Acute effects of ethanol on feeding behavior and leptin-induced STAT3 phosphorylation in rat hypothalamus.

OBJECTIVE: Drinking ethanol stimulates the appetite, producing a positive energy balance. The mechanism by which ethanol regulates the appetite in the central nervous system, however, has not been fully understood. The aim of this study is to investigate the interaction of ethanol with the satiety effect of leptin, a hormone which suppresses the appetite in the hypothalamic region. DESIGN: : Leptin (7.5 micro g) or the same dose of phosphate buffer saline (PBS) was administered into the third ventricle (i.c.v.), 30 min after an intraperitoneal injection (i.p.) of ethanol (0.5 g/kg body weight) or the same dose of PBS. MATERIALS: Adult male Sprague-Dawley rats weighing 290-320 g were used. MEASUREMENTS: Food intake was measured 2, 12 and 24 h after leptin i.c.v. infusion. The tyrosine phosphorylation of signal transducer and activator transcription factor 3 (STAT3) in the hypothalamus was analyzed by Western blotting. RESULTS: The cumulative food intakes in the saline/leptin group (saline i.p.+leptin i.c.v.) were markedly reduced to about 45% of the saline/PBS group (saline i.p.+PBS i.c.v.) at 2, 12 and 24 h time points (P<0.05, 0.001, and 0.005, respectively). As compared with the saline/leptin group, those of the ethanol/leptin group (ethanol i.p.+leptin i.c.v.) were significantly increased to the level seen in the saline/PBS group at 12 and 24 h time points (P<0.05, and P<0.005 vs the saline/leptin group, respectively). Ethanol administration resulted in about a 50% reduction of the leptin-induced STAT3 tyrosine phosphorylation seen in the hypothalamic protein as compared to that of the saline/leptin group. CONCLUSION: These findings suggest that ethanol-induced enhancement of the appetite may, in part, result from leptin resistance transiently caused by ethanol to attenuate the leptin signal transduction.

Early morning surge in blood pressure.

Early-morning blood pressure is generally viewed as an important therapeutic target, for two reasons. First, for antihypertensive agents taken once daily in the morning, the timing of the trough plasma drug level, and thereby the lowest pharmacodynamic effect, often coincides with the early morning rise in blood pressure and heart rate. Evidence has been accumulated to suggest that blood pressure control throughout the 24 h period may be necessary to gain complete benefit from antihypertensive medication. In fact, in a longitudinal study, the regression of cardiac hypertrophy in patients with hypertension was more accurately predicted by treatment-induced changes in average 24 h ambulatory blood pressure than by clinic or home-monitored blood pressure readings. The other reason for the importance of morning blood pressure is that cardiovascular risk is heightened at this time of day. A morning surge in sympathetic activity alters haemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. At the same time as this risk of plaque rupture is greatest, circadian variations in haemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting the formation of intraluminal thrombi. We recently showed that, in older hypertensives, a greater morning blood pressure surge, mediated at least in part by an exaggerated alpha-sympathetic activity, is associated with more advanced silent cerebrovascular disease as well as a higher future incidence of stroke. The early morning surge in blood pressure could become a new therapeutic target for preventing target-organ damage and subsequent cardiovascular events in hypertension. Of greatest interest is the potential benefit of a chronotherapeutic approach, involving, for example, long-acting chronoformulations, which has not yet been extensively studied.

Current status of cancer patients' perception of alternative medicine in Japan. A preliminary cross-sectional survey.

Since there are no large-scale surveys of how cancer patients perceive unproven therapy in Japan, we wanted to clarify this issue by means of a cross-sectional questionnaire conducted among cancer patients. The survey revealed that 32% of cancer patients used unproven therapy without having sufficient information about it. There was a lack of communication between cancer patients and their physicians on topics relating to alternative medicine. Issues that we have to solve are concerned with the education of cancer patients, lay people and physicians on the meaning and role of alternative medicine and on the necessity for scientific evaluation of medical treatments in Japan.

Chronopharmacology of etoposide given by low dose prolonged infusion in lung cancer patients.

We examined the chronopharmacology of prolonged etoposide administration by intravenous infusion over 14 days in 9 patients with lung cancer. Blood samples were obtained every 4 hours between 24 hours and 48 hours after initiation of the infusion. Using the unpaired t-test, the percentage plasma etoposide concentration at 09:00 hours calculated from the 24 hour average value, was significantly higher than that at 21:00 hours (p = 0.024). However, neither ANOVA nor cosinor analysis revealed any significant effect of sampling time (ANOVA: p = 0.29, cosinor analysis: p = 0.46).

CD4+CD45RA+ cells (suppressor-inducer T cells) in thyroid tissue from patients with Graves' disease.

Previously, we used dual immunofluorescent analysis and showed that the thyroid gland from patients with Graves' disease had a reduced number of CD4+CD45RA+ cells, but an increased number of complementary CD4+CDw29+ cells. An immunohistochemical study, however, produced opposite results; interstitial lymphocytes predominantly expressed the CD45RA+ rather than the CDw29+ phenotype. Because the difference in findings may be due to differences in the techniques used, we did the following experiments: Mononuclear cells were treated with various amounts of collagenase (50-1000 mg/l) which had no effect on the cell surface antigens CD3, CD4 and CD45RA. A dual immunofluorescent study showed that the numbers of CD4+CD45RA+ and CD8+CD45RA+ cell population among CD45RA+ cell population were markedly decreased in the thyroid tissue, and that the CD45RA antigen on the intrathyroidal mononuclear cells was mainly expressed on the CD20+ cells. As the thyroid section had been fixed with acetone before immunohistochemical staining, CD45RA- cells were treated with acetone and stained with anti-CD45RA monoclonal antibody using an avidin-biotin peroxidase complex method. The results of this experiment suggest that there are cell surface molecules which react with anti-CD45RA monoclonal antibody after treatment with acetone in CD45RA- cells. The above findings confirm our previous results which showed that the thyroid glands of patients with Graves' disease have decreased numbers of suppressor-inducer T cells. Also, several problems exist in the detection of CD45RA+ cells when using an immunohistochemical method.

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.

[Fundamental study and clinical testing of human tumor clonogenic assay (HTCA)].

Through our retrospective analysis of HTCA and clinical effects as well as fundamental studies, the following results were obtained: In this retrospective study, HTCA for lung cancer showed a predictive accuracy of 71%, a true positive rate of 50% and a true negative rate of 77%. To obtain good predictive accuracy, HTCA should be modified to provide conditions comparable to those in vivo with regard to drug concentration and drug exposure time. More precise analysis of the pharmacokinetics of anticancer agents might yield methodological improvement. A decrease in the chemosensitivity spectrum in vitro was observed after chemotherapy. This might be related to evidence that patients with prior chemotherapy exhibited a poor response rate to chemotherapy. There were no active anticancer agents against specimens with aplating efficiency of more than 0.04%. More extensive prospective trials will be necessary to determine the clinical value of HTCA. HTCA could be a superior assay for detecting the anti-tumor activity of new agents and a useful method for in vitro phase II study.

Attenuation during paradoxical sleep of signals from tooth pulp to thalamus.

Quantitative evaluation of the response of thalamic neurons to tooth pulp stimulation was made in chronically prepared cats. The latency, duration and intensity of the responses were measured from the post-stimulus time histograms to estimate, from various aspects, the alteration in the responsiveness during different phases of sleep and wakefulness. During slow wave sleep, tooth pulp-evoked impulses tended to be transmitted to the thalamus in a similar or slightly higher intensity compared to wakefulness. In contrast, during paradoxical sleep the signals were often attenuated in many aspects. The results seem to be in favor of the idea that the impairment of signal to noise ratio in a variety of neuronal networks is one of the characteristics of paradoxical sleep.