Effects of long-term training on neutrophil function in male university judoists.

OBJECTIVES: To clarify the effects of high-intensity and high-frequency long-term/chronic training on neutrophil function and serum levels of myogenic enzymes in male university judoists. METHODS: The subjects were 24 male judoists who had stopped judo training for 6 months and then restarted their training. The following parameters were examined before and after a 2 h unified exercise loading (UEL) at the beginning of the restarted quotidian training (pre-training) and at 2 months, 4 months and 6 months thereafter: myogenic enzymes, neutrophil and leucocyte counts, and neutrophil phagocytic activity (PA) and oxidative burst activity as a measure of reactive oxygen species (ROS) production capability. RESULTS: Myogenic enzymes that were measured after UEL at all four points significantly increased except for creatine kinase at the 2-month point (p<0.01 in each) and neutrophil counts significantly increased after UEL at the pre-training, 2-month and 4-month points (p<0.01 in each), but these changes became smaller from the 2-month point. PA significantly decreased after UEL at the pre-training and 2-month points (p<0.01 in each), but no change was seen at the 4-month and 6-month points. On the other hand, no change in ROS production per cell after UEL was seen at the pre-training point, but it significantly increased after UEL at the 2-month, 4-month and 6-month points (p<0.01 in each). CONCLUSION: The changing rate of the levels of UEL-mediated myogenic enzymes, neutrophil mobilisation and neutrophil function was seen to decrease at the 2-month, 4-month and 6-month assessments, compared with the pre-training point: these may comprise at least some of the long-term training effects.

Emergence of fluoroquinolone resistance in Campylobacter jejuni in chickens exposed to enrofloxacin treatment at the inherent dosage licensed in Japan.

The objective of the present study was to determine whether selection of fluoroquinolone resistance could be easily induced in Campylobacter jejuni-colonized chickens by treatment with enrofloxacin of representative fluoroquinolones at the inherent dosage licensed in Japan (50 ppm in drinking water for 3 days). In the case of isolates from chickens of study 1, an increase in the population of susceptible isolates appeared after the cessation of treatment and maintained throughout the experiments. On the contrary, our results of study 2 demonstrated that administration of enrofloxacin generated a rapid increase of fluoroquinolone resistance in C. jejuni showing the mutation of Asp-90-Asn in the gyrA gene. Present results indicate that the enrofloxacin treatment for broilers at the inherent dosage is able to select fluoroquinolone resistance in C. jejuni. We conclude that whatever enrofloxacin dosage is used, an emergence of fluoroquinolone resistant of C. jejuni occurs.

Adverse effects of energy restriction on changes in immunoglobulins and complements during weight reduction in judoists.

AIM: A preliminary study to investigate the combined effects of dietary restriction and weight reduction through exercise on markers of immune function in college judoists before and after a single competition. METHODS: Forty-nine judoists participated in the study. Thirty-eight athletes combined exercise and dietary restriction (WR group), and 11 athletes did not require dietary restriction (EX group). Changes in anthropometric parameters, energy intake, concentrations of serum immunoglobulins and complements, and white blood cell counts were assessed at 4 time points: 20 days (pre-values), 4 days and 1 day before the competition, and 7 days after the competition. RESULTS: Compared with pre-values, the WR group exhibited significant decreases in body weight (-2.8 kg at 1 day before) and fat free mass (-1.7 kg at 1 day before); there were no changes in these variables in the EX group. The WR group exhibited significant decreases in IgG, IgM and C3 at 7 days after the competition (all p<0.01). In the EX group, significant decreases in IgM and C3 (both p<0.05) were observed at 7 days after the competition, though to a lesser degree than in the WR group. CONCLUSIONS: Energy restriction seemed to exacerbate alterations in immune markers such as immunoglobulin and complement induced by vigorous exercise at 7 days after a competition. Although the changed values were still within normal limits, we hypothesize that the potential cumulative effect of these changes over many competitions in 1 year might well induce abnormal levels with a possibly harmful clinical effect on judoists.

Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C.

We evaluated the synergistic effect of zinc supplementation on the response to interferon (IFN) therapy in patients with intractable chronic hepatitis C in a pilot study using natural IFN-alpha with or without zinc. No clinical differences were observed between patients treated with IFN alone (n=40) and IFN with polaprezinc (IFN + Zn, n=35). All patients were positive for HCV genotype Ib and had more than 105 copies of the virus/mL serum. Ten million units of natural IFN-alpha was administered daily for 4 weeks followed by the same dose every other day for 20 weeks. In the IFN + Zn group, patients received an additional dose of 150 mg/day polaprezinc orally throughout the 24-week IFN course. No additional side-effects of polaprezinc were noted but four out of 40 IFN alone treatment and three out of 35 IFN + Zn group withdrew because of side-effects. Complete response (CR) was defined as negative HCV RNA in the serum on PCR and normal aminotransferase level 6 months after therapy. Incomplete response (IR) was normal liver enzyme and positive serum HCV RNA. Both of them were evaluated at the 6 months after the completion of the treatment. Patients with higher levels of serum HCV (more than 5 x 105 copies/mL) had little response in both treatment groups. Patients with moderate amount of HCV (105 to 4.99 x 105/mL) showed high response rates in combination group (CR: 11/27, 40.7%; CR + IR 15/27, 64.3%), better than IFN alone (CR: 2/15, 18.2%; CR + IR: 2/15, 18.2%). Serum zinc levels were higher in patients with IFN + Zn group than in the IFN group. Our results indicate that zinc supplementation enhances the response to interferon therapy in patients with intractable chronic hepatitis C.

Growth inhibitory effect of green tea extract and (-)-epigallocatechin in Ehrlich ascites tumor cells involves a cellular thiol-dependent activation of mitogenic-activated protein kinases.

The effect of green tea extract (GTE) in Ehrlich ascites tumor cells (EATC) was studied with respect to changes in the intracellular kinase system involving mitogen-activated protein kinases (MAPKs) and cellular thiol. We have previously shown a reduction in viability of EATC and tyrosine phosphorylation of 42 and 45 kDa proteins by GTE and its polyphenolic component, Epigallocatechin (EGC) (D.O. Kennedy, S. Nishimura, T. Hasuma, Y. Yoshihisa, S. Otani, I. Matsui-Yuasa, Involvement of protein tyrosine phosphorylation in the effect of green tea polyphenols on Ehrlich ascites tumor cells in vitro, Chem. Biol. Interact. 110 (1998) 159-172). Furthermore, GTE and EGC significantly decreased both cellular non-protein and protein sulfhydryl levels in EATC, but replenishing thiol stores with N-acetylcysteine (NAC) caused a recovery in cell viability, and therefore SH groups were identified as a novel target of green tea cytotoxicity (D.O. Kennedy, M. Matsumoto, A. Kojima, I. Matsui-Yuasa, Cellular thiol status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells, Chem. Biol. Interact. 122 (1999) 59-71). In this study, we have observed the stimulation of three forms of MAPK, namely ERK1/2, JNK/SAPK and p38, by EGC, which were dose and time-dependent. These MAPK stimulations were found to be cellular thiol status-dependent events as NAC reversed these stimulations. Furthermore, inhibition of the p38 MAPK pathway using the p38 inhibitor SB203580 caused a marked dose-dependent reduction in the decrease in cell viability caused by EGC treatment. Inhibiting the Erk1/2 MAPK pathway using the MEK inhibitor PD098059 caused a slight change in the decrease in cell viability by EGC. These may suggest that the cytotoxicity associated with EGC was more associated with the other MAPKs than with ERK1/2. This may be the first study of its kind providing a novel evidence of a role for different forms of MAPKs in the antitumor effect of green tea polyphenols, especially EGC, in Ehrlich ascites tumor cells.

Growth inhibitory effect of green tea extract in Ehrlich ascites tumor cells involves cytochrome c release and caspase activation.

We reported previously that the mechanism by which Green tea extract (GTE) elicited growth-inhibitory effects in Ehrlich ascites tumor cells involved a decrease in ornithine decarboxylase (ODC) activity and in cell viability. Decrease in ODC activity has been associated with apoptotic cell death and we therefore studied changes in cytochrome c release and caspase activation, which characterize apoptosis. GTE caused a dose- and time-dependent increase in caspase-3-like protease activation, preceded by a release of cytochrome c from the mitochondria. Inhibiting the activation of caspase-3 with acetyl-Asp-Glu-Val-Asp-alpha-aldehyde (caspase inhibitor) caused a reversal in the effect on cell viability.

Cellular thiols status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells.

Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans, and also breast and prostate cancers in animal models are reduced by green tea, and several mechanisms have been proposed for these effects. In this study the relationship between cellular sulfhydryl (SH) groups and the cytotoxicity of green tea polyphenols in Ehrlich ascites tumor cells was examined. It was found that in the presence of green tea extract (GTE) (100 microg/ml) and one of its polyphenolic components, epigallocatechin (EGC; 100 microM), both cellular non-protein (GSH) and protein-sulfhydryl (PSH) levels were significantly decreased and this was associated with a decrease in cell viability. Replenishing the thiol levels by using N-acetylcysteine (NAC) caused a recovery in cell viability, but this recovery was dependent on the time of thiol replenishment in the presence of EGC (initial 15 min). These results identify SH groups as a novel target of green tea polyphenols cytotoxicity in tumor cells, and a regulatory role for green tea in terms of reducing sulfhydryls in tumor inhibition.

Nausea and vomiting induced by arterial chemo-embolization in patients with hepatocellular carcinoma and the antiemetic effect of ondansetron hydrochloride.

To determine the incidence of nausea and vomiting and the antiemetic effect of ondansetron hydrochloride (OND) in patients with hepatocellular carcinoma treated with arterial chemo-embolization, we studied 59 patients with hepatocellular carcinoma who were treated with transcatheter arterial embolization (TAE) or lipiodolized transcatheter arterial infusion (L-TAI). We investigated the incidence of nausea and vomiting and the amount of food intake when TAE or L-TAI was performed. All patients who experienced nausea and vomiting received OND administered prophylactically at the time of the next TAE or L-TAI to evaluate the antiemetic effect of the drug. Cumulative rates of nausea and vomiting during the week following arterial chemo-embolization were 44.8% and 27.6%, respectively. There was a tendency for the incidence to be higher in patients treated with the anticancer agent zinostatin stimalamer (SMANCS) than in those treated with epirubicin hydrochloride (EPI). Regarding food intake, 53.1% of the patients stated that they ate "half or more than half" of the food provided on the day of arterial chemo-embolization. The rate improved as time went on. In 5 patients who experienced nausea and vomiting at the time of arterial chemo-embolization, nausea and vomiting were inhibited satisfactorily by OND. When arterial chemo-embolization was performed, antiemetic treatment for approximately 3 days was necessary to improve patients' quality of life (QOL) to an acceptable level, and OND was found to be effective for the purpose in our 5 patients who had experienced nausea and/or vomiting at the previous treatment.

An extract of Gymnema sylvestre leaves and purified gymnemic acid inhibits glucose-stimulated gastric inhibitory peptide secretion in rats.

Gastric inhibitory peptide release into the portal vein in response to duodenal infusion of D-glucose was studied in the presence of a leaf extract of Gymnema sylvestre, purified gymnemic acid and inhibitors of some putative glucose sensors and carriers in the intestinal lumen. Intraduodenal infusion of D-glucose significantly increased the portal immunoreactive gastric inhibitory peptide concentration in a dose-dependent manner. The increase in the portal immunoreactive gastric inhibitory peptide induced by glucose was significantly depressed by concomitantly infused leaf extract of Gymnema sylvestre, purified gymnemic acid and phlorizin but not by cytochalasin B. Mannoheptulose, which inhibits glycolysis, and procaine and lidocaine, which inhibit the vagal glucoreceptor in the lumen, did not affect portal immunoreactive gastric inhibitory peptide concentrations. These results suggest that a glucose receptor, which interacts with the leaf extract of Gymnema sylvestre, purified gymnemic acid and phlorizin, exists for the release of immunoreactive gastric inhibitory peptide and that the glucose receptor for gastric inhibitory peptide release is not likely to be identical with a glucose transporter or a vagal glucoreceptor in the lumen.

Negative phase II study of 5-fluorouracil with high-dose leucovorin in non-small cell lung cancer.

Fourteen patients with inoperable or recurrent non-small cell lung cancer (NSCLC) were treated with 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). The administration schedule was 2 h infusion of LV at a dose of 500 mg/m2 and 30 min infusion of 5-FU at a dose of 600 mg/m2 given 1 h after the start of the LV infusion. This regimen was followed weekly, six times. No objective (complete or partial) response was seen in any of the patients. Ten patients showed no change and there were four with progressive disease. One patient experienced grade 3 leukopenia after two courses of treatment. Another experienced grade 2 leukopenia. One patient experienced grade 2 vomiting and six, skin pigmentation. Other myelosuppressive effects and non-hematologic toxicities, including diarrhea and mucositis, were mild. It was concluded that the schedule of 5-FU with high-dose LV therapy employed could not be expected to produce a response rate greater than or equal to 20% against NSCLC. 5-FU plus high-dose LV therapy was, therefore, considered to be ineffective against NSCLC with the schedule of administration followed.

[Combined treatment of irradiation and 8 MHz radiofrequency hyperthermia with chemoembolization in advanced renal tumor].

A combined treatment of irradiation and 8 MHz radiofrequency hyperthermia after chemoembolization, using 20 mg of microencapsulated mitomycin C (MMC.mc), was undertaken in a patient with an advanced left renal tumor. The patient, a 70-year-old man, noticed a gross hematuria in February, 1984. CT showed a left renal tumor, 88 X 70 mm in size. Histological examination revealed clear cell carcinoma of the left kidney. The tumor was unresectable because of an invasion into the surrounding tissues. Chemoembolization was performed before the combined treatment of irradiation and hyperthermia. He received 23.2 Gy of irradiation and 10 sessions of hyperthermia. Intratumoral temperature reached 42.6 degrees C during the heating. After treatment, there was a tumor regression rate of 58%, as well as pain relief, and an improvement in his appetite loss. He died 8 months after this treatment. An autopsy specimen revealed bionecrotic tumor cells among the prominent necrotic and fibrotic tissues.

Effects of propranolol and nifedipine on exercise-induced attack in patients variant angina: assessment by exercise thallium-201 myocardial scintigraphy with quantitative rotational tomography.

To examine the effects of propranolol and nifedipine on exercise-induced attack in patients with variant angina, exercise 201Tl myocardial scintigraphy with quantitative analysis by emission-computed tomography was performed in 20 patients with variant angina after oral propranolol (80 mg), nifedipine (20 mg), and placebo. Exercise-induced attack occurred in 11 patients on placebo, in 14 on propranolol, and in none on nifedipine. The exercise duration was significantly shorter in those on propranolol (p less than .05), but significantly longer in patients on nifedipine (p less than .05) than in those on placebo. The peak rate-pressure product was significantly lower in patients on propranolol (p less than .01), but did not change in those on nifedipine, as compared with that in patients on placebo. The size of the perfusion defect as measured by 201Tl tomography was significantly greater in patients on propranolol (p less than .05), but significantly less in those on nifedipine (p less than .01) than in those on placebo. In conclusion, propranolol does not suppress but rather may aggravate exercise-induced attack in patients with variant angina, while nifedipine suppresses it. This unfavorable effect of propranolol on exercise-induced attack in patients with variant angina is likely to be due to a reduction of regional myocardial blood flow.

Effects of excess iodide and other anions on thyroid hormone secretion in normal or hypophysectomized rats treated with graded doses of thyroid hormone.

In order to obtain further information about the stimulatory action of excess iodide on thyroid hormone secretion in thyroxine (T4)-treated rats, experiments were performed in hypophysectomized rats, or rats treated with graded doses of T4 or triiodothyronine (T3).T3 as well as T4 played a permissive role in the production of the iodide effect in normal animals, but T3 was more effective than T4. Excess iodide stimulated thyroid hormone secretion in hypophysectomized animals, this finding being compatible with the hypothesis that, by inhibiting TSH secretion, T3 and T4 produced a condition in which excess iodide stimulated thyroid hormone secretion in intact rats. However, T4 played an additional role in thyroid hormone secretion by acting directly on the thyroid. In hypophysectomized animals, small doses of T4 stimulated thyroid hormone secretion, and this action was additive to that of excess iodide, whereas large doses of T4 were inhibitory and reduced the effectiveness of excess iodide. The stimulatory action on thyroid hormone secretion was specific for iodide and was not shared by other anions. The action of excess iodide was blocked by methimazole. We suggest that excess iodide stimulates thyroid hormone secretion by increasing intrathyroidal concentrations of cyclic AMP in the absence of TSH, and that this increase in cyclic AMP concentration is blocked by methimazole.

Abnormal thyroid function in spontaneously hypertensive rats.

Thyroid weight, thyroidal radioiodide uptake, and cyclic AMP-dependent protein kinase activity of a thyroid supernatant fraction were increased significantly in spontaneously hypertensive rats (SHR), apparently because of increased secretion of pituitary TSH. However, the thyroids of SHR did not make supernormal amounts of thyroxine (T4), and thyroidal radioiodine release was apparently impaired. In the SHR, proteolytic enzyme activity was less than normal and the thyroglobulin was more resistant to normal proteolytic enzyme than was control thyroglobulin. Presumably because of these abnormalities, plasma T4 was significantly lower than normal, but triiodothyronine (T4) was normal, as a result of compensatory processes occurring in T3 synthesis and hydrolysis of thyroglobulin. T4 and T3 were less effective in depressing pituitary TSH synthesis and secretion in SHR than in controls, possibly because of an abnormal setting of the "hormostat." Although the hypothalamic content of TRH was normal in SHR, the exact site of the abnormality in the "hormostat" is not delineated in the present study.