The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role

PD-1 and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, have been identified recently as CD28-B7 family molecules that are implicated in immune regulation. Lichen planus (LP) is a T cell-mediated chronic inflammatory mucocutaneous disease. We investigated the expression and function of PD-1 and its two ligands in LP. Immunohistochemical examination revealed the abundant expression of PD-1 and B7-H1 in infiltrating T cells and macrophages, and lower-level expression of B7-DC on macrophages in the subepithelium. Interestingly, substantial expression of B7-H1 on keratinocytes (KCs) was found close to the numerous T cell infiltrates in the subepithelium. Unstimulated cultured KCs expressed both B7-H1 and B7-DC, and their expression was upregulated by proinflammatory cytokines, particularly IFN-gamma. The T-cell proliferative responses and IFN-gamma production that were induced by IFN-gamma-treated KCs were augmented preferentially by anti-B7-H1 mAb, but not by anti-B7-DC mAb. These results indicate the regulatory role of B7-H1 on KCs in the interactions with T cells. Our results suggest that the induction of B7-H1 on KCs may play an important role in tolerance induction in the inflamed oral mucosa and skin.     

Detection of local abnormalities in ventricular activation sequence by body surface isochrone mapping in patients with previous myocardial infarction

Body surface isochrone mapping was performed in 36 normal subjects and in 85 patients with previous myocardial infarction. Eighty-seven unipolar electrocardiograms distributed over the anterior chest and the back were recorded simultaneously. For each lead, activation time was measured as the time from the onset of QRS to the peak of the R wave. The lead points where R waves were not observed were designated the "no R wave area" (NR area). Isochrone maps of normal subjects had a consistent pattern, with isochrone lines extending from the right upper anterior chest to the left anterior chest and then to the back. NR area was small and was located only on the right upper chest or the upper back. On the isochrone maps of patients with myocardial infarction, abnormal findings were observed; NR area was found in 26 of 28 patients with anterior infarction on the upper to middle anterior chest, in 13 of 22 patients with inferior infarction on the lower chest, and in 24 of 25 patients with anterior and inferior infarction on the upper to lower anterior chest. Activation time was delayed near the NR area (peri-NR area delay) in 37 patients. In patients with apical infarction, an islandlike zone of delayed activation was typically found on the left precordium. These abnormal patterns are considered to indicate local abnormalities in the activation of infarcted myocardium; the NR area indicates dead unexcitable scar, and the peri-NR area delay and islandlike zone of delayed activation indicate partially infarcted myocardium of slow activation. Patients with NR area had greater degree of left ventricular asynergy and lower ejection fraction than those without.(ABSTRACT TRUNCATED AT 250 WORDS)     

Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation

Transgenic expression in medaka of the Xiphophorus oncogene xmrk, under a pigment cell specific mitf promoter, induces hyperpigmentation and pigment cell tumors. In this study, we crossed the Hd-rR and HNI inbred strains because complete genome information is readily available for molecular and genetic analysis. We prepared an Hd-rR (p53^+/−, p53^−/−) and Hd-rR HNI hybrid (p53^+/−) fish-based xmrk model system to study the progression of pigment cells from hyperpigmentation to malignant tumors on different genetic backgrounds. In all strains examined, most of the initial hyperpigmentation occurred in the posterior region. On the Hd-rR background, mitf:xmrk-induced tumorigenesis was less frequent in p53^+/− fish than in p53^−/− fish. The incidence of hyperpigmentation was more frequent in Hd-rR/HNI hybrids than in Hd-rR homozygotes; however, the frequency of malignant tumors was low, which suggested the presence of a tumor suppressor in HNI genetic background fish. The effects on tumorigenesis in xmrk-transgenic immature medaka of a single 1.3 Gy irradiation was assessed by quantifying tumor progression over 4 consecutive months. The results demonstrate that irradiation has a different level of suppressive effect on the frequency of hyperpigmentation in purebred Hd-rR compared with hybrids.     

A causal model of blood enzyme data and visualization of tissue conditions

Quantitative diagnostics is an important field in which clinical data are converted into medical information. A variety of approaches to obtain medical diagnoses have been developed and multivariate statistical analysis supports the diagnostic process. Although many clinical data are affected by body conditions such as disease and functional failure, only a few models take this phenomenon into consideration. The correlation between laboratory test results can be understood as a causal relationship between body conditions and clinical test data variations. A multivariate statistical method, factor analysis, expresses a causal relationship between latent variables and observed variables. We developed a causal model for blood enzyme data using factor analysis. The latent variables were assumed to be organ specific regarding 9 enzyme data. This causal model expressed clinical knowledge within blood enzymes and allowed visualization of organ conditions. The visualization of laboratory data is useful to screen patient's pathological states.     

Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor,BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth

1. The aim of this study was to determine whether BAYw6228 (BAYw), a newly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol.
2. First, we evaluated the in vitro effect of BAYw on the proliferation of vascular smooth muscle cells (SMC) from various species: Sprague-Dawley (SD) rats, New Zealand (NZ) white rabbits, intimal cells from Watanabe hereditary hyperlipidemic (WHHL) rabbit and SMC from the new-born human aorta. The increasing rate of total protein content of these cells was inhibited by the addition of BAYw in a dose-dependent fashion. In the presence of 2% foetal calf serum (FCS), the value of IC₅₀ was 1.0 μM in SD rats. 2.1 μM in NZ white rabbits, and 0.3 μM in WHHL rabbits. With human SMC, the value was 0.02 μM in the presence of 10% FCS and 0.2 μM with a mixture of growth factors.
3. Based on these above in vitro findings, we next examined the in vivo effect of the agent to determine whether it could suppress rabbit intimal thickening induced by balloon catheterization. A balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japanese white rabbits. After 12 days they were divided into control and BAYw groups. The former were subcutaneously injected with saline and the latter with BAYw 1 mg kg⁻¹ day⁻¹. Two days after the beginning of treatment, a second balloon injury was performed to the previously injured left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significantly lower than in the control (P<0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smaller intima/media ratio than the control group, decreasing to 45% of control (P<0.05). By anti-α smooth muscle actin antibody staining, these intimal thickening areas were entirely occupied by SMCs, and their amount was attenuated by BAYw. By anti-rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P<0.01).
4. These results indicate that BAYw has an inhibitory effect on intimal thickening by attenuating intimal SMC proliferation and infiltration of macrophages, suggesting that BAYw could be effective in the prevention of the progression of atherosclerotic plaque-like restenosis after angioplasty.

     

Improved fertility through superoxide removal by Toki-shakuyaku-san in mice--a preliminary study

The effect of a superoxide dismutase inhibitor on pregnancy rate and fetal survival, and the effect of concomitant treatment with Toki-shakuyaku-san, was studied. Twelve week-old IV CS female mice were given diethyldithiocarbamate (DEDC; 0.9, 9, 45, and 225 mg kg(-1)) intraperitioneally, from Day 3 to Day 5 of pregnancy, every 12 h, for a total of six times. Two additional groups received both 45 mg kg DEDC and Toki-shakuyaku-san (50 or 200 mg/100 mL), by water bottle, from 12 h before to 12 h after DEDC administration. For each group, the pregnancy rate, the number of surviving fetuses, and the number of resorbed fetuses was calculated. Pregnancy rates were 95.5, 81.8, 54.5 and 0%, respectively, in the DEDC groups and were 100% in the control group. The fetal resorption rate was 0.9 in the control group, and 1.0, 1.7, and 2.3, respectively, in the 0.9, 9, 45 mg kg(-1) DEDC groups. Administration of 200 mg Toki-shakuyaku-san significantly (P<0.05) improved the pregnancy rate to 81.8%, and improved the degree of reduced intercellular interactions and insufficient decidual reactions found on Day 5 in the endometrium of the DEDC groups. Toki-shakuyaku-san reduces the adverse effects of excess superoxides on the endometrium during implantation.     

Lipoprotein(a) levels and apolipoprotein(a) isoforms related to life style risk factors

Lipoprotein(a) [Lp(a)] has been considered to be a predictor of premature coronary heart disease and other cardiovascular diseases. Lp(a) levels are largely genetically determined, but the detailed mechanism of Lp(a) elevation is uncertain. We examined the association between Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes as well as that of Lp(a) level and other various conditions. The subjects were 280 healthy Japanese (102 males and 178 females) aged 39 to 70 years who were living in a rural community in 1992. We obtained apo(a) phenotypes determined by SDS-PAGE as well as Lp(a) levels and other cardiovascular risk factors. We combined apo(a) phenotypes form 4 groups according to molecular weights (from high apo(a) molecular weight to low: I, II, III and IV). Lp(a) levels were associated with apo(a) phenotype-groups, that is, they were inversely associated with apo(a) molecular weight. Small apo(a) phenotypes were less frequent than large ones. The median Lp(a) level was higher in smoking (29.2 mg/dL) than in non-smoking subjects (18.5 mg/dL) in phenotype-group III. Adjusted means of total cholesterol and fibrinogen levels in apo(a) phenotype-group IV were the highest of all phenotype-groups. Age, apo(a) phenotype, smoking status, total cholesterol and fibrinogen were positively correlated with Lp(a) levels by multiple regression analysis. Lp(a) levels were found to be mainly associated with apo(a) phenotype, but varied broadly within the same apo(a) phenotype at various conditions, such as smoking status and high total cholesterol.     

Vinylamycin, a new depsipeptide antibiotic, from Streptomyces sp

A new depsipeptide antibiotic, vinylamycin, was isolated from the culture broth of an actinomycete strain. The producing organism, designated MI982-63F1, was identified as a member of Streptomyces. Vinylamycin was isolated from the culture broth by extraction with EtOAc and purified by crystallization from EtOAc. The structure of vinylamycin was determined by spectroscopic analysis and degradation studies. Vinylamycin showed antimicrobial activities against Gram-positive bacteria including MRSA.     

Important role of endothelium-derived hyperpolarizing factor in shear stress--induced endothelium-dependent relaxations in the rat mesenteric artery.

Shear stress is one of the most important stimulators for the release of endothelium-derived relaxing factors. Although shear stress-induced release of nitric oxide (NO) has been extensively investigated, it remains to be elucidated whether endothelium-derived hyperpolarizing factor (EDHF) contributes to the endothelium-dependent relaxations to shear stress. This study was designed to address this point in the isolated rat mesenteric artery. Large mesenteric arteries (400-500 microm) and resistance mesenteric arteries (150-250 microm) of the rat were precontracted with phenylephrine (at 80 mm Hg of perfusion pressure), and the changes in vessel diameter in response to variable flow (0-300 microl/min) were continuously examined. The relative contributions of vasodilator prostaglandins, NO, and EDHF were analyzed by the inhibitory effects of indomethacin (10(-5) M), N(G)-nitro-L-arginine (L-NNA, 10(-4) M), and KCl (40 mM), respectively. The shear stress-induced relaxations were totally endothelium dependent in both-sized blood vessels, and the contribution of NO was more prominent in large arteries than in resistance arteries, whereas that of EDHF was noted in both-sized blood vessels. Tetrabutylammonium (a nonselective inhibitor of K channels) almost abolished, whereas the combination of charybdotoxin (an inhibitor of both large- and intermediate-conductance Ca2+ -activated K channels) and apamin (an inhibitor of small-conductance Ca2+ -activated K channels) significantly inhibited the EDHF-mediated component of the shear stress-induced relaxations. These results indicate that EDHF plays an important role in shear stress-induced endothelium-dependent relaxations, where K channels, especially calcium-activated K channels, appear to be involved.