Human serum paraoxonase concentration predicts cardiovascular mortality in hemodialysis patients.

AIMS: Human serum paraoxonase (PON1) is associated with high-density lipoprotein, and inhibits oxidative modification of low-density lipoprotein. Therefore, PON1 is supposed to contribute to the prevention of atherosclerosis. We and other investigators have shown that the enzymatic activities and concentrations of PON1 were decreased in maintenance hemodialysis (HD) patients. However, the effect of PON1 status on the long-term outcome of HD patients has not been reported. In this study, we examined the association between baseline PON 1 status and cardiovascular mortality in an observation study of an outpatient HD population. PATIENTS AND METHODS: The relation between baseline cardiovascular risk factors and clinical events was investigated, during 6 years of follow-up, in 81 HD patients (50 males and 31 females) whose enzymatic activities, concentrations and genetic polymorphisms of PON1 had been determined in a previous study. RESULTS: During follow-up for 6 years, we recorded 42 deaths, including 24 fatal cardiovascular events. In univariate analyses, baseline PON1 concentration was associated with not only cardiovascular mortality (p < 0.005), but also all-cause mortality (p < 0.001) during the period of follow-up, as were age, preexisting cardiovascular disease (CVD) and hemoglobin concentration. In a multivariate Cox regression analysis, PON1 concentration retained significant associations with cardiovascular mortality (p < 0.05) and all-cause mortality (p < 0.005) even after correction of known risk factors for CVD or mortality in HD patients. Using Kaplan-Meier survival curves, we assessed the association between low and high concentrations of PON1 divided according to the median value (7.52 U/ml). Significantly increased cardiovascular mortality (log rank 6.125, p = 0.01) and all-cause mortality (log rank 7.113, p < 0.01) were detected in the patients with low PON1 concentrations. CONCLUSIONS: These data suggest that low PON 1 concentration may be an independent predictor of cardiovascular mortality in maintenance HD patients.

Weber-Christian disease presenting with ocular manifestations.

A Japanese patient with Weber-Christian disease (WCD) presenting with ocular symptoms is reported. Panniculitis in the retrobulbar fat was diagnosed according to the histological findings from biopsy specimens, and improved over a month under steroid administration. Only three patients showing ocular manifestations have previously been reported. Panniculitis was in the late stage and a medium dose of prednisolone was effective in this patient. A biopsy of the orbital fat was useful for diagnosis. However, it is important to recognise that the stage of inflammation varies according to the fat tissue involved by WCD.

Serum paraoxonase and arylesterase activities in hemodialysis patients.

Cardiac death from atherosclerosis is common in hemodialysis patients. Human serum paraoxonase (PON1), an esterase, is associated with high-density lipoprotein and inhibits the susceptibility to oxidization of low-density lipoprotein (LDL). The PON1 genetic polymorphisms of 192 Gln/Arg and 55 Leu/Met in the amino acid sequence are partly involved in the PON1 enzyme activity. We investigated the PON1 enzyme activities for paraoxon (paraoxonase) and phenylacetate (arylesterase), and the two polymorphisms in 96 patients undergoing hemodialysis and in 136 normal controls. Both activities were significantly lower in the hemodialysis patients than in the controls (97+/-43 vs 155+/-57 micromol/min/l for paraoxonase, and 71+/-20 vs 92+/-22 mmol/min/l for arylesterase, respectively). There was no difference in the distribution of the two polymorphisms between patients and controls, and in every subgroup classified by the polymorphisms, both paraoxonase and arylesterase activities were lower in patients than in controls. This suggested that the enzyme activities of PON1 decreased in hemodialysis patients, independent of the genetic polymorphism. The decrease in PON1 enzyme activity in hemodialysis patients may modify a susceptibility to oxidization of LDL, which contributes to an acceleration of atherosclerosis.

Abrupt-onset diabetes mellitus in the elderly.

We present three elderly Japanese patients with abrupt onset of diabetes mellitus: a 61-year-old male with a complete defect of insulin secretion without insulin resistance, a 60-year-old male with an incomplete defect of insulin secretion associated with insulin resistance, and a 69-year-old female with a complete defect of insulin secretion and insulin resistance. The findings in these cases indicate the heterogeneity in insulin secretion and sensitivity of abrupt onset diabetes mellitus in the elderly. The changes in insulin secretion and sensitivity over time due to glucose toxicity may at least partially explain the heterogeneity.

Serum amyloid A protein in patients with non-insulin-dependent diabetes mellitus.

We determined the serum amyloid A protein (SAA) levels in patients with non-insulin-dependent diabetes mellitus (NIDDM), and investigated the possible association between SAA and the complications of NIDDM. The concentrations of SAA were measured in the plasma of 105 patients with NIDDM (52 men and 53 women, age mean +/- SD, 61 +/- 13 years) and 91 healthy subjects (37 men and 54 women, aged 57 +/- 11 years). SAA concentrations were assayed by enzyme-linked immunosorbent assay. SAA concentrations in the patients with NIDDM were significantly higher than those in healthy subjects (2.1 +/- 1.3 vs. 1.2 +/- 0.5 mg/L). There were no obvious relationships between SAA levels and duration of diabetes, type of therapy, or control of blood sugar in the patients with NIDDM. However, SAA levels in patients with NIDDM increased significantly, with increase of urinary albumin excretion (p = 0.027). The increase of SAA in the patients with NIDDM did not influence the serum concentrations of lipid or lipoprotein. The SAA concentration in NIDDM was unrelated to the type of treatment, but seemed to be related to the development of diabetic nephropathy.

Oxidation of nucleosides and nucleotides by peroxosulfate ions.

Treatment of 5-methylpyrimidine nucleosides and nucleotides with sodium peroxodisulfate in sodium phosphate buffer solution at pH 7.0 at 75 degrees C resulted in the selective oxidation of the methyl group. On the other hand, oxidation of thymidine by potassium peroxomonosulfate gave thymidine glycols.

Oxidation of pyrimidine bases and their derivatives by sodium peroxodisulfate.

Treatment of 1,3-dimethyluracil (1) with sodium peroxodisulfate in water at 80 degrees C under nitrogen gave 5-hydroxy-1,3-dimethyluracil (6) as a main product. Under similar conditions, oxidation of 5-fluoro-1,3-dimethyluracil (2) gave a 6,6'-dimeric compound (10) together with other products. Similar oxidation of 5-bromo-1,3-dimethyluracil (3) and 1,3,6-trimethyluracil (4) was also investigated. Furthermore, reaction of 1,3-dimethylthymine (5) and adenine in the presence of sodium peroxodisulfate gave coupling products (12) and (13).

Oxidation of pyrimidine bases and their derivatives with hydrogen peroxide in hydrochloric acid.

Oxidation of cytosine with H2O2 in 1 N-HCl gave 5-chlorocytosine and 5-chlorouracil. The reaction of uracil gave 5-chlorouracil. Treatment of thymine with H2O2 in 0.1 N-HCl gave 5-chloro-6-hydroperoxy-5,6-dihydrothymine, while the reaction in 1 N-HCl gave 5-chloro-6-hydroxy-5,6-dihydrothymine. Heating of 5-chloro-6-hydroperoxy-5,6-dihydrothymine in water gave 5-chloro-5-methylbarbituric acid.

Reaction of nucleic acids bases and their derivatives with peroxodisulfate ion.

Reaction with peroxodisulfate ion was investigated, that is, reaction of 1,3-dimethyluracil, 1,3-dimethylthymine, and caffeine with carbon radicals formed from decarboxylation of carboxylic acids, oxidation of the methyl group at 5-position of thymines, and halogenation of nucleic acids bases and their derivatives with alkali halides.