown to be essentially the same as those on day 7. 3. In pharmacodynamic examinations, (+/-)-sotalol prolonged QTc intervals on electrocardiograms dose-dependently after single doses of 80 and 160 mg (3.81 +/- 2.96%, 13.23 +/- 5.66%). The correlation between the plasma concentration of (+/-)-sotalol and prolongation of QTc intervals was nearly linear, and showed no hysteresis. 4. In conclusion, we demonstrated that QTc interval was prolonged with a linear correlation to the plasma concentration of (+/-)-sotalol. In addition, our study suggested that differences in the pharmacokinetics of (+)- and (-)-sotalol may be attributable to faster urinary excretion of (-)-sotalol.
Caffeine concentration in plasma and scalp hair has been determined for subjects consuming normal daily amounts of caffeine and the results used as an indicator of individual hepatic metabolic capacity. Daily exposure to caffeine was assessed in six healthy Japanese volunteers by direct HPLC measurement of the concentrations of caffeine in aliquots of all caffeine-containing beverages consumed by the subjects. The measurements were repeated on three different occasions for each subject and caffeine consumption (mean +/- s.d.) was calculated as 178.0 +/- 84.3 mg day-1 with an intra-individual variability of 23.8 +/- 6.3% as coefficient of variation. A survey of daily caffeine consumption in 121 adult Japanese by means of a questionnaire revealed a similar value (231.8 +/- 177.8 mg day-1). Caffeine concentration in the plasma sampled during an overnight caffeine-free interval was measured by HPLC and a comparison made between healthy subjects and patients with liver disease (0.71 +/- 0.32, 0.77 +/- 0.45 and 3.92 +/- 1.91 micrograms mL-1 for healthy volunteers (n = 6), patients with hepatitis (n = 11) and those with liver cirrhosis (n = 4), respectively). Strands of scalp hair were collected from six healthy subjects and six patients with liver cirrhosis. Caffeine in hair was identified and measured by gas chromatography-mass spectrometry after digestion of the hair matrix with protease and extraction of the caffeine with chloroform. Caffeine concentration in hair collected from patients with liver cirrhosis (26.5 +/- 5.04 ng mg-1 hair) was significantly higher than that in hair sampled from healthy subjects (7.21 +/- 3.11 ng mg-1). These findings suggest that the determination of caffeine concentration in the plasma and hair of subjects consuming normal daily amounts of caffeine-containing beverages provides a practical assessment of individual liver metabolic capacity.
BACKGROUND AND PURPOSE: In this study we investigated the effects of a novel compound, MS-153 ([R]-[-]-5-methyl-1-nicotinoyl-2-pyrazoline), on elevated brain glutamate concentrations and cerebral infarct volume induced by middle cerebral artery (MCA) occlusion in the rat. METHODS: The rat MCA was occluded by a thrombus induced by a photochemical reaction between green light and the photosensitizer dye rose bengal, which causes endothelial injury followed by formation of a platelet- and fibrin-rich thrombus at the site of photochemical reaction; this method is routinely used in our laboratory to produce arterial occlusion in experimental animals. Extracellular glutamate concentration at the ischemic border zone was determined by a microdialysis technique. The size of cerebral infarction was measured by a histochemical technique 24 hours after MCA occlusion. MS-153 was administered at various doses as a continuous infusion for 24 hours, beginning 0 to 2 hours after MCA occlusion. RESULTS: At the ischemic border zone, the concentration of glutamate in the extracellular fluid increased by 40-fold after ischemia. At 3.13 mg/kg per hour, MS-153 reduced glutamate concentration (P < .05) and also the size of ischemic cerebral infarction (P < .05). Furthermore, the glutamate uptake inhibitor DL-threo-beta-hydroxyaspartate reversed the effect of MS-153 on glutamate concentration. CONCLUSIONS: The reduction in the size of cerebral infarction by MS-153 may be attributable to the inhibition of glutamate release or an increase in cellular glutamate uptake.
Although inflammatory polyposis of the colon is a recognized local complication of ulcerative colitis, giant inflammatory polyposis that totally obliterates the colonic lumen is uncommon, and most of the patients have been from Western countries. We report a Japanese man who had localized giant inflammatory polyposis that obstructed the retrograde flow of barium in a double-contrast barium enema study at the splenic flexure in ulcerative colitis. After resection by total proctocolectomy and ileostomy, pathological examination of the specimen confirmed localized giant inflammatory polyposis in the descending colon and spelnic flexure without malignancy.
Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in OLETF rat. To determine whether it is, we used partially pancreatectomized rats as a model, with administration of phlorizin to control blood glucose level, to examine whether the capacity for proliferation of beta-cells during hyperglycemia or normoglycemia differs between OLETF and their diabetes-resistant counterparts, Long-Evans-Tokushima-Otsuka (LETO) rats. We also examined whether such a defect, if present, could be improved by nicotinamide. Male rats, 6 weeks of age, were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into four subgroups by date of killing after surgery: 3-day, 7-day, 28-day (treated with phlorizin, nicotinamide, or saline), and 91-day. A sustained hyperglycemia was evident in the Px OLETF rats after surgery, which was associated with insufficient proliferation of beta-cells, characterized by decrease in beta-cell labeling index in proportion to decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. This defect was unaffected by restoration of normoglycemia induced by phlorizin injection. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have poor capacity for proliferation of pancreatic beta-cells and that this change may be the critical pathogenetic event before the onset of overt diabetes.
The Upjohn Pharmaceuticals Limited (UPL) rat is a new dominant hereditary cataract model with two types of cataract formation, early onset (E-type) and late onset (L-type). In the UPL E-type rat cataracts have formed by the time the eyes open. The E-type rat also develops microphthalmos and buphthalmos. In this study, histological observations of cataract development in the E-type rats were performed during the period of fetal development, at birth and at 1, 3 and 62 weeks of age. In addition, the distribution of alpha- and gamma-crystallins in the developing lens was determined using anti-crystallin antisera. Abnormal elongation of the lens fibers was first observed on the 13th day of gestation. Stratification of lens epithelial cells was present on the 19th day of gestation and this change became more severe with age. There was no alteration in alpha- and gamma-crystallin expression during the fetal period. The continuity between the lens epithelial cells and lens fibers was lost at 3 weeks of age and it was assumed that differentiation of lens epithelial cells had ceased. These findings suggested that development of the UPL rat E-type cataract was related to an early abnormality in lens cell differentiation not involving crystallin expression.
Escherichia coli isolated from surgical infections during the period from July 1983 to June 1995 were investigated in a multicenter study involving 19 hospitals in Japan, and the following results were obtained. 1. Although the isolation rate of E. coli was not high from postoperative infections, it was most frequently isolated from primary infections throughout the study period. E. coli, Klebsiella spp. and anaerobic bacteria were predominant from fresh infections. From the cases that had previous antibiotics treatment, Enterococcus spp. were the most predominant isolates followed by MRSA and Pseudomonas spp. in this order. 2. Against E. coli, cefozopran, carumonam and aztreonam had the strongest activity, followed by cefmenoxime, imipenem, latamoxef, gentamicin and ofloxacin. Recently, we have noticed that antibiotic resistant E. coli strains particularly against cefazolin are increasing year by year.
Between September 1994 and January 1995, the inferior epigastric artery (IEA) was used as a free graft for direct coronary artery bypass grafting in 4 patients. The IEA is excised from its origin from the external iliac artery as a pedicle with an "oval cuff" of 3 mm in diameter to facilitate the direct anastomosis with the aorta. The 4-week postoperative angiographic study showed that the IEA grafts were patent in all patients. We found that the IEA varies in length, diameter, and the pattern of branching between patients and between the right and left sides in the same patient. The preoperative digital subtraction angiography was useful for evaluating the suitability of IEA.
Pseudomonas aeruginosa isolated from surgical infections during the period from July 1982 to June 1995 were investigated in a multicenter study involving 19 hospitals in Japan, and the following results were obtained. 1. Though the isolation rate of P. aeruginosa was not high from primary infections, it was more frequently isolated from postoperative infections throughout the study period. Enterococcus spp., P. aeruginosa and Staphylococcus aureus including MRSA were predominant among postoperative infections. From the postoperative cases that had previous antibiotic treatment, Enterococcus spp., MRSA and P. aeruginosa were more predominantly isolated than from those without previous treatments with antibiotics. 2. Cefozopran, ceftazidime, cefsulodin, aztreonam, carumonam, gentamicin, amikacin and ofloxacin had strong activities against P. aeruginosa. We recognize recently that antibiotic-resistant strains of P. aeruginosa against imipenem and ofloxacin have been increasing year by year.
Isolated bacteria from infections in general surgery during the period from July 1994 to June 1995 were investigated by a multicenter study in Japan, and the following results were obtained. One hundred and fifty-three strains were isolated from primary infections, and 143 strains were isolated from postoperative infections. From primary infections, both anaerobic Gram-positive and-negative bacteria were predominant, and from postoperative infections, aerobic Gram-positive bacteria were predominant. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus faecalis was highest, followed by that of Staphylococcus aureus from both types of infections. Among anaerobic Gram-positive bacteria, the isolation rate of Streptococcus intermedius was highest from primary infections, but from postoperative infections anaerobic Gram-positive bacteria was uncommon. Among aerobic Gram-negative bacteria, Escherichia coli was most predominantly isolated from primary infections, followed by Klebsiella pneumoniae and Pseudomonas aeruginosa in this order. From postoperative infections, P. aeruginosa was most predominantly isolated, followed by Serratia marcescens and E. coli. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both types of infections. We have noticed that resistant strains against imipenem and ofloxacin were increasing among P. aeruginosa and resistant strains against cefazolin were increasing among E. coli. MICs of cefazolin against four out of 30 strains of E. coli were higher than 100 micrograms/ml, and MICs of imipenem was higher than 50 micrograms/ml against 5 out of 22 strains of P. aeruginosa.
These effects of polychlorinated biphenyl (PCB) were examined by light and electron microscopy and biochemical analysis of lysosomal enzyme activities. Several experimental protocols with dosage schedules of either 0.2, 2.0, or 20 mg/kg of PCB were used. Typical histological changes were observed in mice given 2 mg/kg of PCB in a single injection. There were no remarkable changes until 4 days after PCB administration; marked cytoplasmic vacuolation was observed in parotid acinar cells at 7 days. The activities of lysosomal enzymes increased after the PCB injection and their maximum values appeared consistently at 4 days after the treatment; the increases were threefold for acid phosphatase, twofold for beta-glucuronidase, threefold for cathepsin D, fivefold for cathepsin H and twofold for cathepsin L. As vacuolation was preceded by a large increase in lysosomal enzyme activities and the vacuoles co-localized with lysosomes, it is suggested that an increase in these activities induced by PCB may be closely related to the development of vacuolation in the parotid acinar cells as a subacute effect of PCB.
To identify the primary disorder causing diabetes mellitus in a model rat (Otsuka Long-Evans Tokushima Fatty [OLETF]) with non-insulin-dependent diabetes mellitus (NIDDM), we studied the temporal relationship between insulin resistance and impairment of pancreatic beta-cell function. Groups of 28 male OLETF rats and male nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats were given an intravenous (i.v.) glucose and glucagon tolerance test (IVGTT) and hyperinsulinemic euglycemic clamp tests at 10, 16, 24, and 40 weeks of age. After the euglycemic clamp test, abdominal fat was measured and the pancreas was examined histologically. At 16 weeks of age, insulin-mediated whole-body glucose uptake as measured by the hyperinsulinemic euglycemic clamp technique was significantly reduced in OLETF rats (glucose infusion rat [GIR], 40.9 +/- 4.2 mumol/kg.min) as compared with LETO rats (78.4 +/- 6.9). On the other hand, plasma insulin responses to glucose and glucagon in OLETF rats were higher than those in LETO rats at 16 and 24 weeks of age, but clearly decreased at 40 weeks of age (sigma immunoreactive insulin [IRI] to glucagon, 8.81 +/- 1.81 v 27.32 +/- 4.59 nmol.min in OLETF and LETO rats, respectively, P < .01). Abdominal fat deposition was significantly greater in OLETF rats than in LETO rats at all ages tested except 10 weeks. Pancreatic islets of OLETF rats became enlarged and fibrotic. These results demonstrated that insulin resistance preceded impairment of pancreatic beta-cell function in OLETF rats, and that insulin resistance seemed closely related to fat deposition in the abdominal cavity.