Characterization of fluoride inhibition in photosystem II lacking extrinsic PsbP and PsbQ subunits.

Photosynthetic oxygen evolution occurs through the oxidation of water at a catalytic Mn4CaO5 cluster in photosystem II and is promoted by chloride, which binds at two sites near the Mn4CaO5 cluster. Fluoride is a competitive inhibitor of chloride activation, but study of its effects is complicated by the possibility that it may form an insoluble CaF2 complex. In this study, the effects of fluoride were studied using PSII lacking the PsbP and PsbQ subunits, which help to regulate the requirements for the inorganic cofactors Ca2+ and Cl-. In this preparation, which allows easy exchange of ions, it was found that F- does not directly remove Ca2+ even when catalytic turnovers take place, suggesting that fluoride is not able to access the inner coordination sphere of Ca2+. By monitoring the loss in O2 evolution activity, the dissociation constant of F- was estimated to be about 1 mM in intact PSII, consistent with previous studies, and about 77 mM in PSII lacking the extrinsic subunits. The significantly higher value for PSII lacking PsbP and PsbQ is consistent with results for other ions. The effects of F- on electron transfer to Tyr Z was also studied and found to show similar trends in PSII with and without the two extrinsic subunits, but with a more pronounced effect in PSII lacking the extrinsic subunits. These results indicate that in PSII lacking PsbP and PsbQ, fluoride does not directly interact with or remove Ca2+ and inhibits O2 evolution in a manner comparable to PSII with the extrinsic subunits intact.

Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients.

BACKGROUND AND OBJECTIVES: No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus METHODS: The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. RESULTS: Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. CONCLUSION: Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.

Effects of water deprivation on the pharmacokinetics of theophylline and one of its metabolites, 1,3-dimethyluric acid, after intravenous and oral administration of aminophylline to rats.

It has been reported that the expressions of hepatic microsomal cytochrome P450 (CYP) 1A1/2, 2B1/2 and 3A1/2 were not changed in rats with water deprivation for 72 h (rat model of dehydration) compared with the controls. It has been also reported that 1,3-dimethyluric acid (1,3-DMU) was formed from theophylline via CYP1A1/2 in rats. Hence, it could be expected that the formation of 1,3-DMU could be comparable between the two groups of rats. As expected, after both intravenous and oral administration of theophylline at a dose of 5 mg/kg to the rat model of dehydration, the AUC of 1,3-DMU was comparable to the controls. After both intravenous and oral administration of theophylline to the rat model of dehydration, the Cl(r) of both theophylline and 1,3-DMU was significantly slower than the controls. This could be due to significantly smaller urinary excretions of both theophylline and 1,3-DMU since the AUC of both theophylline and 1,3-DMU were comparable between the two groups of rats. The smaller urinary excretion of both theophylline and 1,3-DMU could be due to urine flow rate-dependent timed-interval renal clearance of both theophylline and 1,3-DMU in rats.

Pharmacokinetics of DA-7218, a new oxazolidinone, and its active metabolite, DA-7157, after intravenous and oral administration of DA-7218 and DA-7157 to rats.

DA-7218 (a prodrug of DA-7157), a new oxazolidinone, was hydrolysed via phosphatase to form its active metabolite, DA-7157, in rats. The pharmacokinetic parameters of DA-7218 and DA-7157 were evaluated after intravenous (5, 10 and 20 mg kg(-1)) and oral (20, 50 and 100 mg kg(-1)) administration of DA-7218 to rats. DA-7218 and DA-7157 exhibited dose-proportional pharmacokinetics after both intravenous and oral administration of DA-7218 to rats. The stability of DA-7218 and DA-7157, blood partition of DA-7157, and the plasma protein binding of DA-7157 were also evaluated. DA-7218 was unstable in rat blood, plasma, bile and liver homogenates, but DA-7157 was stable, suggesting that DA-7218 is hydrolysed via phosphatase. DA-7157 rapidly reached equilibrium between plasma and blood cells, and the mean equilibrium plasma-to-blood cells ratio was 3.18, indicating that binding of DA-7157 to blood cells was not considerable. The protein binding of DA-7157 in fresh rat plasma was 93.4%.

Seasonality in a community sample of bipolar, unipolar and control subjects.

BACKGROUND: This study examined seasonality in a community sample of five diagnostic groups: normal subjects, those with non-seasonal depression (NSD), seasonal depression (SD), non-seasonal bipolar disorder (NSBD) and seasonal bipolar disorder (SBD). METHODS: Telephone interviews were conducted across the Province of Ontario. Seasonal changes in mood and behaviour were determined using the Seasonal Pattern Assessment Questionnaire (SPAQ). Five additional seasonality items consisting of depressive symptoms were included in the interview. The mean global severity of seasonality (GSS) scores were obtained and the entire inventory of 11 seasonality items were compared across the identified groups. RESULTS: The mean GSS score for the controls was 5.2 (S.D. = 4.0), 8.0 (S.D. = 4.9) for NSD, 10.5 (S.D. = 3.9) for SD, 10.5 (S.D. = 5.4) for NSBD and 13.4 (S.D. = 5.4) for SBD. These scores differed significantly (F = 61.68, df = 4, p < 0.001). For the majority of the individual items, the SBD group rated the highest degree of seasonal fluctuation, while the NSBD and SD groups had nearly identical item scores. LIMITATIONS: Limitations in this study include the relatively small number of subjects in the NSBD and SBD groups, and the inherent limitations in a telephone interview. CONCLUSIONS: Individuals with bipolar disorder experience greater seasonality than those with depression or healthy controls. Even the non-seasonal bipolar group had as much seasonal fluctuation as the seasonal depression group, which has important implications for the management of bipolar illness.

Risk of cesarean delivery in nulliparous women at greater than 41 weeks' gestational age with an unengaged vertex.

OBJECTIVE: The purpose of this study was to determine whether an unengaged vertex significantly increased the risk of cesarean delivery in nulliparous patients at 41 weeks or greater. STUDY DESIGN: The medical records from all nulliparous patients greater than 41 weeks' gestation delivered at a single institution were reviewed. Patients undergoing both spontaneous and induced labor were included. Multivariate analyses were used to compare the influence of admission fetal station versus induction of labor on the risk of cesarean delivery. RESULTS: Four hundred forty-eight nulliparous women at greater than 41 weeks' gestation were delivered at our institution during the study period. Sixty-two percent of these patients underwent induction of labor. There was a statistically significant increase in cesarean delivery rate compared with station (6% of patients at -1 station, 20% at -2 station, 43% at -3 station, and 77% at -4 station; P=.001). Compared with patients with an engaged vertex, patients with an unengaged vertex had 12.4 times the risk of cesarean delivery. Most of the cesarean deliveries were performed for failure to progress. On the basis of multivariate analysis, the odds of cesarean delivery were better predicted by fetal station than induction of labor. CONCLUSION: Nulliparous patients at 41 weeks or greater with an unengaged vertex are 12.4 times more likely to be delivered by cesarean section than a patient with an engaged vertex.