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Background. This study aimed to determine the perioperative change in serum double-strand DNA (dsDNA) as a marker potentially reflecting neutrophil extracellular trap concentration in samples from patients undergoing cardiac surgery and to analyze a relationship between serum dsDNA concentrations and perioperative renal dysfunction. Methods. Serum dsDNA concentrations in samples that were collected during a previously conducted, prospective, multicenter, observational study were measured. Eighty patients undergoing elective cardiac surgery were studied. Serum samples were collected at baseline, immediately after surgery, and the day after surgery (POD-1). Results. Serum dsDNA concentration was significantly increased from baseline (median, 398 ng/mL [interquartile range, 372–475 ng/mL]) to immediately after surgery (median, 540 ng/mL [437–682 ng/mL], p < 0.001), and they were reduced by POD-1 (median, 323 ng/mL [256–436 ng/mL]). The difference in serum creatinine concentration between baseline and POD-1 was correlated with dsDNA concentration on POD-1 (r s = 0.61, p < 0.001). Conclusions. In patients undergoing cardiac surgery, serum dsDNA concentration is elevated postoperatively. Prolonged elevation in dsDNA concentration is correlated with perioperative renal dysfunction. Further large-scale studies are needed to determine the relationship between serum concentration of circulating dsDNA and perioperative renal dysfunction.

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PurposePropofol infusion syndrome (PRIS) is a lethal condition caused by propofol overdose. Previous studies suggest that pathophysiological mechanisms underlying PRIS involve mitochondrial dysfunction; however, these mechanisms have not been fully elucidated. This study aimed to establish an experimental model of propofol-induced cytotoxicity using cultured human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to determine the mechanisms behind propofol-induced mitochondrial dysfunction, and to evaluate the protective effects of coenzyme Q10 (CoQ10).MethodsHuman iPSC-derived cardiomyocytes were exposed to propofol (0, 2, 10, or 50 µg/ml) with or without 5 µM CoQ10. Mitochondrial function was assessed by measuring intracellular ATP, lactate concentrations in culture media, NAD+/NADH ratio, and the mitochondrial membrane potential. Propofol-induced cytotoxicity was evaluated by analysis of cell viability. Expression levels of genes associated with mitochondrial energy metabolism were determined by PCR. Intracellular morphological changes were analyzed by confocal microscopy.ResultsTreatment with 50 µg/ml propofol for 48 h reduced cell viability. High concentrations of propofol (≥ 10 µg/ml) induced mitochondrial dysfunction accompanied by downregulation of gene expression of PGC-1alpha and its downstream targets (NDUFS8 and SDHB, which are involved in the respiratory chain reaction; and CPT1B, which regulates beta-oxidation). Cardiomyocytes co-treated with 5 µM CoQ10 exhibited resistance to propofol-induced toxicity through recovery of gene expression.ConclusionsPropofol-induced cytotoxicity in human iPSC-derived cardiomyocytes may be associated with mitochondrial dysfunction via downregulation of PGC-1alpha-regulated genes associated with mitochondrial energy metabolism. Co-treatment with CoQ10 protected cardiomyocytes from propofol-induced cytotoxicity.

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Many b 2 -adrenoceptor agonists possess a benzylalcohol moiety with chirality at the b-carbon atom, and the pharmacological activity resides predominantly in the (R)-(Ϫ)-enantiomer.1) It is well known that the racemization of b 2 -adrenoceptor agonists such as catecholamines occurs in aqueous solution, 2,3) though many studies were conducted only in the acidic region. 4,5) Meluadrine tartrate ( Fig. 1) is a novel b 2 -adrenoceptor agonist which inhibits spontaneous rhythmic contraction of the uterus.6) The drug is used as the optically pure (R)-enantiomer. This paper deals with a kinetic study of meluadrine tartrate racemization over the pH range from 1.2 to 12. ExperimentalMaterials Meluadrine ((R)-enantiomer) L-tartrate and its (S)-enantiomer L-tartrate were synthesized at Hokuriku Seiyaku Co., Ltd. All other reagents were of analytical grade.HPLC Conditions for Enantiomer Assay HPLC (Jasco, Tokyo, Japan) with a ULTRON ES-OVM (4.6 i.d.ϫ150 mm, 5 mm particle size) column was used to determine the ratio of (R)-enantiomer and (S)-enantiomer. The mobile phase was a mixture of pH 6.8 phosphate buffer-methanol (9 : 1, v/v). The detector wavelength was set at 220 nm, the flow rate of the mobile phase was 0.6 ml min Ϫ1 and the column temperature was 30°C. The retention times of (R)-enantiomer and (S)-enantiomer were about 8 and 18 min, respectively.HPLC Conditions for Assay of Total Residual Percent of Meluadrine HPLC (Jasco, Tokyo, Japan) with a TSKgel ODS-80T M (4.6 i.d.ϫ150 mm, 5 mm particle size) column was used to determine the total residual percent of (R)-enantiomer and (S)-enantiomer. The mobile phase was a mixture of pH 2.5 phosphate buffer containing sodium 1-heptanesulfonate-acetonitrile (3 : 1, v/v). The detector wavelength was set at 220 nm, the flow rate of mobile phase was 1.0 ml min Ϫ1 and the column temperature was 30°C. The retention times of meluadrine and internal standard (clorprenaline) were about 6 and 8 min, respectively. Calculation of Residual Percent of (R)-Enantiomer and Formed Amount of (S)-EnantiomerThe residual percent of (R)-enantiomer and the formed amount of (S)-enantiomer were calculated from enantiomer ratio of the above enantiomer assay and total residual percent.Kinetic Procedure The sample ((R)-enantiomer or (S)-enantiomer) was dissolved in Britton-Robinson buffer or diluted hydrochloric acid adjusted to the appropriate pH from 1.2 to 12, to give a concentration of 10 mg ml Ϫ1 . Aliquots of 10 ml were put in glass ampules, which were then sealed. The ampules were placed in a chamber heated at 40, 60 or 80°C. At intervals, samples were removed from the chamber and assayed. Determination of Ionization ConstantsThe apparent ionization constants of meluadrine were determined by potentiometry and spectrophotometry. The apparent ionization constants pK a1 and pK a2 , which refer to the dissociation of the phenolic group and the amino group, were 8.35 and 9.99, respectively (Chart 1). Results and DiscussionAs shown in Fig. 2, semilogarithmic plots of the residual percent of total meluad...

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Because of the large variation in the recovery from rocuronium-induced paralysis, TOF-based evaluation of residual paralysis is essential to determine the appropriate indication for reversal, especially for elderly patients.