The levels of blastogenesis in allogeneic MLR containing T cells from one normal volunteer and irradiated dendritic cells from 29 patients with PBC, 17 patients with chronic hepatitis type C (CH-C) and 22 allogeneic normal controls were compared to see if there is any role of antigen-presenting cells (APC) in the pathogenesis of PBC. The stimulatory capacity of dendritic cells from PBC was significantly lower compared with that of dendritic cells from CH-C (P < 0.05) and normal controls (P < 0.05), which could not be attributable either to the levels of expression of surface molecules, such as HLA-DR and CD86 on dendritic cells, or to the levels of cytokines, such as IL-10 and IL-12. Significantly higher levels of NO were seen in the allogeneic MLR supernatants containing dendritic cells from PBC compared with the supernatants from cultures containing dendritic cells from CH-C (P < 0.001) or normal controls (P < 0.001). Moreover, dendritic cells from PBC produced 10 times more NO compared with dendritic cells from CH-C and normal controls (21.9 +/- 2.8 microM versus 1.6 +/- 0.3 microM and 1.6 +/- 0.3 microM, respectively; P < 0.001). The addition of N(G)-monomethyl-L-arginine monoacetate (L-NMMA), a known inhibitor of NO in allogeneic MLR containing dendritic cells from PBC, resulted in a significant decrease of NO and increase of blastogenesis. The selective impairment of dendritic cell function, increased production of NO by dendritic cells and restoration of blastogenesis using NO inhibitor in PBC have suggested a role for NO and dysfunction of dendritic cells in the pathogenesis of PBC. This inspires optimism that modulating the function of dendritic cells and controlling NO production, an improved therapeutic approach, might be planned for PBC.

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When mice were exposed to restraint stress for 12 or 24 h, severe lymphopenia was induced in all immune system organs, including the liver and the thymus. However, in adrenalectomized mice, this response was completely absent. Phenotypic characterization revealed that interleukin (IL)-2Rbeta+CD3int cells (i.e. extrathymic T cells) with CD4+ phenotype and the NK1.1+ subset of CD3int cells (i.e. NKT cells) in the liver as well as the mature conventional T cells in the thymus were resistant to such stress. In adrenalectomized mice, there was no significant change in the distribution of lymphocyte subsets in all tested organs before stress. Interestingly, the number of lymphocytes in the liver and spleen and the proportion of NKT cells in the liver rather increased after stress in these adrenalectomized mice. Therefore, endogenous steroid hormones were indicated to be important in the induction of immunosuppressive states after stress. Among stress associated cytokines, the secretion of tumour necrosis factor (TNF)-alpha was completely suppressed while that of IL-6 was partially suppressed in adrenalectomized mice. These results suggest that endogenous steroid hormones are important for the induction of the stress associated immunosuppression and that NKT cells are resistant to stress, namely, resistant to exposure to endogenous steroid hormones.

Lodging has been a major roadblock to attaining increased crop productivity. In an attempt to understand the mechanism for culm strength in rice, we isolated an effective quantitative trait loci (QTL), STRONG CULM3 (SCM3), the causal gene of which is identical to rice TEOSINTE BRANCHED1 (OsTB1), a gene previously reported to positively control strigolactone (SL) signaling. A near-isogenic line (NIL) carrying SCM3 showed enhanced culm strength and increased spikelet number despite the expected decrease in tiller number, indicating that SL also has a positive role in enhancing culm strength and spikelet number. We produced a pyramiding line carrying SCM3 and SCM2, another QTL encoding APO1 involved in panicle development. The NIL-SCM2+SCM3 showed a much stronger culm than NIL-SCM2 and NIL-SCM3 and an increased spikelet number caused by the additive effect of these QTLs. We discuss the importance of utilizing suitable alleles of these STRONG CULM QTLs without inducing detrimental traits for breeding.

Pemphigus vegetans is a rare variant of pemphigus vulgaris and is characterized by flaccid bullae, which become eroded and form vegetations or papillomatous proliferations, especially in the intertriginous areas. Oral administration of corticosteroids alone does not always induce disease remission in pemphigus vegetans. We report a 44-year-old Japanese man with pemphigus vegetans. Although corticosteroid therapy resulted in healing of the oral ulcers and skin bullae, verrucous vegetations continued to develop. In contrast, by combining corticosteroid with etretinate, verrucous vegetations improved. Thus we propose that the combination therapy of steroid and etretinate might be an effective adjunct in the therapy of pemphigus vegetans.

AimsThe aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2. Methods The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2. Results Propafenone and mexiletine inhibited phenacetin O-deethylation with IC 50 values of 29 and 37 mm, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC 50 >1 mm). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC 50 values ranging from 86 to 704 mm. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2. Conclusions These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.Keywords: CYP1A2, phenacetin O-deethylation, human liver microsomes, mexiletine, propafenone I antiarrhythmic drug, has been reported to elevate plasma Introduction levels of concomitantly administered theophylline [19][20][21][22][23][24], by inhibiting 1-and 3-demethylation and 8-hydroxylation Cytochrome P450 1A2 (CYP1A2), an isoform of the CYP1A subfamily [1], accounts for about 10 to 15% of the total CYP of theophylline [19,20]. Recent studies using human liver microsomes and cDNA-expressed human CYP isoforms content of human livers [2]. This enzyme is known to catalyse the metabolism of imipramine [3], propranolol [4], indicated that CYP1A2 is the enzyme mainly responsible for the 1-and 3-demethylation and 8-hydroxylation of clozapine [5], caffeine [6], theophylline [7] and phenacetin [6,8]. The kinetic disposition of these drugs is altered by the theophylline in humans [25, 26]. Several studies using rat liver microsomes also showed that mexiletine inhibits administration or exposure to inducers or inhibitors of CYP1A2. For example, the clearance of propranolol [9], ethoxyresorufin O-dealkylation catalysed by CYP1A1, another isoform of the CYP1A subfamily [27]. However, in clozapine [10] and theophylline [11] is greater in smokers than in nonsmokers, as a result of marked induction of vivo [28,29] and in vitro [30,31] studies showed that mexiletine is mainly metabolized by CYP2D6. Therefore, CYP1A2 by cigarette smoking. On the other hand, the plasma concentrations of imipramine [12], clozapine [13], it remains obscure as to whether the pharmacokinetic interaction between theophylline and mexiletine occurs by caffeine [14,...

The involvement of serotonin (5-HT) receptor subtypes in motor activity of the ex vivo vascularly perfused rat duodenum was investigated. Clusters of phasic contractions (CPCs), migrating in an oral to anal direction, were obtained without any stimulation. Drug effects were evaluated by changes in different components of the pressure waves, such as motor index (MI), frequency, amplitude and duration of the CPC. The effect of 5-HT depletion on motor activity was examined in animals treated with p-chlorophenylalanine (PCPA). The MI, frequency and duration of CPC were decreased by PCPA, but the amplitude was not affected, suggesting that endogenous 5-HT may play an important role in regulation of the motor activity of the rat intestine. The importance of the 5-HT receptor subtypes in the regulation of motor activity was examined. Neither the nonselective 5-HT1 and 5-HT2 receptor antagonist, methysergide, nor the 5-HT2 receptor antagonist, ketanserin, affected motor activity. However, the 5-HT3 receptor antagonists, granisetron and azasetron, decreased percentage MI, frequency, percentage amplitude and percentage duration of CPC. The 5-HT4 receptor antagonist, SB204070, exerted both excitatory and inhibitory actions, with a higher dose (10 nM) stimulating percentage MI, frequency, percentage amplitude and percentage duration, and a lower dose (0.1 nM or 1 nM) decreasing percentage MI and percentage duration of CPC. These results suggest that endogenous 5-HT regulates the motor activity of the rat duodenum through 5-HT3 and 5-HT4 receptors, with the former mediating the stimulatory influence and the latter mediating both stimulatory and inhibitory influences.