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Intramolecular M(II)...H-C interactions (M(II)=Cu(II), Pd(II)) involving a side chain alkyl group of planar d8 and d9 metal complexes of the N-alkyl (R) derivatives of N,N-bis(2-pyridylmethyl)amine with an N3Cl donor set were established by structural and spectroscopic methods. The methyl group from the branched alkyl group (R=2,2-dimethylpropyl and 2-methylbutyl) axially interacts with the metal ion with the M...C and M...H distances of 3.056(3)-3.352(9) and 2.317(1)-2.606(1) A, respectively, and the M-H-C angles of 122.4-162.3 degrees . The Cu(II) complexes showing the interaction have a higher redox potential as compared with those without it, and the (1)H NMR signals of the interacting methyl group in Pd(II) complexes shifted downfield relative to the ligand signals. Dependence of the downshift values on the dielectric constants of the solvents used indicated that the M(II)...H-C interaction is mainly electrostatic in nature and may be regarded as a weak hydrogen bond. Implications for possible environmental effects of the leucine alkyl group at the type 1 Cu site of fungal laccase are also discussed.

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OBJECTIVE: Endothelial dysfunction is thought to represent the initial stage in the development of atherosclerosis. Recently, noninvasive examination of endothelial function has become possible using flow-mediated endothelium-dependent dilation of the brachial artery (FMD) during reactive hyperemia. We examined whether FMD has prognostic value for the prediction of subsequent cardiovascular events. METHODS: Patients were followed prospectively every month until the occurrence of the cardiovascular events. PATIENTS: The study subjects comprised 221 consecutive patients (men 108, mean age 61.4+/-10.6, ischemic heart disease 152, cardiomyopathy 28, arrhythmia 12, valvular disease 5, congenital heart disease 3, and cardioneurosis 21). The mean FMD was 4.77+/-2.85% and this value was used to divide the patients into the 2 groups (Group 1: FMD > or =4.7%; Group 2: FMD <4.7%). RESULTS: There were 110 patients in Group 1 (men 36, mean age 60.5+/-10.9), and 111 patients in Group 2 (men 72, mean age 62.2+/-10.3). Patients were followed until the occurrence of at least 1 of the major clinical cardiovascular events. Seven cardiovascular events occurred in Group 1 (6.4%, 1.14 events per 100 patient-years), while 16 occurred in Group 2 (2.88 events per 100 patient-years). Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiovascular events in Group 2 than in Group 1. CONCLUSION: The present results demonstrated that the magnitude of FMD in the brachial artery was a good predictor of subsequent cardiovascular events.

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Synthetic, structural, spectroscopic, and kinetic studies have been carried out on the Pd(II) complexes of new 2N1O-donor ligands containing a pendent indole, 3-(N-2-pyridylmethyl-N-2-hydroxy-5-methoxybenzylamino)ethylindole (HMeO-iepp), 3-(N-2-pyridylmethyl-N-2-hydroxy-5-nitrobenzylamino)ethylindole (HNO2-iepp), and (N-2-pyridylmethyl-3-indolylethylamino)acetic acid (Hiepc) (H denotes a dissociable proton). [Pd(MeO-iepp)Cl] (2), [Pd(NO2-iepp)Cl] (3), and [Pd(iepc)Cl] (4) were prepared and revealed by X-ray analysis to have a pyridine nitrogen, an amine nitrogen, a phenolate or carboxylate oxygen, and a chloride ion in the coordination plane. UV absorption and 1H NMR spectral changes indicated that all the complexes could be converted to the indole-binding complexes where the O donor was replaced by the indole C2 atom by cyclopalladation in DMSO or DMF in the temperature range of 40-60 degrees C. Formation of the indole-binding complex species obeyed the first-order kinetics, from which the activation parameters were estimated. The formation rate was dependent on the properties of the O-donor group, a lower pKa value of its conjugate acid causing faster conversion to the indole-binding species in the order 2 (methoxyphenolate) < 3 (nitrophenolate) < 4 (carboxylate). On the other hand, the ratio of the indole-binding complex to the O-donor complex as a result of the conversion was greater for the complexes with a higher pKa value of the ligand OH group, the order being 2 > 3 > 4.

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The Pd(II) complexes of new 2N1O-donor ligands containing a pendent indole, 3-[N-2-pyridylmethyl-N-2-hydroxy-3,5-di(tert-butyl)benzylamino]ethylindole (Htbu-iepp), 1-methyl-3-[N-2-pyridylmethyl-N-2-hydroxy-3,5-di(tert-butyl)benzylamino]ethylindole (Htbu-miepp), 3-[N-2-pyridylmethyl-N-2-hydroxy-3,5-di(tert-butyl)benzylamino]methylindole (Htbu-impp), and 3-(N-2-pyridylmethyl-N-4-hydroxybenzylamino)ethylindole (Hp-iepp) (H denotes a dissociable proton), were synthesized, and the structures of [Pd(tbu-iepp)Cl] (1a), [Pd(tbu-iepp-c)Cl] (1b), [Pd(tbu-miepp)Cl] (3), and [Pd(p-iepp-c)Cl] (4) (tbu-iepp-c and p-iepp-c denote tbu-iepp and p-iepp bound to Pd(II) through a carbon atom, respectively) were determined by X-ray analysis. Complexes 1a prepared in CH(2)Cl(2)/CH(3)CN and 3 prepared in CH(3)CN have a pyridine nitrogen, an amine nitrogen, a phenolate oxygen, and a chloride ion in the coordination plane. Complex 1b prepared in CH(3)CN has the same composition as 1a and was revealed to have the C2 atom of the indole ring bound to Pd(II) with the Pd(II)-C2 distance of 1.973(2) A. The same Pd(II)-indole C2 bonding was revealed for 4. Interconversion between 1a and 1b was observed for their solutions, the equilibrium being dependent on the solvent used. Reaction of 1b and 4 with 1 equiv of Ce(IV) in DMF gave the corresponding one-electron-oxidized species, which exhibited an ESR signal at g = 2.004 and an absorption peak at approximately 550 nm, indicating the formation of the Pd(II)-indole pi-cation radical species. The half-life, t(1/2), of the indole radical species at room temperature was calculated to be 20 s (k(obs) = 3.5 x 10(-)(2) s(-)(1)) for 1b. The cyclic voltammogram for 1b in DMF gave two irreversible oxidation peaks at E(pa) = 0.68 and 0.80 V (vs Ag/AgCl), which were ascribed to the oxidation processes of the coordinated indole and phenolate moieties, respectively.

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Chronic inflammation contributes to the pathogenesis of several complications of hemodialysis therapy. It is thought that backfiltration of bacteria-derived contaminations during dialysis may induce a chronic inflammatory state. High-sensitivity C-reactive protein (hs-CRP) is one of the tools which can take a hold on such a chronic inflammatory condition. We examined the effect of ultrapure dialysate which contributes to chronic inflammation with hs-CRP and tried to reduce endotoxin (ET) levels at the end of the dialysate from 70 EU/l to <1.0 EU/l (ultrapure dialysate). Other dialysis conditions, except ET level, were fixed. We investigated the hs-CRP of 23 patients receiving regular dialysis before the use of ultrapure dialysate and 1 year after use of it prospectively. The data showed a significant decrease in the median value of the hs-CRP from 0.16 to 0.07 mg/dl (p < 0.05). The value of serum beta(2)-microglobulin decreased from 33.2 to 28.4 mg/dl (p < 0.01) and the hemoglobin level increased from 10.0 to 11.0 g/dl (p < 0.05). These results indicate that even a dialysate containing 70 EU/l of ET level may induce a chronic inflammatory state. hs-CRP is a very useful marker of chronic inflammation and the use of ultrapure dialysate is necessary to improve a chronic inflammatory state. The targeted ET level at the end of the dialysate should be set at < or = 1.0 EU/l.

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OBJECTIVE: Host response to infection and other forms of tissue injury have been termed systemic inflammatory response syndrome (SIRS). This inflammatory response can frequently be accompanied by oxidative injury in one or more organ systems in the body. The objective of this report was to clarify the possible role of oxidative stress in the development of multiple organ failure (MOF) in patients with SIRS. DESIGN: Prospective clinical study. SETTING: Intensive care unit in a university hospital. PATIENTS: A total of 214 consecutive patients (mean age, 57.1 +/- 17.4 yrs; range, 13 to 84 yrs; 148 men and 66 women). At the time of admission, 139 patients fulfilled the clinical criteria for SIRS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured plasma concentrations of thiobarbituric acid reactant substances (TBARS), as an index of oxidative stress, every day from the point of admission to the intensive care unit until discharge or death. Furthermore, all variables of the SIRS score and the Sequential Organ Failure Assessment score were collected every day. At the time of admission, plasma TBARS concentrations in SIRS patients with MOF were significantly higher than those in SIRS patients without MOF (2.3 +/- 0.9 vs. 1.9 +/- 0.6 nmol/mL, p <.01), and there was a significant correlation between plasma TBARS concentration and Sequential Organ Failure Assessment score (r2 =.18, p <.001). Furthermore, the duration of SIRS persistence was significantly associated with the percentage increase in plasma TBARS concentration during SIRS persistence in those patients in whom the duration of SIRS was confirmed (r2 =.73, p <.001). The duration of SIRS was significantly higher in patients who developed MOF than in patients who did not develop MOF (6.9 vs. 3.2 days, p <.001). The percentage increase in plasma TBARS concentration during SIRS was also significantly higher in patients who developed MOF than in patients who did not develop MOF (57.1% vs. 15.8%, p <.001). CONCLUSIONS: It can be concluded that processes of oxidative stress in connection with continued SIRS may promote the development of MOF.

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The interaction between glucose oxidase (GOx) and a typical metal complex, which is chemically stable in both oxidized and reduced forms, has been investigated by a voltammetric method. The evaluation of an electron-transfer mediator useful for glucose oxidation is discussed from thermodynamic and kinetic points of view, i.e. the redox potentials of various metal complexes and the second-order rate constants for the electron transfer between GOx in reduced form and the metal complexes in oxidized form. No mediation of glucose oxidation by [Co(bpy)(3)](2+) (bpy=2,2'-bipyridine) or [Cu(bpy)(2)](2+) occurred, in spite of their appropriate redox potentials. This was attributed mainly to the lower electron-self-exchange rates of the mediator and the reaction with GOx. All three types of osmium(II) complexes, [Os(PP) (n)](2+) ( n=2 or 3; PP=polypyridine), [OsL(2)(PP)(2)](2+) (L=imidazole and its derivatives), and [OsClL(bpy)(2)](+), acted as excellent electron-transfer mediators for the glucose oxidation. Mixed ligand complexes, [OsL(2)(PP)(2)](2+) and [OsClL(bpy)(2)](+), have been concluded to be more efficient electron-transfer mediators. The electron-transfer rates between the mediator and GOx have been found to be accelerated by intermolecular electrostatic interactions or hydrogen bonds.

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OBJECTIVES: The aim of the present study was to investigate whether there is diurnal fluctuation in the endothelial function of patients with variant angina (VA). BACKGROUND: Coronary spasm is induced by acetylcholine and is promptly relieved by nitroglycerin. Thus, it is possible that endothelial dysfunction is involved in the pathogenesis of coronary spasm. Furthermore, the frequency of ischemic episodes is known to display diurnal variation. METHODS: Flow-mediated, endothelium-dependent vasodilation of the brachial arteries was measured in the early morning (6 AM), afternoon (2 PM) and evening (8 PM) in 20 patients with VA (mean age 54.5 years; 10 men and 10 women) and in 20 control subjects (mean age 54.2 years; 10 men and 10 women). All patients underwent 24-h ambulatory electrocardiographic monitoring during the study. RESULTS: Flow-mediated vasodilation in patients with VA was deteriorated by the early morning and improved by the afternoon (patients with VA at 8 PM vs. 6 AM vs. 2 PM: 7.8 +/- 2.1% (p < 0.01 vs. VA at 6 AM) vs. 5.4 +/- 2.3% vs. 8.8 +/- 1.9% (p < 0.01 vs. VA at 6 AM); control subjects: 9.5 +/- 2.8% vs. 9.0 +/- 2.2% vs. 9.9 +/- 1.9%, respectively). The frequency of spontaneous ischemic episodes was highest from midnight to morning and was lowest from morning to late afternoon (4 PM to midnight: 7 episodes; midnight to 8 AM: 25 episodes; 8 AM to 4 PM: 3 episodes). CONCLUSION: There is diurnal fluctuation in endothelial function, which is associated with variation in the frequency of ischemic episodes.

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Hypercholesterolemia impairs endothelial function. However, the production/release of nitric oxide from the hypercholesterolemic aorta is reported to be enhanced rather than impaired in animal studies. L-arginine improves endothelial function in hypercholesterolemic subjects. The goal of the present study was to investigate the effects of L-arginine on endothelial function and oxidative stress in hypercholesterolemic subjects. In 17 hypercholesterolemic male subjects (mean age 41.7 years, mean total cholesterol 264.3 +/- 5.9 mg/dl) and 17 age-matched healthy men as controls (mean total cholesterol 187.1 +/- 6.8 mg/dl), we measured flow-mediated endothelium-dependent vasodilation of the brachial artery during saline infusion and after saline plus L-arginine infusion (30 g for 1 h) with ultrasound technique. In addition, we measured the levels of thiobarbituric acid reactive substances (TBARS), as a marker of lipid peroxide. The flow-mediated vasodilation was lower and the TBARS concentration was higher in the hypercholesterolemic group than in the control group during the saline infusion. The addition of L-arginine increased flow-mediated vasodilation and decreased TBARS concentration in the hypercholesterolemic group (from 3.92 +/- 0.58 to 7.27 +/- 0.53% [P<0.01 by analysis of variance (ANOVA)], from 7.74 +/- 0.46 to 5.71 +/- 0.35 nmol/ml [P<0.01 by ANOVA], respectively), but not in the control group (from 7.74 +/- 0.40 to 8.21 +/- 0.47%, from 5.45 +/- 0.43 to 4.83 +/- 0.35 nmol/ml, respectively). The endothelial function is blunted, and the oxidative stress is increased in hypercholesterolemic subjects. L-arginine improves endothelial function with decreasing oxidative stress. The augmentation of nitric oxide production/release induced by L-arginine may act as an antioxidant, and contributes to the improvement of endothelial function in hypercholesterolemic subjects.

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