Cortical pyramidal neurons alter their responses to input signals depending on behavioral state. We investigated whether changes in somatic inhibition contribute to these alterations. In layer 5 pyramidal neurons of rat visual cortex, repetitive firing from a depolarized membrane potential, which typically occurs during arousal, produced long-lasting depression of somatic inhibition. In contrast, slow membrane oscillations with firing in the depolarized phase, which typically occurs during slow-wave sleep, produced long-lasting potentiation. The depression is mediated by L-type Ca2+ channels and GABA(A) receptor endocytosis, whereas potentiation is mediated by R-type Ca2+ channels and receptor exocytosis. It is likely that the direction of modification is mainly dependent on the ratio of R- and L-type Ca2+ channel activation. Furthermore, somatic inhibition was stronger in slices prepared from rats during slow-wave sleep than arousal. This bidirectional modification of somatic inhibition may alter pyramidal neuron responsiveness in accordance with behavioral state.

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.

3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid, which cannot be removed by conventional hemodialysis due to its strong albumin binding, was found to be efficiently removed by continuous ambulatory peritoneal dialysis (CAPD), resulting in a lower serum level in uremic patients on CAPD than in those on hemodialysis. 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid was demonstrated in vitro to inhibit erythroid colony formation. The anemia in patients on CAPD was significantly less severe than in those on hemodialysis. These results suggest that the efficient removal by CAPD of 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, an inhibitor of erythropoiesis, is related to an improvement of anemia in patients on CAPD.

We examined the effects of soybeans, a soy product (miso) and biochanin A, an isoflavone derivative, on N-nitroso-N-methylurea (MNU)-induced rat mammary carcinogenesis. Seven-week-old female CD/Crj rats received a single i.v. dose (40 mg/kg body weight) of MNU. After administration of MNU, rats were fed diet containing 0% (control), 2% or 10% soybeans, or 10% miso as a soy-supplemented diet, or 10 or 50 mg/kg biochanin A. All rats were observed for 18 weeks after MNU administration. At 18 weeks, the multiplicity (mean tumors/rat) of palpable mammary tumors was significantly decreased in the 10% soybean (1.1) and 10% miso (1.2) diet groups compared to the control (2.2) (P<0.05, respectively). In the biochanin A-supplemented diet groups, the incidence (percentage of rats with tumors) was significantly decreased in the 50 mg/kg (32%) diet group compared to the control (80%) (P<0.01), and the multiplicity was significantly decreased in both the 10 mg/kg (0.7) and 50 mg/kg (0.5) diet groups compared to the control (2.2) (P<0.01 and P<0.001, respectively). The proliferative cell nuclear antigen labeling index of mammary tumors was significantly decreased in both biochanin A-supplemented diet groups compared to the control. The present results indicate that soybeans, miso, and biochanin A are useful for the prevention of mammary cancer.