Clozapine attenuates mitochondrial burdens and abnormal behaviors elicited by phencyclidine in mice via inhibition of p47 phox; Possible involvements of phosphoinositide 3-kinase/Akt signaling.

BACKGROUND: Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of schizophrenia. AIMS: We investigated whether antipsychotic clozapine modulates nicotinamide adenine dinucleotide phosphate oxidase and mitochondrial burdens induced by phencyclidine in mice. METHODS: We examined the effect of clozapine on nicotinamide adenine dinucleotide phosphate oxidase activation, mitochondrial burdens (i.e. oxidative stress and mitochondrial dysfunction), and activities of enzymatic antioxidant in the prefrontal cortex, and subsequent abnormal behaviors induced by repeated treatment with phencyclidine. p47 phox Knockout mice and LY294002, a phosphoinositide 3-kinase inhibitor, were employed to elucidate the pharmacological mechanism of clozapine. RESULTS: Phencyclidine treatment resulted in an early increase nicotinamide adenine dinucleotide phosphate oxidase activity, membrane translocation of p47 phox, interaction between p-Akt and p47 phox, and mitochondrial burdens in wild-type mice. Although these increases returned to near control level four days post-phencyclidine, mitochondrial superoxide dismutase and glutathione peroxidase activities were decreased at that time. Clozapine, LY294002, or p47 phox knockout significantly ameliorated social withdrawal and recognition memory deficits produced by phencyclidine. Importantly, LY294002 did not significantly alter the effects of clozapine against abnormal behaviors and the interaction between p-Akt and p47 phox induced by phencyclidine. Furthermore, neither LY294002 nor clozapine exhibited any additive effects to the protection afforded by p47 phox knockout against phencyclidine insult. CONCLUSION: Our results suggest that p47 phox gene mediates phencyclidine-induced mitochondrial burdens and abnormal behaviors, and that the interactive modulation between p47 phox and phosphoinositide 3-kinase/Akt is important for the understanding on the pharmacological mechanism of clozapine.

Unconstrained Sleep Stage Estimation Based on Respiratory Dynamics and Body Movement.

OBJECTIVES: The aim of this study is to establish a sleep monitoring method that can classify sleep into four stages in an unconstrained manner using a polyvinylidene fluoride (PVDF) sensor for continuous and accurate estimation of sleep stages. METHODS: The study participants consisted of 12 normal subjects and 13 obstructive sleep apnea (OSA) patients. The physiological signals of the subjects were unconstrainedly measured using the PVDF sensor during polysomnography. The respiration and body movement signals were extracted from the PVDF data. Rapid eye movement (REM) sleep was estimated based on the average rate and variability of the respiratory signal. Wakefulness was detected based on the body movement signal. Variability of the respiratory rate was chosen as an indicator for slow-wave sleep (SWS) detection. Sleep was divided into four stages (wake, light, SWS, and REM) based on the detection results. RESULTS: The performance of the method was assessed by comparing the results with a manual scoring by a sleep physician. In an epoch-by-epoch analysis, the method classified the sleep stages with an average accuracy of 70.9 % and kappa statistics of 0.48. No significant differences were observed in the detection performance between the normal and OSA groups. CONCLUSIONS: The developed system and methods can be applied to a home sleep monitoring system.

Extremely low frequency magnetic field induces oxidative stress in mouse cerebellum.

We have investigated whether extremely low frequency magnetic field (ELF-MF) induces lipid peroxidation and reactive oxygen species in mouse cerebellum. After exposure to 60 Hz ELF-MF at 2.3 mT intensity for 3 hours, there was a significant increase in malondialdehyde level and hydroxyl radical. ELF-MF significantly induced concomitant increase in superoxide dismutase without alteration in glutathione peroxidase activity. While glutathione contents were not altered, ascorbic acid levels were significantly decreased by ELF-MF exposure. These results indicate that ELF-MF may induce oxidative stress in mouse cerebellum. However, the mechanism remains further to be characterized.

A clinical study of the pulse wave characteristics at the three pulse diagnosis positions of chon, gwan and cheok.

In this work, we analyze the baseline, signal strength, aortic augmentation index (AIx), radial AIx, time to reflection and P_T2 at Chon, Gwan, and Cheok, which are the three pulse diagnosis positions in Oriental medicine. For the pulse measurement, we used the SphygmoCor apparatus, which has been widely used for the evaluation of the arterial stiffness at the aorta. By two-way repeated measures analysis of variance, we tested two independent measurements for repeatability and investigated their mean differences among Chon, Gwan and Cheok. To characterize further the parameters that were shown to be different between each palpation position, we carried out Duncan's test for the multiple comparisons. The baseline and signal strength were statistically different (P < .05) among Chon, Gwan and Cheok, respectively, which supports the major hypothesis of Oriental medicine that all of the three palpation positions contain different clinical information. On the other hand, aortic AIx and time to reflection were found to be statistically different between Chon and the others, and radial AIx and P_T2 did not show any difference between pulse positions. In the clinical sense, however, the aortic AIx at each palpation position was found to fall within the 90% confidence interval of normal arterial compliance. The results of the multiple comparisons indicate that the parameters of arterial stiffness were independent of the palpation positions. This work is the first attempt to characterize quantitatively the pulse signals at Chon, Gwan and Cheok with some relevant parameters extracted from the SphygmoCor apparatus.

Individual and village-level study of water contact patterns and Schistosoma japonicum infection in mountainous rural China.

OBJECTIVE: To describe the exposure patterns related to schistosomiasis transmission in 10 villages in rural Xichang County, Sichuan, China. METHODS: Individual and village-level study of water contact exposure and Schistosoma japonicum reinfection; after initial infection survey and treatment, reinfection was determined 2 years later for 1604 individuals, of whom 578 also participated in a cross-sectional survey to assess their water contact behaviours. RESULTS: The highest intensity of reinfection was observed in farmers aged 20-29 years, with no difference between sexes. While water contact measured as m(2)-minutes of contact was not associated with reinfection, an exposure metric computed by spatially weighting water contact by cercarial risk was correlated with both infection status and intensity. Village-level indicators based on snail density, number of infected snails, mouse bioassay data, and averaged individual-level exposures were associated with village reinfection rates. CONCLUSION: Age-acquired immunity may be present in this population, but the study lacked sufficient power to discern differences in the exposure infection relationship with age.