Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer.

BACKGROUND: In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity. METHODS: S-1 was given orally at a dose of 80 mg/m(2)/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity. RESULTS: We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1 months, and median overall survival (OS) was 11.2 months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P = 0.0288). Median PFS was 4.8 and 2.5 months (P = 0.038), and median OS was 22.4 and 8.4 months (P = 0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients. CONCLUSIONS: S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.

Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial.

BACKGROUND: Interferon therapy decreases the incidence of hepatocellular carcinoma in patients with chronic hepatitis C. OBJECTIVE: To evaluate effects of interferon-alpha on recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. DESIGN: Randomized, controlled trial. SETTING: University hospital, medical center, and affiliated hospital in Osaka, Japan. PATIENTS: 30 men were randomly allocated after resection to the interferon-alpha group (n = 15) or the control group (n = 15). INTERVENTION: Patients in the interferon-alpha group received interferon-alpha, 6 MIU intramuscularly daily for 2 weeks, then three times weekly for 14 weeks, and finally twice weekly for 88 weeks. MEASUREMENTS: Recurrence rates after resection. RESULTS: Recurrent tumors were detected in 5 patients in the interferon-alpha group and in 12 control patients. The recurrence rate was significantly lower in the interferon-alpha group than in the control group (P = 0.037). CONCLUSION: Postoperative interferon-alpha therapy appears to decrease recurrence after resection of hepatitis C virus-related hepatocellular carcinoma.

Mixed longitudinal study (6 years) of bone mineral density, muscle mass and muscle strength in the leg of aged females--relations to gravitational load and aging.

NASA: Researchers examined the relationship between changes in physiological function in space and aging in older females. The hypotheses were that some of the changes may be due to a decrease in gravitational stimulation, but that some could be caused by aging itself. Data are based on a mixed longitudinal research study performed in aged females since 1995.^ieng

Effect of long-term bedrest on lower leg muscle activation patterns during quiet standing.

It has been well known that balance instabilities after long-term exposure to microgravity (e.g., Anderson et al. 1986) or bedrest (BR) can be related to alterations and/or adaptations to postural control strategies. Little is known, however, how the reduced muscular activity affects the activation pattern of the lower limb muscles during quiet standing (QS). The purpose of this study was to investigate whether or not any changes in the lower limb muscle activation patterns during QS would occur after BR.

Suppressive effects of genistein dosage and resistance exercise on bone loss in ovariectomized rats.

This study was designed to determine whether combined treatments with genistein dosage and moderate resistance exercise would exhibit synergistically preventive effects on bone loss following the onset of menopause. Forty-one 12 wk-old female SD rats were assigned to five groups: 1) Sham operated (Sham); 2) ovariectomized (OVX-Cont); 3) OVX received genistein (OVX-GEN); 4) OVX exercised (OVX-EXE); and 5) OVX treated with both genistein and exercise (OVX-GEN-EXE). All rats were fed a low Ca (0.1%) diet ad libitum. Daily genistein dosage was 12 mg/kg body weight. Exercising rats took 40 sets of 1-min run interspersed with 1-min rest with a 100 g weight on the back on an uphill treadmill at 20 m/min. The experimental duration consisted of the adaptation and treatment periods of 4 weeks each. Uterine weight in OVX-Cont, OVX-GEN, OVX-EXE and OVX-GEN-EXE decreased to about 15% of that in Sham (p < 0.001). The femoral BMD (mg/cm2; mean +/- SE), assessed by DEXA (Lunar), of OVX-Cont was significantly lowered to 206 +/- 5 by -9%, as compared to 226 +/- 2 of Sham (p < 0.001). The BMD of OVX-GEN, OVX-EXE and OVX-GEN-EXE were 217 +/- 2, 217 +/- 2 and 222 +/- 2, respectively, and genistein dosage and resistance exercise equally increased the BMD of OVX rats by 5% (p < 0.01). Combined treatment of genistein and exercise more successfully recovered their decreased BMD by 8% (p < 0.001). BMD of the fourth lumbar vertebrae in OVX-Cont was declined to 191 +/- 7 by -15%, as compared to 225 +/- 4 in Sham (p < 0.001). OVX-EXE and OVX-GEN-EXE gained the BMD by 6% to 205 +/- 4 and 203 +/- 3, respectively, as compared to that of OVX-Cont (p < 0.01). These results suggest the possibility that the combined treatment of genistein dosage and resistance exercise have more beneficial effects by acting rather independently than their separate trials on the prevention of ovx-induced bone loss in femurs.

Soluble dietary fibre improves insulin sensitivity by increasing muscle GLUT-4 content in stroke-prone spontaneously hypertensive rats.

1. The effects of soluble dietary fibre (psyllium) on peripheral insulin sensitivity and skeletal muscle GLUT-4 protein expression were studied in 12 male stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-caloric diet from 5 to 9 weeks of age. 2. In the psyllium-supplemented group, fasting plasma glucose was significantly reduced and glucose levels following an oral glucose tolerance test were significantly lower than in the cellulose-supplemented group at 30 (P < 0.05) and 60 min (P < 0.01). However, there was no difference in insulin secretion. 3. In the psyllium-supplemented group, skeletal muscle GLUT-4 content was significantly increased in the plasma membrane (P < 0.001), but not in the intracellular membrane. 4. No significant difference was found in phosphatidylinositol 3 (PI3)-kinase activity between cellulose and psyllium diet not only in the basal state but also when stimulated by insulin. 5. These results demonstrate that psyllium increases blood glucose disposal by increasing skeletal muscle plasma membrane GLUT-4 content without PI3-kinase activation.

Prolonged swimming exercise training induce hypophosphatemic osteopenia in stroke-prone spontaneously hypertensive rats (SHRSP).

Stroke-prone spontaneously hypertensive rats (SHRSP) induce spontaneous osteoporosis. To elucidate the specific characteristics of bone metabolism, the SHRSP was compared with age matched Wistar-Kyoto (WKY) rats. We investigated the effects of prolonged swimming exercise training on bone mineral density (BMD) and metabolism in the SHRSP. Seven-week-old male SHRSP and WKY were divided into three groups; the sedentary control WKY group (n = 6, WKY), the sedentary control SHRSP group (n = 6, SP) and the swimming exercise training SHRSP group (n = 6, SWIM) (in pool with 60 min./day, 5 days/week for 12 weeks). The femoral BMD, bone mineral content (BMC), strength, Ca and P contents (%) of SHRSP were approximately 17, 27, 25, 20 and 9%, respectively, lower than that of WKY (p < 0.001). Serum alkaline phosphatase (AlP) had not changed between both of SP and WKY, but tartrate-resistant acid phosphatase (TrAcP) of SP approximately 3-fold higher than that of WKY (p < 0.05). Both serum calcium (Ca) and intact parathyroid hormone (i-PTH) were similar between SP and WKY. However, serum phosphate (P) of SP was approximately 18% lower than that of WKY (N.S.). These results suggested that SHRSP induces osteopenia by the bone turnover of the promoted osteoclast activity with disturbed phosphate homeostasis. On the other hand, the femoral BMD and strength were approximately 7% and 20%, respectively, decreased in the SWIM (p < 0.001), and femoral bone Ca and P contents (%) were also approximately 11% and 14%, respectively, lower than that of SP (p < 0.001). There were no significant difference between SWIM and SP on serum Ca, but serum P of SWIM was significantly lower than that of SP (p < 0.05). These results suggested that the prolonged swimming exercise training in the SHRSP induces more cruelly hypophosphatemia, and leading to osteopenia eventually. We conclude that SHRSP induces osteopenia with disturbance of phosphate homeostasis, and the prolonged swimming exercise in the SHRSP might deteriorate hypophosphatemia and osteopenia.

H-reflex and motor evoked potential changes during head down bed rest.

The purpose of the present study was to investigate effect of un-loading lower limb on H-reflex and motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) during bed rest.

Training in swimming reduces blood pressure and increases muscle glucose transport activity as well as GLUT4 contents in stroke-prone spontaneously hypertensive rats.

Exercise improves muscle insulin sensitivity and GLUT4 contents. We investigated the beneficial effects of swimming training on insulin sensitivity and genetic hypertension using stroke-prone hypertensive rats (SHRSP). We studied the relationship between genetic hypertension and insulin resistance in SHRSP and Wistar Kyoto rats (WKY) as a control. The systolic blood pressure of SHRSP was significantly reduced by 4-week swimming training (208.4 +/- 6.8 mmHg vs. 187.2 +/- 4.1 mmHg, p < 0.05). The swimming training also resulted in an approximately 20% increase in the insulin-stimulated glucose transport activity (p < 0.05) of soleus muscle strips and an approximately 3-fold increase in the plasma membrane GLUT4 protein expression (p < 0.01) in SHRSP. However, basal and insulin-stimulated glucose transport activity and GLUT4 contents were not significantly different between WKY and SHRSP. There was no difference in insulin resistance in skeletal muscle of SHRSP as compared with WKY. Our results indicated swimming training exercise improved not only hypertension but also muscle insulin sensitivity and GLUT4 protein expression in SHRSP.

Effect of bed rest immobilization on metabolic turnover of bone and bone mineral density.

Immobilization induces abnormal bone metabolism and severe decalcification of bone. To investigate the effect of middle-term immobilization on bone metabolism, we studied 10 young healthy males and females during bed rest for 20 days. Bone mineral density (BMD) rapidly decreased in both lumbar and metacarpal bones. No bone showed consistent BMD alterations, partial increase and partial decrease, and both lumbar and metacarpal bone showed similar rapid BMD change. Urinary excretion of pyridinoline tended to slightly increase by day 10, and to decline by day 20 (mean +/-SE: 34.2 +/-7.4, 26.3+/-4.6 nmol day-1, respectively). Neither alkaline phosphatase (isoform III) nor tartrate-resistant acid phosphatase, changed, suggesting that in the early stage of immobilization bone matrix in some part might increase or be resorbed without any activation of osteoblast or osteoclast, resulting in rapid calcification or decalcification, respectively.

Antioxidant enzymes response to endurance exercise training and dietary proteins in rat skeletal muscle and liver.

This study was conducted to observe the effects of endurance exercise training on antioxidant enzyme activity in the liver and gastrocnemius muscle of rats being fed dietary casein and soy protein. The respective influences of dietary casein and soy protein on the activity of antioxidant enzymes were also compared. Thirty-nine male Wistar rats, aged 3 weeks, were randomly assigned to six groups: a normal protein control group, a normal protein endurance training group, a casein protein control group, a casein protein endurance training group, a soy protein control group, and a soy protein endurance training group. The endurance exercise training groups were adapted to a treadmill for 2 weeks prior to the date the rats were forced to run for 60 min at 25 m/min, 5 days/week for 12 weeks. We found that antioxidant enzyme activity in the gastrocnemius muscle was neither effected by the dietary proteins (casein and soy protein) nor by the above endurance exercise training load. However, hepatic Cu,Zn-SOD activity increased significantly for the dietary casein and soy protein diet groups as compared with the normal protein diet group (P < 0.01). Furthermore, significant increases both in hepatic Cu,Zn-SOD activity in the normal protein group and hepatic GSHpx activity in the casein and soy protein groups were observed when rats were loaded with 25 m/min of endurance exercise training (P < 0.01). These results suggest that, under the above experimental conditions, a casein or soy protein diet increase hepatic Cu,Zn-SOD activity, while endurance exercise training is effective in increasing hepatic Cu;Zn-SOD activity on a normal protein diet and in increasing hepatic GSHpx activity for cysteine and methionine deficient diets.

Decrease of bone mineral density and muscle and/or strength in the leg during 20 days horizontal bed rest.

NASA: Ten individuals underwent 20 days of horizontal bed rest for this study of the influence of muscle mass and strength on bone mineral density. Muscle mass volume and cross sectional area were measured using magnetic resonance imaging and bone mineral density was determined by dual energy X-ray absorptiometry before and after bed rest. Measurements were made at various parts of the leg, including the knee. Gender differences were also determined. Results are presented and discussed.^ieng

Systemic arterial blood pressure responses of stroke-prone spontaneously hypertensive rats to treadmill exercise.

The present study was undertaken to compare the systemic blood pressure responses during graded acute exercise of stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Systemic blood pressure was measured by left carotid artery catheter during exercise. Systolic blood pressure incre-ments with running exercises at 10, 15, and 20 m/min were significantly greater in SHRSP than in WKY. Diastolic blood pressure increments with exercise were singnificantly greater only at 20 m/min in SHRSP compared to WKY. This study suggests that the blood pressure response to exercise is accentuated in SHRSP.

Effects of 20 days bed rest on mechanical efficiency during upright cycling and leg muscle mass in young males.

Delta efficiency defined as increase in work over the corresponding increase in energy liberation (delta work/delta energy) may be used to express the efficiency of working muscles under standard conditions where work is performed with similar changes in muscle length, identical pedal revolution frequencies, and contraction-to-relaxation ratios. The Delta efficiency is probably the most valid measure of the efficiency of muscular work, so it may be influenced by the difference in distribution and/or density of muscle fiber types in exercising muscles. It has been reported that after bed rest of 7-14 days, not only maximum oxygen uptake (VO2 max) but also oxygen uptake (VO2) at 3-min submaximal upright exercise decreased. However, the decrease might be apparent, and the mechanical efficiency might be unchanged. On the other hand, muscle mass of bicycling legs was decreased after continuous horizontal bed rest of 10 days and 20 days. Because the decreased muscle mass is probably related to decrease in the density of the slow twitch muscle fibers (ST-fiber), the decrease in submaximal VO2 during bicycle exercises after bed rest may result from a decrease in ST-fiber mass. Therefore, it could be hypothesized that the mechanical efficiency should increase during upright exercise because of the relative increase in amount of more efficient fast twitch muscle fibers (FT-fiber) than ST fibers in exercising muscles. The purpose of the present study was to investigate whether delta efficiency in working muscle is influenced by the decrease in muscle mass after 20 days horizontal bed rest in young males.

Case of possible true aneurysm of the posterior tibial artery.

A 37-year-old man with a possible true aneurysm of the posterior tibial artery is reported. Only four cases of true aneurysm of the posterior tibial artery were reported in the English literature but none reported in Japan.

[Warming-up under cold environment].

Warming up procedures in the many antecedent reports, are almost under normal ambient temperature and they do not treat the warming up under low temperature. The purpose of this study was to investigate the effects of warming up by intensity and time in submaximal treadmill exercise (90% VO2max intensity during 10 minutes) on physiological parameters under cold environment in climate chamber (room temperature: 10 degrees C, relative humidity: 70%, wind velocity: under 0.2 m/sec). Eight trained collegiate basic skiers performed main exercise for 5 minutes after the following warming up conditions: NoW-up (no warming up), W50-15 (50% VO2max intensity 15 minutes), W70-15(70% VO2max intensity 15 minutes), W50-30(50% VO2max intensity 30 minutes) or W70-30(70% VO2max intensity 30 minutes). It was concluded that the most effective intensity and time of warming up in these conditions were 50% VO2max intensity and 30 minutes duration, that is, rather low intensity and longer duration time. It was suggested that a warming up with a high intensity and short duration was effectless under cold.

[Case of primary aorto-jejunal fistula caused by gram-positive cocci].

A 46 year-old man was transferred to our department with a pulsating abdominal mass and back pain. On arrival he suddenly developed hematemesis. CT suggested the presence of an infrarenal aortic aneurysm and the jejunum was filled with contrast medium. An emergency operation was done. We found an aorto-jejunal fistula at the branching point of the renal artery. We directly sutured the aortic wall laceration and the jejunum wall in two layers. Then we resected infrarenal pseudoaneurysm as completely as possible, with replacement by a Dacron Y-shaped prosthesis. Culture of the aortic wall showed gram-positive cocci, but the species could not be identified. Gram stain of the aortic wall also showed infection by gram-positive cocci. The patient is alive and well 3 months after surgery.

[Effects of rapid weight reduction diet on protein metabolism and physical performance].

The purpose of this study was to provide information on the requirement of nutrition, especially of the protein during rapid weight reduction immediately before a competition of a weight-classification system sport, boxing. Weight reduction period was 9 days. Subjects were divided into three groups of free diet group (group A: n = 5), high protein diet group (group B: n = 5) and ordinary protein diet group (group C: n = 4). Group A had taken food ad libitum. Group B had taken 2.0 g/kg/day of protein in the first half and 1.5 g/kg/day of protein in the second half of weight reduction period, and Group C had taken 1.0 g/kg/day of protein throughout weight reduction period. Groups B and C had taken 2,000 kcal/day in the first half and 1,200 kcal/day in the second half of weight reduction period. Anthropometry and nutritional investigation were performed, and urine components were analyzed. The main results obtained were as follows: 1) Calorie and protein intake in Group A averaged 883 kcal/day and 0.9 g/kg/day in the second half of weight reduction period. 2) 3-methylhistidine and urea nitrogen in urine and 3-Me/Cr increased significantly at the end of weight reduction period in Group A, but decreased significantly in groups B and C. Nitrogen balance changed to a negative value only in group A. Differences in each of urine components were statistically significant between group A and the other two groups at the end of period. 3) Heart rate and oxygen intake at the same submaximal work load increased significantly in group A at the end of weight reduction period, but in groups B and C no noticeable changes were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Minerals in plasma and urine and gustatory function tests for salt in a group of healthy young men.

Detection threshold for salt (NaCl) and discrimination between two levels of NaCl concentration (0.6 and 0.7%) in foods, and their relation to some selected biochemical parameters in plasma and urine (Zn, Na, K, Mg, Ca, Se for plasma and urine, Cu and retinol binding protein for plasma) were investigated in 15 healthy male college students. No subject failed to discriminate the NaCl concentrations in more than 50% of the tests. The rate of correct discrimination (RCD) was not associated with plasma Zn (P-Zn), plasma retinol binding protein (P-RBP), urinary potassium (U-K) or urinary sodium (U-Na), which significantly correlated with RCD in our previous study, while the detection threshold was significantly correlated with urinary Ca-Mg ratio (U-Ca/Mg), urinary Ca (U-Ca), U-Na, and urinary Mg. In the stepwise multiple regression analysis, U-Ca/Mg, plasma Ca, plasma Na, and RCD were selected as significant independent variables. These indicate that the status of minerals such as Na, Ca, and Mg is related to the gustatory function. One possible explanation for the discrepancy between the present and previous results is the elevated P-Zn and P-RBP levels in the present subjects.