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The therapeutic goals of patients with chronic pain are not only to relieve pain but also to improve the quality of life. Chronic pain negatively affects various aspects of daily life, such as by decreasing the motivation to work and reward sensitivity, which may lead to difficulties in daily life or even unemployment. Human and animal studies have shown that chronic pain damages reward processing; the exploration of associated internal mechanisms may aid the development of treatments to repair this damage. Incentive salience theory, used widely to describe reward processing, divides this processing into “liking” (reward-induced hedonic sensory impact) and “wanting” (reward-induced motivation) components. It has been employed to explain pathological changes in reward processing induced by psychiatric disorders. In this review, we summarize the findings of studies of reward processing under chronic pain and examine the effects of chronic pain on “liking” and “wanting.” Evidence indicates that chronic pain compromises the “wanting” component of reward processing; we also discuss the neural mechanisms that may mediate this effect. We hope that this review aids the development of therapies to improve the quality of life of patients with chronic pain.

For the problem of voltage imbalance among different types of sub-module in VSC-UHVDC hybrid MMC group with DC link short-connected, a controllable pre-charging strategy was proposed. Firstly, the locked-charging characteristic of hybrid MMC group with HBSM and FBSM was analyzed, and the problem that different types of submodules can't be charged equally as well as HBSM can't be powered up were pointed out. Therefore, to pre-charge both sub-modules balanced and controllable, a strategy that switch-off some sub-modules in the special arms was proposed, and the selection criteria for arm and calculating method for sub-module's cut-off number were given. Finally, simulation in Matlab/Simulink was conducted. The results show that the controllable pre-charging strategy can effectively respond to the DC link short-connected start-up condition of hybrid MMC and has engineering feasibility.

In order to investigate the effects of slurry recirculation technology on anaerobic digestion performance of maize straw silage, maize straw silage was fermented with recirculated biogas slurry, and the gas production, pH value, methane content, volatile organic acids (VFAs) contents, chemical oxygen demand (COD) removal rate and other indicators were studied. The results showed that the fermentation time was positively correlated with daily gas production, methane content, cumulative gas production, VFAs and COD removal rate. Although the pH value fluctuated, it was still in the normal reaction range. The daily gas production was about 1.26 L. The acetic acid content increased first, then decreased, then increased, and finally stabilized. The biogas slurry recirculation technology saves water resources by 40 mL/d without affecting the normal gas production of anaerobic fermentation, and reduces the consumption of environmental resources. It has important development significance for the sustainable use of biomass resources.

To decrease fertilization amount of chemical fertilizer and improve the quality of vegetable crops, spinach was taken as the test material, and the impact of different fertilizer on spinach growth and yield was studied via the manners of biological organic fertilizer and organic fertilizer+chemical fertilizer. Experimental results showed that in the formula of organic fertilizer+chemical fertilizer, chlorophyll and nitrogen contents in spinach leaves obviously increased; in the formula of only adding organic fertilizer, spinach leaf temperature, leaf width, root length, plant height and fresh weight were all better than those in the formula of organic fertilizer+chemical fertilizer, and better formulas were A5, E5, F3 and I5, in which spinach plant height in E5 was 5.63 times higher than G5, root length in E5 was 2.67 times higher than G5, and fresh weight in G5 was 32.6 times higher than G5. By comprehensive analysis, the most suitable formula for spinach production was E5, and the research could provide theoretic basis for fertilization amount of organic fertilizer required by spinach growth and development.

The aim of this study was to investigate effects of type 2 diabetes on the pharmacokinetics of verapamil after intravenous administration. Diabetes mellitus (DM) rats were induced by combination of high-fat diet (HFD) and streptozotocin. Plasma concentrations of verapamil in DM rats, rats fed with HFD, and control (CON) rats were measured after intravenous administration of 1 mg/kg verapamil and corresponding pharmacokinetic parameters were estimated. Area under the plasma concentration in DM rats was significantly smaller than that in CON rats. In vitro microsomal study showed that intrinsic clearance of verapamil in DM rats was significantly higher than those in CON rats. Compared to CON rats, higher intrinsic clearance was also observed in HFD rats. Western blot results demonstrated higher levels of CYP3A2 in DM and HFD rats, which was in line to activity of CYP3A. All the results gave a conclusion that diabetes may enhance metabolism of verapamil in rat, and the enhancement may partly result from induction of CYP3A.

A recent focus was to investigate whether antofloxacin, an 8-NH(2) derivative of levofloxacin, inhibited cytochrome P450 (CYP) 1A2 activity in rats. Phenacetin, the representative substrate of CYP1A2, was used as the model drug to evaluate the activity of CYP1A2. In an in vivo study, an oral single dose of antofloxacin (20 mg kg(-1)) did not affect the pharmacokinetic behaviour of phenacetin, but a multidose (20 mg kg(-1) twice daily for 7.5 days) significantly increased phenacetin's area under the curve (AUC). In an in vitro study, only when pre-incubated with beta-nicotinamide adenine dinucleotide phosphate, a reduced form (NADPH) system in rat liver microsomes, did antofloxacin inhibit phenacetin O-deethylation. The inhibition was NADPH-, pre-incubation time-, and antofloxacin concentration-dependent. A physiologically based pharmacokinetic model with mechanism-based inhibition was successfully developed for predicting the interaction between antofloxacin and phenacetin in vivo from the in vitro data. The simulated AUC was 1.4-fold of the control, which was near the observed value of 1.6-fold. From the results, it can be concluded that the inhibition of CYP1A2 by antofloxacin is mechanism-based.

Our aim was to investigate whether renal impairment induced by cisplatin altered the pharmacokinetics of antofloxacin. Antofloxacin (7.5 mg kg−1, i.v.) was given to normal or renally impaired rats (induced by cisplatin). Concentrations of antofloxacin in plasma and urine were measured using HPLC. Pharmacokinetic parameters were estimated. The plasma concentrations of antofloxacin in the renally impaired rats were significantly higher than those in the normal rats, accompanied by significant increase of the area under the plasma concentration-time curve (AUC) (968.78 ± 259.39 μg min mL−1 versus 509.84 ± 46.19 μg min mL−1 in normal rats P < 0.05). The system clearance (CL) and renal clearance (CLR) of antofloxacin decreased from 12.66 ± 1.15 mL kg−1 min−1 and 3.21 ± 1.80 mLkg−1 min−1 in normal rats, to 6.63 ± 2.82 mLkg−1 min−1 and 0.31 ± 0.15 mLkg−1 min−1, respectively. No differences between two treatments in half-life and mean residence time were found. We concluded that renal impairment induced by cisplatin significantly altered the pharmacokinetics of antofloxacin and resulted in decrease of the renal elimination.

1. The aim of the current study was to investigate the characteristics of biliary excretion of antofloxacin (ATFX) in rats. Rats received a bolus intravenous injection followed by a constant-rate infusion of ATFX. When plasma concentrations of ATFX reached steady state, cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac were administered intravenously to the rats. Samples of blood and bile were collected and the concentrations of ATFX were measured and the corresponding pharmacokinetic parameters were estimated. 2. Biliary excretion of ATFX was observed in rats subjected to CCl(4)-induced experimental hepatic injury for 24 h (CCl(4)-EHI(24h)). Steady state concentrations of ATFX were attained at 60 min following infusion. 3. A slight increase in concentration of ATFX in plasma was observed after cyclosporin A, erythromycin, probenecid and cimetidine treatment. Significant increases in ATFX plasma levels were found in rats treated with diclofenac. Cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac treatment significantly decreased the steady state biliary clearance of ATFX to 55, 68, 54, 53 and 56% of control values, respectively. 4. Cyclosprin A, probenecid, erythromycin and cimetidine also inhibited the biliary excretion of ATFX glucuronide. Significant decrease in the steady state biliary clearance of ATFX and its glucuronide was observed in CCl(4)-EHI(24h) rats. 5. These results indicate that multiple transporters are possibly involved in the biliary excretion of ATFX.

Protein deacetylases play an extremely crucial role in cellular biological processes and have been categorized into four families (HDACⅠ, HDACⅡ, HDACⅢ and HDACⅣ) in human. Of them, HDACⅢ, also known as the Sir2 (Silent information regulator 2) family, contains seven members, SIRT1-7, each exhibiting different cellular localization and biological function. As a major mitochondrial deacetylase, SIRT3 not only modulates cellular metabolism, but also plays important roles in apoptosis, tumor growth, aging and a number of other diseases. In this review, we summarize recent findings related to SIRT3 with an emphasis on its biological functions in regulating cell metabolism and its possible roles in cardiovascular diseases.

In the present study, the pharmacokinetics of limonin (LM) were investigated in male and female rats. LM concentrations in the plasma were determined after the oral administration of 36 mg/kg LM or after intravenous (i.v.) injection of LM 3.6 mg/kg respectively. Concentrations in the tissues, urine, feces and bile were also analyzed following the oral administration of 36 mg/kg of the test product. It was found that the plasma concentrations of LM in female rats were significantly higher (P < 0.01) than those in male rats. Assessment of the effects of limonin based on the C(max) and AUC in female rats showed that levels were about 50-fold higher than those in male rats after oral administration of 36 mg/kg LM. Furthermore, after i.v. administration of 3.6 mg/kg LM, the C(max) and AUC in female rats was found to be about 3-fold higher than those in male rats. The total excretion of LM in the urine and bile of female rats was also found to be significantly higher than in male rats, which displayed lower concentrations of LM in the tissues, amounting to around one-half to one-tenth of those in female rats, apart from levels in the rectum and duodenum. In conclusion, the present results demonstrate the existence of marked gender difference in LM pharmacokinetics in rats.

Astrocytes are organized in networks via gap junction channels constituted by connexin (Cx) 30 and Cx43. Since we observed that the mRNA expression of Cx30, but not Cx43, was enhanced after sleep deprivations (SD) in the mouse cortex and hippocampus, the goal of my thesis was to investigate whether and how Cx30 is involved in sleep homeostasis. First, I investigated the effects of sleep/wake-affecting molecules on gap junctional communication (GJC) of astrocytes in acute slices of the mouse cortex. We found that modafinil, a wakefulness-promoting drug, enhanced astroglial GJC, whereas γ-Hydroxybutyric acid (GHB), a sleep-promoting agent, and two general anesthetics, propofol and ketamine, decreased GJC, suggesting that astroglial networks are bidirectionally regulated by sleep/wake-affecting drugs. Then I addressed the role of Cx30 using Cx30 knockout (KO) mice. Compared to wild type (WT) mice, Cx30 KO exhibited a deficit in maintaining wakefulness during periods of high sleep pressure: they needed more stimuli to be maintained awake during gentle SD and they exhibited an increase in slow wave sleep during instrumental SD. To probe the possible causes of the phenotype, we found that: 1) astroglial GJC was enhanced in WT mice after SD, and such enhancement depended on both neuronal activity and the presence of Cx30; 2) mRNA levels of several genes involved in brain energy metabolism were decreased in multiple brain structures of the Cx30 KO. In summary, these results suggest that astroglial Cx30 plays an important role in sleep homeostasis, possibly by enhancing astroglial metabolic functions to fulfil the high energy demand during periods of elevated sleep pressure., Une propriété des astrocytes réside dans leur organisation en réseaux grâce à la présence de jonctions communicantes (CJ) composées par les connexines (Cxs) 43 et 30. A partir de l’observation indiquant que les ARN messagers codant pour la Cx30, mais pas ceux pour la Cx43, sont augmentés suite à une privation de sommeil (PDS), l’objectif de ma thèse a été de déterminer si et comment la Cx30 est impliquée dans la régulation du cycle veille-sommeil. D'abord, mon travail a consisté à analyser les effets de molécules qui perturbent veille-sommeil sur CJ astrocytaire étudiée dans des tranches aigues de cortex de souris. J’ai observé que le modafinil, un psychostimulant, augmentent la CJ. Par contre le GHB (acide γ-Hydroxybutyric), un agent qui induit le sommeil, et deux anesthésiques généraux, le propofol et la kétamine, ont des effets opposés. Ces résultats suggèrent que les réseaux astrocytaires sont régulés de manière différentielle par des drogues qui perturbent veille-sommeil. Et ensuite, ma thèse a consisté à étudier le rôle de la Cx30 en utilisant des souris dont le gène codant pour cette Cx a été invalidé (Cx30 KO). Les Cx30 KOs présentent un déficit dans le maintien de l’éveil lors d’épisodes de forte pression de sommeil: Cx30 KO présentent une augmentation du sommeil à ondes lentes pendant une PDS et elles requièrent un plus grand nombre de stimuli pour rester éveillée lors d’une PDS «douce». Afin d’identifier les causes de ce déficit nous avons observé que: 1) le CJ est augmenté après une PDS et cette augmentation ne s’observe que lorsque la Cx30 est présente 2) le niveau d’expression des ARN messagers de 7 gènes impliqués dans le métabolisme énergétique cérébral est diminué dans plusieurs régions du cerveau chez Cx30 KO. En résumé, ces résultats suggèrent que la Cx30 joue un rôle important dans la régulation du veille-sommeil, probablement en contribuant à la fonction métabolique des astrocytes, ceci afin de répondre à une demande énergétique accrue lors de situations de forte pression de sommeil.

In this paper we discuss a relatively general kind of iterative functional equation G(x,f(x),…, f n (x)) =0 (for all x∈J ), where J is a connected closed subset of the real number axis R , G ∈ C m ( J n+1 , R )，and n ≥2.Using the method of approximating fixed points by small shift of maps, choosing suitable metrics on functional spaces and finding a relation between uniqueness and stability of fixed points of maps of general spaces, we prove the existence, uniqueness and stability of C m solutions of the above equation for any integer m ≥0 under relatively weak conditions, and generalize related results in reference in different aspects.

Cefixime (CFX) absorption kinetics after oral administration to humans was studied. Four distinct models, incorporating a delay of absorption and first-order elimination kinetics, i.e. first-order absorption (M1), zero-order absorption (M0), Michaelis-Menten type absorption (MM) and Michaelis-Menten type absorption with 'an absorption window' (MM-delta t) were used to fit concentration data of CFX in 10 Chinese men following an oral dose of 400 mg. r2 and AIC were selected as measures of goodness-of-fit. The results show that the MM-delta t model provided a better fit than the other three models. The kinetic parameters were estimated as follows: Vmax' = 10.80 +/- 3.80 mg.l-1.h-1; K(m)' = 88.31 +/- 2.75 micrograms.ml-1; delta t = 4.75 +/- 0.85 h; T1/2 = 4.20 +/- 0.92 h; Tmax = 5.20 +/- 0.92 h; and Cmax = 6.04 +/- 1.70 mg.l-1.

Weibull function C = Bts-1exp(-lambda ts) was used to describe plasma concentration-time data of ribavirin in 6 healthy subjects following an i.v. dose of 600 mg. A good fit was found in each of the subjects, where the coefficients of determination r2 were0.99. The parameters estimated were as follows: B, 5.90 +/- 1.86 micrograms.h1-s; lambda, 0.607 +/- 0.156 h-s; and s, 0.339 +/- 0.085, respectively. The results were compared with those by triexponential function. By providing lower values of AIC and SD, as well as higher values of r2, the Weibull function proved to be superior to triexponential function for data of 3 subjects. These results indicated that both Weibull function and triexponential function provided a good fit of plasma concentration-time data of ribavirin in man following an i.v. dose.

Clinical studies and animal models have shown that pharmacoresistant epilepsy is partly due to the overexpression of ATP-binding cassette transporters at the brain. The purposes of the study were to investigate the function and expression of multidrug resistance-associated protein 2 (Mrp2) in the brain of pentylenetetrazole (PTZ)-kindled rats, and the effect of the altered Mrp2 function and expression on phenytoin (PHT) distribution in the brain. Kindled rats were developed by sub-convulsive dose of PTZ (33 mg/kg, every day, intraperitoneal (i.p.)) for 28 days. Mrp2 expression and function were measured by western blot and bromosulfophthalein (BSP) distribution in the brain. PHT concentrations in the brain of PTZ-kindled rats were measured alone or with co-administration of probenecid (50mg/kg). Further experiment was designed to investigate whether PHT treatment prevented the up-regulated brain Mrp2 expression and function induced by PTZ-kindling. The results showed that PTZ-kindling resulted in an increase of Mrp2 level in the hippocampus and cortex of rats, accompanied by significant decreases in the brain-to-plasma concentration ratio of BSP. PTZ-kindling also decreased PHT levels in the hippocampus and cortex without altering PHT concentrations in plasma, resulting in a lower brain-to-plasma concentration ratio of PHT. Co-administration of probenecid increased the brain-to-plasma ratio of BSP and PHT in the brain of both normal and PTZ-kindled rats. A 14-day PHT treatment prevented the up-regulation of Mrp2 expression and function induced by PTZ-kindling, accompanied by increases of PHT concentrations in the brain and good anticonvulsive effects. The present study demonstrated that chronic PTZ-kindling increased Mrp2 expression and function in the rat brain, and the up-regulation partly came from epileptic seizure.

International audience; We report the observation of a coherent nonlinear signal in pump-probe experiments on a ferromagnetic GaMnAs. The coherent signal, which is originating due to coherent interaction between pump and probe beams, depends on the polarization configuration of each beam and follows the sample magnetization as it changes with the applied magnetic field and/or the sample temperature. Cop. 2007 American Institute of Physics.

Transport of 11 quinolones at the blood-brain barrier (BBB) was studied in vitro by using primarily cultured rat brain capillary endothelial cells (BCECs) and in vivo brain-to-plasma concentration ratios. In vitro, when cells reached confluence, a time course of quinolone uptake was recorded by incubation with a medium contraining quinolones 20 microg/ml at 37 degrees C. A simple two-compartment model was used for fitting the uptake time course and corresponding uptake parameters were estimated. In vivo rats were anesthetized, after in 10 mg/kg of quinoloes followed by infusion of 4 mg/kg/h for 2 hours, the drug concentrations in plasma and brain were measure and brain-to-plasma concentration ratios were calculated. Result showed that sparfloxacin and prulifloxacin have higher uptakes by BCECs and brain-to-plasma concentration ratios, compared with other quinolones, which indicated that the two drugs more easily penetrate into BBB. A good correlation between uptakes by BCECs and brain-to-plasma concentration ratios was found. These results demonstrated uptakes by BCECs in vitro might give prediction of brain-to-plasma ratio for quinolones.

Effect of erythromycin (ERY) on oral absorption of nimodipine (NMD) in female and male rat was investigated in vivo and in vitro. In vivo, at 15 min following oral dose of 50 mg/kg ERY, an oral dose 20 mg/kg NMD was given to rats, plasma concentrations of NMD were determined. In vitro, everted jejunum sac and ileum sac were used, NMD transport from mucosal side to serol side was measured, in absences of ERY and cyclosprin A (CSA) or in presence of ERY and CSA. Large gender difference was found after oral dose NDM. Male rats had lower plasma concentration than female rat did. AUC180 and Cmax in male rats were less than 5-folds and 3-folds than those in female rats, respectively. Co-administrating ERY may increase plasma concentrations of NMD in rats. AUC180 in male rats and female rats were 2.2-folds and 1.9-folds of those NMD alone, respectively. Cmax was about 3-folds of that NMD alone. The NMD transport in intestine showed a regional variation and gender differences. In female rat, transport rate in the jejunum was about 1.3 higher than ileum. Both ERY and CSA significant increases transport of NMD. Contrast to female, NMD transport in jejunum was lower that that in ileum. Bothe ERY and CSA had little effect on NMD transport in intestine. These results indicated that there existed gender difference in oral absorption of NMD and effect of ERY on oral absorption kinetics of NMD in female rats was different from that in male rat.

Effect of P-glycoprotein (P-gp) inhibitors erythromycin (Ery) and cyclosporin A(CsA) on brain pharmacokinetics of nimodipine (NMD) in rats was studied. NMD concentrations in rat plasma and brain were determined after iv 2 mg/kg NMD alone, co-administration with Ery and CsA, respectively. It was found that concentrations of NMD in plasma of the three groups had a little difference, but brain concentrations of NMD in rats co-administrated with Ery and CsA were significantly higher than those in rats NMD alone. Significances of NMD in rat brain were found at 20, 40, 60 and 90 min after iv NMD. The brain T(1/2) in rat treated with ery(75.0 min) and CsA(79.0 min) were larger than that (44.2 min) in rats NMD alone. The results indicated that P-gp inhibitors Ery and CsA may increase concentration in rat brain by inhibiting elimination of NMD from brain.

The object of the study was to develop a new allometric equation for clearance from laboratory animals to humans based on body surface area (BSA allometric method). Human clearances for 30 drugs were predicted from animal data obtained from the literature. The results predicted with the method were compared with those observed. The results were also compared with values predicted with clearance versus body weight (BW simple allometric method), the product of brain weight and clearance versus body weight (Cl x BRW method) and the product of maximum life span potential and clearance versus body weight (Cl x MLP method), respectively. Good predictions were found in 21 out of 30 with the BAS allometric method. Both BSA allometric method and BW simple allometric method can give good predictions of clearance in humans for many drugs. Similarly to BW simple allometric method, Cl x BRW method and Cl x MLP method, BSA allometric method may be used to accurately predict human clearance from laboratory animal data.

The plasma concentrations of repaglinide in 16 male subjects were determined after an oral dose of 4 mg. Two-peak concentrations in plasma were observed. A type of one-compartment model with double sites of drug absorption was developed and successfully used to fit the data. A good agreement between observed and predicted data was found in all subjects with correlation index r20.97. The corresponding pharmacokinetic parameters were estimated as follows: Tmax1 0.61 +/- 0.14 h, Tmax2 1.45 +/- 0.43 h, Cmax1 40.60 +/- 20.57 ng/ml, Cmax2 42.70 +/- 17.54 ng/ml, T1 0.12 +/- 0.07 h, T2 0.67 +/- 0.30 h and T3 1.03 +/- 0.35 h.

Sleep wake cycle is characterized by changes in neuronal network activity. However, for the last decade there is increasing evidence that neuroglial interaction may play a role in the modulation of sleep homeostasis and that astrocytes have a critical impact in this process. Interestingly, astrocytes are organized into communicating networks based on their high expression of connexins, which are the molecular constituents of gap junction channels. Thus, neuroglial interactions should also be considered as the result of the interplay between neuronal and astroglial networks. Here, we investigate the effect of modafinil, a wakefulness-promoting agent, on astrocyte gap junctional communication. We report that in the cortex modafinil injection increases the expression of mRNA and protein of connexin 30 but not those of connexin 43, the other major astroglial connexin. These increases are correlated with an enhancement of intercellular dye coupling in cortical astrocytes, which is abolished when neuronal activity is silenced by tetrodotoxin. Moreover, gamma-hydroxybutyric acid, which at a millimolar concentration induces sleep, has an opposite effect on astroglial gap junctions in an activity-independent manner. These results support the proposition that astroglia may play an important role in complex physiological brain functions, such as sleep regulation, and that neuroglial networking interaction is modified during sleep wake cycle. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. (C) 2013 Published by Elsevier Ltd.