Species differences in the tissue distribution of catechol and methylsulphonyl metabolites of 2,4,5,2',5'-penta- and 2,3,4,2',3',6'-hexachlorobiphenyls in rats, mice, hamsters and guinea pigs

Polychlorinated biphenyls (PCBs) are metabolized to phenolic or methylsulphonyl PCBs (MeSO(2)-CBs) in animal species. The study determined the species differences in the tissue distribution of persistent PCB metabolites in rats, mice, hamsters and guinea pigs 4 days after exposure to 2,4,5,2('),5(')-pentachlorobiphenyl (CB101) or 2,3,4,2('),3('),6(')-hexachlorobiphenyl (CB132). For CB101 metabolism, the hydroxylation in rats, mice and hamsters occurred primarily at the 3(')-position in the 2('),5(')-dichlorinated phenyl ring, whereas the hydroxylation in guinea pigs occurred preferentially at the 3-position. Metabolite profiles in tissues of hamsters were dominated by 3('),4(')-catechol-CB101, whereas metabolite profiles in rats and mice were dominated by 3(')- or 4(')-MeSO(2)-CBs. For CB132 metabolism, rats and mice produced 4(')- and 5(')-MeSO(2)-CBs at similar concentration ratios, whereas guinea pigs produced MeSO(2)-CBs at higher levels and selectively retained 5(')-MeSO(2)-CB in liver. In contrast, hamsters preferentially produced 4('),5(')-catechol-CB132 that was retained in serum. Consequently, hamsters produced catechols, whereas guinea pigs produced meta-substituted MeSO(2)-CBs, preferentially from CB132. These findings indicate that PCBs with 2,3,6-chlorine substitution are preferred substrates for the formation of catechols or MeSO(2)-CBs and the differences in metabolite profiles are related to species-dependent metabolic capacities.     

Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after balloon injury in porcine coronary arteries

HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.     

Coronary microvascular dysfunction in patients with microvascular angina: analysis by TIMI frame count

We have previously reported that angina pectoris persists in patients with coronary microvascular spasm (MVS) even on calcium channel blockers. Because measurement of myocardial lactate production in the coronary sinus is necessary to diagnose MVS, a more feasible diagnostic method needs to be developed. In this study, we examined the diagnostic significance of Thrombolysis in Myocardial Infarction (TIMI) frame count, a marker of coronary blood flow, in 131 consecutive patients who underwent provocation test for coronary spasm with acetylcholine (ACh). Epicardial coronary spasm (ES) was diagnosed as more than 75% of ACh-induced vasoconstriction noted by coronary angiography. MVS was diagnosed as ACh-induced myocardial ischemia (chest pain, ischemic ECG changes, and myocardial lactate production) without ES. TIMI frame count was significantly increased in patients with MVS alone (n = 35) and those with ES + MVS (n = 16) compared with those with ES alone (n = 53) or those with no myocardial ischemia (Normal, n = 27) either before and after intracoronary ACh and even after intracoronary isosorbide dinitrate (ISDN) in both the left anterior descending (LAD) and the left circumflex coronary artery (LCX). TIMI frame count in LAD correlated well to that in LCX in patients with MVS, suggesting diffuse impaired coronary microcirculation in the myocardium. These results suggest that increased TIMI frame count in response to ACh reflects microvascular dysfunction in MVS and that ISDN may not be enough to relieve MVS. Thus, TIMI frame count may be useful to diagnose MVS without requiring coronary sinus catheterization or myocardial lactate production measurement.     

Effect of high dose of pyridoxine on mammary tumorigenesis

The effect of high-dose pyridoxine (PN) on mammary tumorigenesis was examined in female Sprague-Dawley rats. The first mammary tumors appeared between 84 and 90 days after 7,12-dimethylbenzanthracene treatment. There was no effect of PN level on tumor incidence at 90 days but at 98, 104, and 111 days. Tumor incidence was lower in the high-dose group (35 mg PN/kg diet) compared with the controls (7 mg PN/kg diet). All tumors were identified as adenocarcinoma and most as papillary type. The number of microcarcinomas in mammary glands of the 35-mg PN group tended to be reduce than that of the 7-mg group. The number of proliferating Ki67-positive cells was significantly reduced by supplementation with PN.     

Steroid-free living-donor liver transplantation in adults

To examine the benefits of steroid avoidance in adult living donor liver transplantation, we compared the clinical courses of nine recipients receiving basiliximab or daclizumab and 13 historical patients who received steroids. The 1-year patient and graft survival and the incidence of acute cellular rejection were similar in both groups. The side effects of immunosuppression tended to be more frequent in the steroid group. Hepatitis C virus (HCV)-RNA levels measured early after transplantation remained suppressed in the steroid-free group. Steroid avoidance was beneficial in the recipients, as both steroid side effects and recurrence of HCV could be avoided.     

Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo

BACKGROUND: Regulatory T cells (Tregs) are increasingly recognized as playing a major role in nondeletional tolerance. To avoid rejection before tolerance is established, clinical trials of tolerance induction include immunosuppressive drugs early posttransplant. It is therefore essential that immunosuppressive protocols do not block Tregs generation. Tregs function has been shown to depend upon interleukin-2 signaling, but there are limited data available on how calcineurin inhibitors influence Tregs development and function in vivo. METHODS: To study this, we used a previously established rat cardiac allograft model where donor-specific Tregs and tolerance are induced by pretransplant donor-specific blood transfusion (DSBT). RESULTS: In this model, we found that adjunction of 50 mg/kg cyclosporine (CsA) (not a lower dose, 10 mg/kg) at the time of DSBT (not at the time of transplantation) abrogates Tregs development and causes rejection. Interestingly, 10 mg/kg CsA given posttransplant (day 0-11) in the absence of pretransplant DSBT induced the development of Tregs and provoked a state of tolerance indistinguishable from the one induced by DSBT. Finally, DSBT given the day of transplantation did not promote tolerance, unless recipients also received a delayed short course (day 5-9) of 10 mg/kg CsA. CONCLUSIONS: Adjunction of high-dose CsA to pretransplant DSBT abrogates Tregs generation. On the contrary, a lower dose (10 mg/kg) of CsA promotes Tregs development either in synergy with perioperative DSBT (providing that a drug-free interval is respected) or by its own effect. These data provide new guidelines for a more tolerogenic use of calcineurin inhibitors in the clinic, particularly when immunomodulatory strategies aimed at inducing Tregs are applied.     

Lack of correlation between results of ABO-incompatible living kidney transplantation and anti-ABO blood type antibody titers under our current immunosuppression

In this study, we examined the impact of preoperative anti-A/B antibody titers on the results of ABO-incompatible living kidney transplantation (LKT). In all, 167 recipients underwent ABO-incompatible LKT at our institution between 1989 and 2002. These patients were subdivided into those transplanted under cyclosporine with azathioprine or mizoribine (Group 1, n=78) and those transplanted under tacrolimus or mycophenolate mofetil (Group 2, n=89). Overall patient survival at 5 and 10 years was 93.8% and 88.0%, respectively. Overall graft survival at 5 and 10 years was 76.9% and 55.9%, respectively. Graft survival in the patients with anti-A/B IgG titers over 1:128 was significantly lower in group 1, whereas no significant correlation between the anti-A/B IgG titers and graft survival was found in group 2. In conclusion, no correlation between anti-A/B antibody titers and the results of ABO-incompatible LKT was seen after tacrolimus or mycophenolate mofetil application.     

A specific COX-2 inhibitor attenuates cell infiltration but does not prolong graft survival in murine cardiac transplantation

COX-2 is a key factor in the progression of inflammation, the effects of a specific COX-2 inhibitor in cardiac transplantation have not yet been elucidated. To test the hypothesis that a COX-2 inhibitor can alter cardiac rejection, we analyzed graft survival using totally allomismatched grafts. Although the COX-2 inhibitor attenuated myocardial cell infiltration, the inhibitor did not prolong survival. We conclude that the COX-2 inhibition may have potential for the suppression of inflammation in cardiac allografts.     

An autopsy case of Down's syndrome with moyamoya syndrome

We reported an autopsy case of Down's syndrome with moyamoya syndrome. A 30-year-old male with Down's syndrome suffered from a cerebral infarction and died of brain herniation. Cerebral angiography showed vascular abnormalities that were the same as moyamoya disease. Pathological findings revealed multiple stenosis of main trunk of the cerebral arteries. Pathologically, the stenosed vessels showed eccentric intimal thickness with cholesterin deposit, unlike moyamoya disease. There are only two previous reports of autopsied cases of Down's syndrome with moyamoya syndrome. We postulate that a protein encoded on chromosome 21 may be related to the pathogenesis of Down's syndrome with moyamoya syndrome.