A composite computational model of liver glucose homeostasis. II. Exploring system behaviour.

Using a composite model of the glucose homeostasis system, consisting of seven interconnected submodels, we enumerate the possible behaviours of the model in response to variation of liver insulin sensitivity and dietary glucose variability. The model can reproduce published experimental manipulations of the glucose homeostasis system and clearly illustrates several important properties of glucose homeostasis-boundedness in model parameters of the region of efficient homeostasis, existence of an insulin sensitivity that allows effective homeostatic control and the importance of transient and oscillatory behaviour in characterizing homeostatic failure. Bifurcation analysis shows that the appearance of a stable limit cycle can be identified.

A composite computational model of liver glucose homeostasis. I. Building the composite model.

A computational model of the glucagon/insulin-driven liver glucohomeostasis function, focusing on the buffering of glucose into glycogen, has been developed. The model exemplifies an 'engineering' approach to modelling in systems biology, and was produced by linking together seven component models of separate aspects of the physiology. The component models use a variety of modelling paradigms and degrees of simplification. Model parameters were determined by an iterative hybrid of fitting to high-scale physiological data, and determination from small-scale in vitro experiments or molecular biological techniques. The component models were not originally designed for inclusion within such a composite model, but were integrated, with modification, using our published modelling software and computational frameworks. This approach facilitates the development of large and complex composite models, although, inevitably, some compromises must be made when composing the individual models. Composite models of this form have not previously been demonstrated.

The effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise.

OBJECTIVES: L-Ornithine has an important role in ammonia metabolism via the urea cycle. This study aimed to examine the effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise. SUBJECTS/METHODS: In all, 14 healthy young adults (age: 22.2±1.0 years, height: 173.5±4.6 cm, body mass: 72.5±12.5 kg) who trained regularly conducted incremental exhaustive ergometer bicycle exercises after -ornithine hydrochloride supplementation (0.1 g/kg, body mass) and placebo conditions with a cross-over design. The exercise time (sec) of the incremental ergometer exercise, exercise intensity at exhaustion (watt), maximal oxygen uptake (ml per kg per min), maximal heart rate (beats per min) and the following serum parameters were measured before ingestion, 1 h after ingestion, just after exhaustion and 15 min after exhaustion: ornithine, ammonia, urea, lactic acid and glutamate. All indices on maximal aerobic capacity showed insignificant differences between both the conditions. RESULTS: Plasma ammonia concentrations just after exhaustion and at 15 min after exhaustion were significantly more with ornithine ingestion than with placebo. Plasma glutamate concentrations were significantly higher after exhaustion with ornithine ingestion than with placebo. CONCLUSIONS: It was suggested that, although the ingestion of L-ornithine hydrochloride before the exercise cannot be expected to improve performance, it does increase the ability to buffer ammonia, both during and after exercise.

Differences and relationships between residual volumes measured on land and in water calculated from estimate equations.

AIM: Residual volume error influences percent body fat estimated by hydrostatic. The aim of this study was to examine the differences and relationships between the residual volumes measured on land and in water and calculated from estimate equations developed in previous studies. PARTICIPANTS: 20 males and 20 females, aged 18-25 years, participated in this study. SETTING: the residual volumes on land and in water without submerging their head were measured twice in each setting. In addition, the residual volume was calculated from 6 estimate equations developed in previous studies. RESULTS: Residual volumes measured on land and in water have very good trial-to-trial reliabilities (intraclass correlation coefficients: <0.98), and high relationships, and did not show a significant difference. It is inferred that their difference is approximately 500 mL, being larger than trial-to-trial error. If we attach great importance to practicability rather than the above error, the residual volume on land can be used. There were no significant differences between measured volumes and those estimated by equation 5 in males and all equations except equation 6 in females. The relationships between measured and estimated residual volumes were poor in males except for equation 4, but were fair in females. Trial-to-trial reliability of residual volumes measured on land and in water is very good, and they have insignificant differences and high relationships. CONCLUSION: Of 6 estimate equations, equation 4 calculated from vital capacity has high accuracy in both sexes.

Comparison of force-time parameters and EMG in static explosive gripping by various exertion conditions: muscle fatigue state and submaximal exertion.

AIM: The purpose of this study was to compare the exertion and electromyography (EMG) properties during the developmental phase (DFmax) in static explosive grip (SEG), rapid submaximal exertion grip, namely fake SEG exertion (FAKE), and SEG in a muscle fatigue state. METHODS: Thirty healthy males and females performed the SEG and FAKE exertions (50% and 75% of peak value as a target value). Then, they performed sustained repeated rhythmic grip for 6 min (30 times x min(-1)), and SEG after 1-min, 4-min, and 7-min (SEG after the exertion). EMG was measured concurrently to compare with the muscle activation property during each grip exertion. Eight force-time parameters evaluating the DFmax in addition to the peak value were selected. RESULTS: The peak value significantly decreased, and the mean power spectrum density shifted to the low-wave in SEG after the exertion as compared with before. Therefore, SEG after the exertion was judged to be a muscle fatigue state. In addition, because the frequency properties in each exertion differed, the muscle activation properties during their DFmaxs were considered to differ. From the comparison between SEG before and after the exertion and FAKE, it is suggested that the time of reaching the peak value and the relative muscle strength when reaching an inflection point are not useful as parameters to evaluate the explosive muscle function during SEG. CONCLUSIONS: The maximal increasing volume during the DFmax and integrated area until 0.25 and 0.5 s could discriminate a difference of the DFmaxs according to each exertion and they are useful parameters.

The characteristics of simple muscle power by gripping: gender differences and reliability of parameters using various loads.

AIM: There are few studies on muscle power during local muscle contractions with a small range of motion such as in gripping. The purposes of this study were to clarify the properties of the developmental phase based on time series of muscle power output, the reliability of the parameters, their relationships and the load intensity derived peak power by gender differences, and to examine the possibility of evaluating muscle power using gripping. METHODS: Fifteen young males and 15 females participated in this study. Based on a crossover experimental design, each subject carried out 2 explosive grips at 20%, 30%, 40% and 50% loads of maximal using a voluntary grip contraction (MVC). The grip contraction velocities, sampled at 100 Hz, were measured accurately using a power instrument with an accelerometer. Muscle power curves were drawn from the product of the velocity and the set-up load. RESULTS: The cross-correlation coefficients between the trials for the average curve of the time-series moving distance, the velocity, and the power in any load were very high (over 0.95) in both genders. The reliability of each parameter was mostly good in both genders (intraclass correlation coefficient, ICC>0.75). The peak power curve differed between genders, and the curve around the peak value in females was irregular. CONCLUSIONS: A gender difference was found in the maximal power and the properties of the power curve. The maximal muscle power appeared at 30-50% MVC in males, and at 20-40% MVC in females. The peak power during the whole contraction, and the time to peak may reflect the conditions throughout the whole of the contraction. The new device used in this study to evaluate local regional muscle power (grip) is a very reliable and useful tool.

Inhibitory effects of aloe carboxypeptidase fraction on streptozotocin-induced enhancement of vascular permeability in the pancreatic islets.

The protective actions of components isolated from Aloe arborescens Miller var. natalensis Berger (Kidachi aloe in Japanese) on streptozotocin (Sz)-induced necrosis of B cells in the pancreatic islets of the mouse were investigated to clarify its action mechanism involved in anti-diabetic effects. In this experiment, phenol low molecular weight components of aloin and aloin A that were anti-oxidants and derived from the leaf skin or pulp extract, an aloe carboxypeptidase fraction that is a inhibitor of enhanced vascular permeability and a glycoprotein component that decreases blood glucose were tested with mice precedently administered with Sz which is known as a cytotoxin specific to B cells. The results showed that the treatment group receiving Sz followed by the aloe carboxypeptidase fraction increased the inhibition of dye leakage by 75.8% (p<0.001) in the extract of whole pancreas in comparison to the control group and the aloe carboxypeptidase fraction group also increased the inhibition effect by 68.4% (p<0.001) in the extract of pancreatic islets as compared to the control group. The carboxypeptidase is an aloe-derived protease known to inhibit the acetic acid-related enhancement of intraperitoneal vascular permeability in mice. Further, the elevation of blood glucose in Sz-induced diabetic mice intraperitoneally given the aloe carboxypeptitase fraction was significantly (p<0.01-0.001) restrained at 3, 7 and 14 days after the injection as compared to the control group given solvent only. The results of this experiment suggested that the inhibitory effect on the enhancement of vascular permeability related to the vascular acute inflammatory response at Sz-induced lesions of pancreatic islets was involved in the action mechanism of this enzyme.

Reliability and gender differences of static explosive grip parameters based on force-time curves.

AIM: The purpose of this study was to examine the reliability and gender differences of static explosive grip (SEG) parameters based on force-time curves. EXPERIMENTAL DESIGN: data were collected from 2 trials of SEG tests on the same day and 2 trials 1 week later. PARTICIPANTS: 50 healthy young males (21.2+/-1.57 yrs) and females (20.1+/-1.18 yrs) participated in this study. MEASURES: 12 variables based on factors such as time-course of force, average force, integrated area, maximal rate of force development, the product of force and inclination and exponential function of force development (EXP-M) were selected as force-time parameters in SEG testing. RESULTS: A significant reliability was obtained for all force-time parameters except the time to 90% of maximal grip strength (MAX), with the reliability of integrated area, average force, maximal rate of force development (DFmax), and the product of force and inclination being particularly high (ICC=0.633-0.930 for the same day, ICC=0.612-0.828 for different days). There were gender differences for all parameters except the time to MAX and EXP-M (p<0.05). In addition, many of the correlation coefficients between parameters were high, particularly for males. The average force, integrated area for 1 sec, and the product of force and inclination during the developmental phase significantly correlated with MAX in both males and females. The ratio between males and females in these force-time parameters was smaller than that of MAX (71.3%). CONCLUSION: It is considered that these parameters are dependent on the speed of muscle contraction. These results suggest that the evaluation parameters, such as average force, integrated area, the product of force and inclination, and maximal rate of force development are useful for evaluating static explosive grip.

Effect of linear polarized near-infrared light irradiation on flexibility of shoulder and ankle joints.

BACKGROUND: There is a possibility that heat stimulus by linear polarized near-infrared light irradiation (PL: Super Lizer HA-30, Tokyo Medical Laboratory) improves the range of joint motion, because the flexibility of soft-part tissues, such as a muscle or a tendon, is improved by increasing the muscle temperature. The purpose of this study was to examine the influence of PL-irradiation on the ranges of shoulder and ankle motions. EXPERIMENTAL DESIGN: 30 healthy young adults (15 males: mean+/-SD, age 19.1+/-0.8 yrs, height 173.3+/-4.6 cm, body mass 68.5+/-8.0 kg and 15 females: mean+/-SD, age 19.2+/-0.7 yrs, height 162.3+/-4.5 cm, body mass 58.1+/-6.6 kg) participated in the experiment under PL-irradiation and no-irradiation (placebo) conditions. MEASURES: the angles of shoulder and ankle joint motions were measured twice, before and after the PL- and placebo-irradiations. The angle of a motion was defined as the angle connecting 3 points at linearity as follows: for the shoulder, the greater trochanter, acromion, and caput ulnare, and for the ankle, the knee joint, fassa of lateral malleolus and metacarpal bone. Each angle was measured when a subject extended or flexed maximally without support. RESULTS: The trial-to-trial reliability of each range of joint motion was very high. All parameters in PL-irradiation were significantly larger in postirradiation than pre-irradiation, and the value of postirradiation in PL-irradiation was significantly greater than that for placebo. The ranges of shoulder and ankle motions in placebo-irradiation were also significantly greater in postirradiation than pre-irradiation. Moreover, the change rate for each range of joint motion between pre- and postirradiations was significantly greater in PL-irradiation in both joints. In PL-irradiation, most subject's motions were greater in postirradiation than pre-irradiation, but not in the placebo-irradiation. The effect of PL-irradiation tended to be greater on subjects with a small range of a joint motion. CONCLUSIONS: It is considered from the present results that the ranges of shoulder and ankle motions became greater with PL-irradiation, and is effective as a warming-up method.

The influence of transient change of total body water on relative body fats based on three bioelectrical impedance analyses methods. Comparison between before and after exercise with sweat loss, and after drinking.

BACKGROUND: The purpose of this study was to clarify the influence of change of total body water caused by exercise and drinking, on relative body fat (%BF) based on three bioelectrical impedance analyses (BIA) methods, between hand and foot (H-F), between hand and hand (H-H), and between foot and foot (F-F). METHODS: The subjects were 30 Japanese healthy young adults aged 18 to 23 years (15 males, 15 females). Measurements were made three times for each BIA method; before and after exercise with sweat, and after drinking, and also twice according to the under water weighing (UW) method, before exercise and after drinking. A pedaling exercise, with a bicycle ergometer, was used for 60 minutes as the exercise. RESULTS: The relationship of %BF between the UW method and each BIA method was mid-range or more (r=0.765-0.839). However, %BF based on the H-F and F-F BIA methods were higher than that based on the UW method. After drinking, %BF of all the BIA methods were higher than the UW method. %BF of the BIA methods after exercise indicated values lower than those before exercise. %BF of the H-F and H-H BIA methods after drinking were a little higher than those before exercise, indicating that those measurements reflect a slight change of body water. CONCLUSIONS: It was demonstrated that %BF of any BIA method reflect the change of body water caused by exercise, sweating, and drinking.

Lateral dominance of legs in maximal muscle power, muscular endurance, and grading ability.

The purpose of this study was to examine lateral dominance in maximal muscle power, muscular endurance, and grading ability, using isokinetic mulscular strength in knee extension and flexion. The subjects were 50 healthy male students whose ages ranged from 19 to 23 years (M height: 173.6+/-6.2 cm, M weight: 67.2+/-6.8 kg). Their dominant legs for power exertion and for functional use were based on questionnaire items selected from those used in previous studies. The angular velocities of extension and flexion for exerting maximal muscle power were 60, 180, and 300 x sec.(-1). A continuous exertion 30 times at an angular velocity of 180 sec.(-1) was used as the load for muscular endurance. For grading ability, 25%, 50% and 75% of the maximal muscle strength at angular velocities of 60 and 180 x sec.(-1) were the required values, and the difference between these values and the exerted muscular strength was evaluated. The dominant leg and nondominant leg were compared for both power exertion and functional use. There was no lateral dominance in maximal muscle power and muscular endurance. In muscular endurance, especially, some subjects showed one leg superior in power exertion and some superior in functional use. Lateral dominance was noted across maximal muscle power and muscular endurance in grading ability. The dominant leg tended to be better than the nondominant leg in functional use. However, lateral dominance was not remarkable for flexing motion and in exertion for a short time.

Effects of food intake and age on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic. Comparison with cefpodoxime proxetil.

The effects of food intake and age on intestinal absorption of AS-924, a novel prodrug-type cephem antibiotic, were examined in 16 healthy adult volunteers (eight young volunteers and eight elderly volunteers) by the cross-over method, using cefpodoxime proxetil (CPOD-PR) as the control drug. The gastrointestinal absorption of AS-924 and CPOD-PR was increased slightly by food intake and the extent of increase was slightly greater after administration of CPOD-PR. The absorption of AS-924 was not affected by age, whereas intestinal absorption of CPOD-PR increased with age. In conclusion, these results confirmed that AS-924 has the unique characteristics as a novel prodrug and that its absorption is less likely to be affected by food intake and age.

Effects of the quantity of water and milk ingested concomitantly with AS-924, a novel ester-type cephem antibiotic, on its pharmacokinetics.

The effect of the quantity of water ingested concomitantly with drugs, on the absorption of AS-924, a novel prodrug-type cephem antibiotic, was studied in five healthy adult volunteers by a cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. In addition, the effect of milk on the absorption of AS-924 was also investigated. The absorption of CTER-PI was significantly reduced when administered together with 30 ml of water compared with its absorption when administered together with 150 ml of water, whereas no such reduction was found in the case of AS-924. Ingestion of milk did not significantly affect the absorption of AS-924. These results confirm that absorption of AS-924 after oral administration is not likely to be affected by the quantity of water taken concomitantly with the drug, nor by milk.

Effect of antacid pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic--comparison with cefteram-pivoxil.

The effect of pretreatment with ranitidine, an antacid, on the absorption of AS-924, a novel prodrug-type cephem antibiotic derived from ceftizoxime (CTIZ), was examined in eight healthy adult male volunteers by the cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. The C(max) and area under the concentration (AUC) values and cumulative urinary excretion rate (0-24 h) of cefteram (CTER) after administration of CTER-PI decreased by 32, 38 and 37%, respectively, in the ranitidine pretreatment group whereas those of AS-924 were not affected by the antacid. The urinary levels of pivaloyl-carnitine determined to evaluate the solubility of these antibiotics in the gastrointestinal tract suggested that this was not affected by ranitidine. These results indicate that the absorption of CTER-PI was affected by pretreatment with ranitidine largely due to inactivation of this antibiotic in the gastrointestinal tract at high pH rather than to a decrease in solubility. In contrast, isomerization of AS-924 was hardly induced by the elevation of pH, thus demonstrating that AS-924 was less likely to be affected by pretreatment with antacids.

Effects of gastrointestinal stimulant and suppressant pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic.

The effects of pretreatment with the gastrointestinal stimulant domperidone and the suppressant scopolamine butylbromide on the absorption of AS-924, a novel prodrug-type cephem antibiotic, were investigated in six healthy adult male volunteers by a cross-over method. The T(max) of ceftizoxime (CTIZ), the active moiety of AS-924, was slightly prolonged by scopolamine butylbromide (T(max)=1.8 vs. 1.5 h for the group without pretreatment). However, there were no significant differences in pharmacokinetic parameters including T(max), cumulative urinary excretion rates of CTIZ and cumulative urinary excretion rates of pivaloylcarnitine for 12 h after the dosing between the pretreated and control groups. Domperidone did not affect the absorption of AS-924.

Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells.

Trace metals influence the absorption of each other from the diet and it has been suggested that the divalent metal transporter (DMT1) represents a common uptake pathway for these important micronutrients. However, compelling evidence from our laboratory suggests that DMT1 is predominantly an iron transporter, with lower affinity for other metals. Several studies have shown that increasing dietary iron downregulates DMT1. Interestingly, our current data indicate that zinc upregulates DMT1 protein and mRNA expression and also pH-dependent iron uptake. Transepithelial flux of iron was also increased and was associated with a rise in IREG1 mRNA expression.

Therapy-related CD7+ acute myeloid leukemia with trisomy 8 following acute monocytic leukemia.

We report a patient who developed CD7+ therapy-related acute myeloid leukemia (t-AML) with trisomy 8 after chemotherapy for AML.

[Successful second transplant from one-locus HLA-mismatched unrelated donor for graft rejection following initial transplant from another unrelated donor in a patient with chronic myelogenous leukemia].

We report a patient with chronic myelogenous leukemia who received a second transplant from a one-locus HLA-mismatched unrelated donor after rejection of an initial bone marrow graft. For the first transplant, HLAs were fully matched, conditioning with busulfan + cyclophosphamide (CY) was applied, and cyclosporin A + short-term methotrexate (sMTX) was used for prophylaxis against GVHD. A complete chimera was not obtained, and the graft was rejected on day 122. For the second transplant, there was a one-HLA locus (DR) mismatch, conditioning was done with total body irradiation + cytarabine + CY, and GVHD prophylaxis consisted of FK506 + sMTX. Engraftment was obtained on day 27, and no graft failure was occurred at the time of writing. This case suggests that strong immunosuppression may have prevented rejection of the second bone marrow graft.