Biomedical subjects
K Tokuyama
Publications and source records attributed to K Tokuyama.
A bout of resistance exercise increases urinary calcium independently of osteoclastic activation in men.
Metabolic acidosis increases urinary calcium excretion in humans as a result of administration of ammonium chloride, an increase in dietary protein intake, and fasting-induced ketoacidosis. An intense bout of exercise, exceeding aerobic capacity, also causes significant decrease in blood pH as a result of increase in blood lactate concentration. In this study we investigated changes in renal calcium handling, plasma parathyroid hormone concentration, and osteoclastic bone resorption after a single bout of resistance exercise. Ten male subjects completed a bout of resistance exercise with an intensity of 60% of one repetition maximum for the first set and 80% of one repetition maximum for the second and third sets. After exercise, blood and urine pH shifted toward acidity and urinary calcium excretion increased. Hypercalciuria was observed in the presence of an increased fractional calcium excretion and an unchanged filtered load of calcium. Therefore, the observed increase in urinary calcium excretion was due primarily to decrease in renal tubular reabsorption of calcium. Likely causes of the increase in renal excretion of calcium are metabolic acidosis itself and decreased parathyroid hormone. When urinary calcium excretion increased, urinary deoxypyridinoline, a marker of osteoclastic bone resorption, decreased. These results suggest that 1) strenuous resistance exercise increased urinary calcium excretion by decreasing renal tubular calcium reabsorption, 2) urinary calcium excretion increased independently of osteoclast activation, and 3) the mechanism resulting in postexercise hypercalciuria might involve non-cell-mediated physicochemical bone dissolution.
Effect of maturation on allergen-induced airflow obstruction and airway plasma exudation in sensitized guinea pigs.
Airway reactivity to bronchoconstrictor mediators changes with age. We studied the effects of maturation on airway responses provoked by allergen challenge [ovalbumin (OA) 0.05, 0.15 and 0.5 mg/kg i.v] in passively sensitized immature (190 +/- 2 g: 2 weeks old) and adult guinea pigs (566 +/- 16 g: 13 weeks old). In both groups of animals, we measured both lung resistance (RL) to monitor airflow obstruction and extravasation of Evans blue dye, to quantify airway plasma exudation. Immature guinea pigs required a larger dose of OA at the challenge to induce a significant increase in RL and extravasation of Evans blue dye compared with adult guinea pigs. In addition, immature animals responded less to the lower doses of OA than adults. Pretreatment with pyrilamine, an antihistamine, suppressed the increase in RL in immature animals, whereas the remaining component of the increase in RL was seen in adult animals. Intravenous allergen challenge causes less airflow obstruction and airway plasma exudation in immature than in adult guinea pigs. Allergen-induced airflow obstruction is mediated mainly via histamine in immature animals, whereas this may not be the case in adult animals.
Troglitazone ameliorates insulin resistance in patients with Werner's syndrome.
Insulin resistance in Werner's syndrome (WS) is probably due to defective signaling distal to the insulin receptor. To analyze the metabolic effects of troglitazone (TRO) in these patients, we performed frequently sampled iv glucose tolerance tests. Glucose kinetics were analyzed by the minimal model. Five patients with WS (mean age, 41.2 yr; body mass index, 17.0 kg/m2) were treated with TRO (400 mg/day) for 4 weeks. Each subject underwent a 75-g OGTT and frequently sampled iv glucose tolerance tests. Treatment reduced the area under the curve of glucose and insulin in the OGTT by 26% and 43%, respectively. Glucose tolerance, as manifested by the glucose disappearance rate improved significantly (1.36 +/- 0.16 to 1.94 +/- 0.30%/min; P < 0.05). Although the first phase insulin secretion was unchanged, insulin sensitivity and glucose effectiveness increased significantly [0.47 +/- 0.11 to 1.38 +/- 0.37 x 10(-4) min/pmol.L (P < 0.05) and 1.72 +/- 0.17 to 2.52 +/- 0.24 x 10(-2) min-1 (P < 0.05), respectively]. However, treatment did not change glucose effectiveness at zero insulin. In patients with WS, TRO ameliorates glucose intolerance mediated by increased insulin sensitivity as well as glucose effectiveness, as assessed by minimal model analysis. TRO may modulate the postreceptor signaling component and be a clinically useful regimen for the treatment of patients with the intracellular insulin signaling defect.
Effect of resistance exercise training on bone formation and resorption in young male subjects assessed by biomarkers of bone metabolism.
We studied the effects of high intensity resistance exercise training on bone metabolism in 17 young adult Oriental males (23-31 years) by measuring sensitive biomarkers of bone formation and resorption. The subjects were assigned to a training group and a sedentary group. The training group followed a weight training program three times per week for 4 months. In the training group, serum osteocalcin concentration and serum bone-specific alkaline phosphatase activity were significantly increased within the first month after the beginning of resistance exercise training, and the elevated levels remained throughout the training period, while there was no significant change in plasma procollagen type-I C-terminal concentration. Urinary deoxypyridinoline excretion was transiently suppressed and returned to the initial value but was never stimulated during the 4 months. These results suggest that the resistance exercise training enhanced bone formation without prior bone resorption. In the sedentary group, there was no significant difference in bone metabolic markers except plasma procollagen type-I C-terminal, which continuously decreased during the experimental period. There were no significant changes in total and regional bone mineral density in either group. In conclusion, (1) resistance exercise training increased markers of bone formation, while it transiently suppressed a marker of bone resorption, and (2) such adaptive changes of bone metabolism to resistance exercise training occurred during the early period of the training, before changes in bone density were observable through densitometry.
Roxithromycin attenuates acid-induced cough and water-induced bronchoconstriction in children with asthma.
In the present study, we evaluated the effect of roxithromycin, a semisynthetic macrolide antibiotic, on the cough response to inhaled acetic acid (AA) and on the bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in children with asthma. Ten hospitalized asthmatic children (8 boys and 2 girls, mean +/- SEM age 12.6 +/- 0.4 years) were enrolled in this study. They were treated with 150 mg of roxithromycin once a day orally for 8 weeks without any side effects. All the patients underwent AA inhalation challenge before and 2, 4, and 8 weeks after the administration of roxithromycin. Seven of the 10 patients, who had a fall in FEV1 of at least 20% after UNDW inhalation, underwent UNDW inhalation challege at the same time. The cough threshold values, the lowest concentrations of AA eliciting coughs, and UNDW provocative dose producing a 20% fall in FEV1 (UNDW PD20) values 4 or 8 weeks after the administration of roxithromycin increased significantly over the initial values (p < 0.05). No significant change was observed in baseline FEV1 or serum theophylline concentrations throughout the study. These results support the notion that administration of roxithromycin may have favorable results in the treatment of childhood asthma.
Utility of endoscopic hemoclipping for colonic diverticular bleeding.
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[A case of bronchial asthma for whose status asthmaticus an anticholinergic drug was effective in weaning from inhaled anesthesia].
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Effect of age, height, and prechallenge respiratory resistance on bronchial hyperresponsiveness in childhood asthma using the forced oscillation technique.
To evaluate the effects of age, height and prechallenge respiratory system resistance (Rrs) on bronchial responsiveness to methacholine inhalation (BRm) as measured by the oscillation technique in children with mild asthma, we studied BRm in 92 atopic children aged from 8 to 13 years (mean +/- SD, 10.5 +/- 1.7 years). Inhalation challenge was performed by administering progressively doubling doses of methacholine, until a twofold increase in Rrs from baseline had been reached. The minimum cumulative dose of methacholine (Dmin) at which Rrs deviated from baseline was identified by the point of deflection of the continuously recorded Rrs tracing. The Dmin represented the amount of methacholine which elicited BRm. By using single-regression analysis, height was negatively correlated with Rrs (p < 0.001). Height was positively and Rrs was negatively correlated with age (p < 0.001 and p < 0.001, respectively). Furthermore, height and age were correlated with Dmin (p < 0.001 and p < 0.001, respectively), but prechallenge Rrs was not correlated with Dmin (p > 0.1). To minimize the effect of height and prechallenge Rrs on BRm, the relationships between Dmin and age was studied in a subgroup with a narrow range of heights (135-155 cm, n = 32), and a narrow range of prechallenge Rrs (5.0-6.9 cmH2 O/L/s, n = 42); there remained a statistically significant correlation between Dmin and age in the groups with comparable heights (p = 0.026) and Rrs (p = 0.003). These data suggest that the BHR in childhood asthma may be affected by height and age when measured by the oscillation technique. Considering the many advantages of the oscillation method, this technique may be very suitable for measuring BHR in childhood asthma.
Effects of short-term dietary change from high fat to high carbohydrate diets on the storage and utilization of glycogen and triacylglycerol in untrained rats.
The effects of short-term diet change from high fat (F) to high carbohydrate (C) (or vice versa) on the storage and utilization of glycogen and triacylglycerol (TG) in muscle and liver were studied in untrained rats. Rats were fed on an F or C diet for 28 days. For an additional 3 days, half of the rats in both F and C groups were fed the same diets as before (F-F and C-C) and the other half of the rats were switched to the counterpart diets (F-C and C-F). On the final day of the experiment, half of the rats in each diet group were exercised by swimming for 1.5 h and the other half were rested. Short-term diet change from F to C diets increased, but the change from C to F diets decreased, glycogen stores of soleus and plantaris muscles and liver, resulting in no difference in glycogen stores between F-C and C-C, and between F-F and C-F. The dietary change also had an affect on TG stores of red gastrocnemius muscle and liver-however, muscle TG stores were still higher in F-C than in C-C and C-F, and there were no differences in liver TG stores between F-C and C-F. Exercise decreased muscle glycogen contents markedly in F-C and C-C, whereas, it decreased muscle TG concentrations in F-F and C-F. Liver glycogen depletion was lower in F-C than in other groups. Lipolytic activities of epididymal adipose tissue at rest and postexercise were no differences between F-F and F-C, and were higher in F-C than in C-C and C-F. beta-adrenergic receptor binding was determined with [125I] iodocyanopindolol, and maximal numbers of beta-adrenergic receptor of plasma membrane from perirenal adipose tissue were approximately 170%-200% higher in F-C than in other groups at rest and postexercise. These results suggested that short-term C diet fed rats adapted to F diet enhanced not only glycogen stores of muscle and liver but also did not decrease lipolytic activity of adipose tissue with increased beta-adrenergic receptor density, resulting in the preservation of energy reserves (glycogen and TG) of muscle at rest, and liver glycogen sparing during exercise.
Gene expression of insulin signal-transduction pathway intermediates is lower in rats fed a beef tallow diet than in rats fed a safflower oil diet.
To elucidate the effects of dietary fatty acid composition on the insulin signaling pathway, we measured the gene expression of the earliest steps in the insulin action pathway in skeletal muscle of rats fed a safflower oil diet or a beef tallow diet. Rats were meal-fed an isoenergetic diet based on either safflower oil or beef tallow for 8 weeks. Both diets provided 45%, 35%, and 20% of energy as fat, carbohydrate, and protein, respectively. Insulin resistance, assessed from the diurnal rhythm of plasma glucose and insulin and the oral glucose tolerance test (OGTT), developed in rats fed a beef tallow diet. Body fat content was greater in rats fed a beef tallow diet versus a safflower oil diet. The level of insulin receptor mRNA, relative expression of the insulin receptor mRNA isoforms, and receptor protein were not affected by the composition of dietary fatty acids. The abundance of insulin receptor substrate-1 (IRS-1) and phosphatidylinositol (PI) 3-kinase mRNA and protein was significantly lower in rats fed a beef tallow diet versus a safflower oil diet. We conclude that long-term feeding of a high-fat diet with saturated fatty acids induces decrease in IRS-1 and PI 3-kinase mRNA and protein levels, causing insulin resistance in skeletal muscle.
Impact of the initial levels of laboratory variables on survival in chronic dialysis patients.
Besides the age at start of dialysis and the presence of diabetes mellitus, serum albumin has been shown to be a significant predictor of survival in prevalent dialysis patients. However, this was not evaluated in incipient dialysis patients. The initial biochemical variables were retrieved for a large dialysis population (N = 1,982) who were started on chronic dialysis in Okinawa, Japan from 1971 to 1990. Biochemical data that included blood urea nitrogen, serum creatinine, serum electrolytes (sodium, potassium, calcium, and phosphate), total cholesterol, triglyceride, total protein, serum albumin, and hematocrit obtained just before the first dialysis session were available for 1,491 (75.2%) patients. Six hundred sixty-four (43.2%) patients died by the end of 1993. Cox proportional analysis adjusted for sex, age, year of start of dialysis, presence of diabetes mellitus, and the laboratory variables was performed to examine the significance of the initial biochemical data on survival. The risk ratio was 0.577 (P = 0.0025) in serum albumin, 1.291 (P = 0.0138) in serum potassium, and 0.966 (P = 0.0202) in serum sodium. The study results support the notion that nutritional status is important for survival in chronic dialysis patients. Causes of hypoalbuminemia, hyperkalemia, and hyponatremia should be evaluated carefully at initiation of dialysis.
Diurnal rhythm of plasma insulin and glucose in rats made obese by a high fat diet.
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Relationship between the acid-induced cough response and airway responsiveness and obstruction in children with asthma.
BACKGROUND: In children with asthma little is known about the direct effect of the bronchoconstrictor and bronchodilator response on the cough threshold, or the relationship between bronchial responsiveness and the cough threshold. A study was undertaken to determine the effect of histamine-induced bronchoconstriction and salbutamol-induced bronchodilatation on the cough threshold in response to inhaled acetic acid, and to examine the relationship between the acetic acid cough threshold and bronchial hyperresponsiveness to histamine in children with asthma. METHODS: Nineteen children with asthma (16 boys) of mean (SE) age 10.6 (0.6) years were enrolled in the study. On day 1 each underwent a histamine inhalation challenge to determine the provocative concentration causing a fall in forced expiratory volume in one second (FEV1) of more than 20% (PC20) as an index of individual bronchial hyperresponsiveness. On day 2 the acetic acid cough threshold was determined before and just after the inhalation of the PC20 concentration of histamine, and then salbutamol (1 mg/m2) was inhaled to relieve the bronchoconstriction. Ten of the 19 patients (eight boys) of mean age 12.2 (0.7) years also tried acetic acid inhalation challenge just after salbutamol inhalation. RESULTS: There was no relationship between the bronchial responsiveness to histamine and acetic acid cough threshold in these patients. The acetic acid cough threshold after histamine inhalation was similar to that before histamine, although FEV1 decreased after histamine. In the 10 patients who also tried acetic acid inhalation challenge after salbutamol the cough threshold did not change. CONCLUSIONS: These findings suggest that acid-induced cough sensitivity and bronchomotor tone are independently regulated in children with asthma.
Effects of a single bout of exercise on glucose effectiveness.
The effects of a single bout of exercise on glucose effectiveness (SG) and insulin sensitivity (SI) in 22 sedentary subjects were estimated with a minimal model approach. The intravenous glucose tolerance test (IVGTT) was performed 1) 11 h after an exercise bout on a cycle ergometer at the lactate threshold level (mild exercise) for 60 min, 2) 11 h after an exercise bout at the 4 mM lactate level (hard exercise) for 36 +/- 1 min, 3) 11 h after an exhaustive-exercise bout (exhaustive exercise) for 96 +/- 7 min, or 4) without any prior exercise (control). Only the exhaustive exercise increased the glucose disappearance constant (2.69 +/- 0.28 vs. 2.05 +/- 0.13%/min; P < 0.05) and SI (15.0 +/- 2.0 vs. 10.3 +/- 0.9 x 10(-5) min/pM: P < 0.05) in comparison with the control condition. The SG and SG at zero insulin (GEZI) were not affected by any exercise condition. However, a marked individual difference in GEZI emerged after the exhaustive exercise and could be divided into two subgroups: one decreased in GEZI (0.014 +/- 0.001 vs. 0.007 +/- 0.001 min-1) and the other increased in GEZI (0.014 +/- 0.001 vs. 0.021 +/- 0.003 min-1). The former subgroup was accompanied by elevated levels of plasma creatine kinase (100 +/- 16 vs. 598 +/- 315 IU/l; P < 0.05) and myoglobin (Mb; 46 +/- 4 vs. 126 +/- 47 ng/ml; P < 0.05), whereas the latter subgroup showed no significant change in creatinine kinase (99 +/- 10 vs. 128 +/- 9 IU/l; P > 0.05) and Mb (50 +/- 7 vs. 51 +/- 4 ng/ml; P > 0.05). In both subgroups, SI was similarly increased after the exhaustive exercise. These results thus suggest that a single bout of exercise that results in muscle damage or changes in muscle permeability, as reflected in the increased creatine kinase and Mb levels, decreases GEZI, whereas exhaustive exercise without such alterations increases GEZI.
Relation between theophylline and circulating vitamin levels in children with asthma.
We investigated the effect of theophylline administration on circulating vitamin levels in children with asthma. Twenty-three asthmatic children, ranging in age from 7 to 15 with a mean of 10.8 years and including 16 patients who were treated with slow-release theophylline and 7 patients not receiving any type of theophylline preparation, were enrolled in this study. They all were inpatients who had been hospitalized for the control of asthma. Steady-state serum theophylline and vitamin A, B1, B2, B6, B12 and C levels were evaluated in these patients. Circulating vitamin B1 and B6 levels were depressed in asthmatic children treated with theophylline compared to those not receiving the agent (38.4 +/- 1.6 (mean +/- SEM) vs. 46.4 +/- 3.5 ng/ml and 7.1 +/- 0.5 vs. 11.8 +/- 2.1 ng/ml, respectively, p < 0.05). A significant negative correlation between theophylline and circulating levels of vitamin B6 was demonstrated in the subjects of this study (rs = -0.657, p < 0.001). In contrast, no relationship was noted between theophylline and circulating vitamin B1 levels. Theophylline did not affect circulating vitamin A, B2, B12 or C levels. We conclude that theophylline induces depression of circulating vitamin B1 and B6 levels in asthmatic children, although a dose-dependent interaction between theophylline and vitamin B1 would be unlikely.
Increased risk of cardiovascular disease with erythropoietin in chronic dialysis patients.
Recombinant human erythropoietin is widely used in chronic dialysis patients. However, the long-term effect, especially on the incidence of cardiovascular disease, has not been critically evaluated. We observed the annual incidence of stroke and acute myocardial infarction from April 1988 through March 1993 in Okinawa, Japan. Until April 1990, erythropoietin was not generally used. Therefore, we have two periods: pre-erythropoietin, April 1988 through March 1990, and post-erythropoietin, April 1990 through March 1993. Two thousand one hundred and sixteen patients (1,219 males and 897 females) were on chronic dialysis during the study period by March 31, 1993. Every case of stroke and acute myocardial infarction during the study period was registered. The odds ratio was calculated using the data of the general population in each sex and age class obtained in the same area. A total of 86 cases of stroke and 15 cases of acute myocardial infarction were registered during the study period. The annual incidence, per 1,000 patient-years, of stroke was 12.5 (1988), 10.5 (1989), 12.7 (1990), 14.0 (1991), and 17.5 (1992). The incidence of stroke was increased in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.22 and 95% confidence interval (95% CI 1.06-1.41, p < 0.01). The annual incidence of acute myocardial infarction was 1.0 (1988), 1.8 (1989), 0.8 (1990), 2.9 (1991) and 4.7 (1992). The incidence of acute myocardial infarction was increased significantly in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.87 (95% CI 1.66-2.10, p < 0.01). The odds ratio of stroke to the general population was 4.25 (95% CI 3.10-5.82) in the pre-erythropoietin and 4.58 (95% CI 2.14-9.80) in the post-erythropoietin period. In acute myocardial infarction, it was 2.98 (95% CI 2.84-3.12) and 3.81 (95% CI 3.18-4.56). The odds ratio of acute myocardial infarction was significantly increased (p < 0.01). The introduction of erythropoietin was associated with an increased risk of cardiovascular disease, especially acute myocardial infarction. Erythropoietin may unmask the sclerotic lesion in chronic dialysis patients.
High-dose but not low-dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic beta-cells in normal men.
The diabetogenic effects of glucocorticoids appear to be dose dependent. To determine the effects of different doses of dexamethasone on glucose metabolism, we performed frequently sampled intravenous glucose tolerance tests in 20 healthy young men. Glucose kinetics were analysed by the minimal model. Ten subjects received low-dose dexamethasone (2 mg/day) for 3 days, and the other 10 received high-dose dexamethasone (6 mg/day) for 3 days. The rate of glucose disappearance (KG) did not decrease in the low-dose group (2.46 +/- 0.20 to 2.19 +/- 0.11% min-1, P = 0.35). In contrast, KG in the high-dose group did decrease significantly (2.43 +/- 0.29 to 1.81 +/- 0.11% min-1, P < 0.05). The factor responsible for the decline in KG in the high-dose group was not glucose effectiveness because these values did not change in either group. The insulin sensitivity decreased significantly, by 46% in the low-dose group and 69% in the high-dose group [17.1 +/- 2.7 to 9.2 +/- 1.5 and 18.5 +/- 3.7 to 5.8 +/- 0.9 x 10(-5) min-1 (pmol/L)-1, P < 0.001 and P < 0.01, respectively]. The insulin area (0-20 min) increased significantly, by 104% in the low-dose group and 114% in the high-dose group [3412.6 +/- 609.7 to 6972.7 +/- 1450.1 and 4086.7 +/- 864.5 to 8750.0 +/- 1451.6 (pmol/L) min, P < 0.01 and P < 0.01, respectively]. Insulin sensitivity x insulin area as an estimate of insulin-dependent glucose uptake and insulin's action to suppress hepatic glucose production decreased significantly in the high-dose group (0.588 +/- 0.112 to 0.441 +/- 0.073, P < 0.05), but did not change in the low-dose group (0.436 +/- 0.050 to 0.484 +/- 0.032, P = 0.77). Therefore, the decline in KG in the high-dose group may be associated with the compensatory failure of pancreatic beta-cells against for the insulin resistance.