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Background: The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. Objectives: This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. Methods: Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. Results: Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan‐induced steatosis might be linked to the high expression of glutathione S‐transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan‐induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. Conclusion: While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug‐induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics. [ABSTRACT FROM AUTHOR]

Exposure to xenobiotics can adversely affect biochemical reactions, including hepatic bile acid synthesis. Bile acids are essential for dissolving lipophilic compounds in the hydrophilic environment of the gastrointestinal tract. The critical micellar concentration of bile acids depends on the Δ4-reduction stereochemistry, with the 3-oxo-5 β -steroid-Δ4-dehydrogenase (AKR1D1) introducing the cis ring A/B conformation. Loss-of-function mutations in AKR1D1 cause hepatic cholestasis, which, if left untreated can progress into steatosis and liver cirrhosis. Furthermore, AKR1D1 is involved in clearing steroids with an A-ring Δ4-double bond. Here, we tested whether anabolic-androgenic steroids (AAS), often taken off-label at high doses, might inhibit AKR1D1, thereby potentially causing hepatotoxicity. A computational molecular model was established and used for virtual screening of the DrugBank database consisting of 2740 molecules, yielding mainly steroidal hits. Fourteen AAS were selected for in vitro evaluation, as such compounds can reach high hepatic concentrations in an abuse situation. Nandrolone, clostebol, methasterone, drostanolone, and methenolone inhibited to various extent the AKR1D1-mediated reduction of testosterone. Molecular modeling suggests that 9 out of 14 investigated AAS are competitive inhibitors. Moreover quantum mechanical calculations show that nadrolone and clostebol are substrates of AKR1D1 with different activation energy barriers for the hydrogen transfer from cofactor to the C5 position affecting their turnover. In this multidisciplinary approach, we established a molecular model of AKR1D1, identified several AAS as inhibitors, and described their binding mode. This approach may be applied to study other classes of inhibitors including non-steroidal compounds. [ABSTRACT FROM AUTHOR]

Reducing operating balancing costs is paramount for an affordable transition towards renewable-dominated power systems. In European balancing markets, operating balancing costs are driven by the activation of automatic and manual frequency restoration reserves, respectively aFRR and mFRR. An inadequate combination of both products for resolving grid imbalances may result in economic inefficiencies where, e.g., saturated aFRR can lead to balancing price spikes. To avoid such situation, we propose a proactive activation policy of manual reserves, aiming at an optimal trade-off between aFRR and mFRR products via a stochastic optimization method. The tool is fed with 1-min time trajectories of system imbalances covering the next quarter hour. The one minute temporal granularity allows modeling the ramping phenomena of mFRR products, while keeping track of the faster activation of aFRR products. The proposed balancing energy activation methodology is tested on Belgian market data, which currently adopts a reactive balancing strategy. Ex-post comparisons of the proposed balancing strategy with a reactive one show that our methodology allows a decrease of the balancing activation costs. This is expected as early activation of mFRR, when appropriately provided, allows avoiding the activation of extremely high aFRR bids. • Cost-optimal proactive activation of manual frequency reserves is analyzed. • A probabilistic prediction — scenario-based decision chain approach is proposed. • The proposed activation strategy is compared to a typical TSO's reactive strategy. • Prediction errors and their impacts on the manual reserves activation are assessed. • Balancing costs can be reduced by the use of the proposed proactive strategy. [ABSTRACT FROM AUTHOR]

Key points: Spinal cord lamina I neurons receiving dense input from nociceptors and projecting to the parabrachial area at the ponto‐mesencephalic junction form the major ascending pain‐related pathway in rodents.Lamina I spinoparabrachial (SPB) neurons have never been characterized in mice, despite the growing and extensive use of this species to understand the contribution of lamina I SPB neurons in chronic pain.The electrophysiological properties of lamina I SPB neurons recorded here in anaesthetized mice are comparable to those of rat or cat, forming a nociceptive and thermoreceptive pathway. It was confirmed 'on line' that lamina I SPB neurons that normally encode noxious stimuli can receive input from low threshold mechanoreceptors in certain conditions. The present work indicates that the study of lamina I SPB neurons in vivo could take advantage of the use of genetically modified mice. Ongoing studies investigating the role of lamina I projection neurons in the generation of chronic pain are mainly based on the use of genetically modified mice. However, lamina I projection neurons have never been physiologically characterized in this species. The present work aimed to fill this gap, and to assess the effect of spinal 'disinhibition' that may occur in chronic pain states on the responses of these neurons to light touch. Seventy lamina I spinoparabrachial (SPB) neurons were characterized in anaesthetized mice. These neurons showed low central conduction velocities (<12.4 m s−1) and wide range of responses. Fifty‐six neurons responded equally to noxious mechanical and thermal (heat) stimuli (16% responded consistently to light touch). Modality‐specific neurons responded preferentially to thermal (cold) stimuli (n = 10) and pinch (n = 2), or specifically to heat (n = 2). Spinal bicuculline and strychnine application induced responses to brush in half of the neurons tested, confirming directly the potential connection between low threshold mechanoreceptors and nociceptive‐specific neurons, responsible for mechanical allodynia. Remarkably, the effect of the treatment was highly variable and apparently independent of the initial profile of the neurons. The present data confirm that mice lamina I SPB neurons have the expected characteristics to form a nociceptive and thermoreceptive pathway, but they constitute a highly heterogeneous group. The differential effect of spinal disinhibition observed here suggests that a subgroup of lamina I SPB neurons might be responsible for abnormal pain in pathological conditions, and emphasizes the importance of in vivo recording, a neglected approach. Key points: Spinal cord lamina I neurons receiving dense input from nociceptors and projecting to the parabrachial area at the ponto‐mesencephalic junction form the major ascending pain‐related pathway in rodents.Lamina I spinoparabrachial (SPB) neurons have never been characterized in mice, despite the growing and extensive use of this species to understand the contribution of lamina I SPB neurons in chronic pain.The electrophysiological properties of lamina I SPB neurons recorded here in anaesthetized mice are comparable to those of rat or cat, forming a nociceptive and thermoreceptive pathway. It was confirmed 'on line' that lamina I SPB neurons that normally encode noxious stimuli can receive input from low threshold mechanoreceptors in certain conditions. The present work indicates that the study of lamina I SPB neurons in vivo could take advantage of the use of genetically modified mice. [ABSTRACT FROM AUTHOR]

Clinical evaluation of a colchicine specific antigen-binding fragment (Fab) in order to treat colchicine poisoning required the development of an accurate method allowing quantification of free and Fab-bound colchicine in plasma and urine, and free colchicine in tissues, to measure colchicine redistribution after Fab administration. Three methods have been developed for this purpose, and validated in plasma, urine and liver: total colchicine was determined after denaturation of Fab by dilution in water and heating; free colchicine was separated from Fab-bound colchicine by filtration with 30 KDa micro-filters; tissues were homogenized in a tissue mixer. Deuterated colchicine was used as internal standard. Samples were extracted by liquid–liquid extraction and analyzed with a LC–MS/MS. LOQ were 0.5 ng/mL in plasma and urine for free and total colchicine and 5 pg/mg in tissues. The methods were linear in the 0.5–100 ng/mL range in plasma and urine, and 5–300 pg/mg in tissues with determination coefficients > 0.99. Precision and accuracy of QC samples presented a CV < 9.4%. The methods require only 200 μL of sample and allow a high throughput due to short analytical run (2 min). These methods were successfully applied to a pig intoxicated with colchicine and treated with colchicine specific Fab fragments. [ABSTRACT FROM AUTHOR]

MRI showed significant regression of white matter lesions (Fig, C) and complete resolution of lesion enhancement (Fig, D). Cerebral magnetic resonance imaging (MRI; Fig) showed multiple hyperintensities on fluid-attenuated inversion recovery-weighted sequence (Fig, A) involving deep and periventricular white matter. Because the brain MRI showed characteristic imaging findings of levamisole toxicity, and following exclusion of other hypotheses, he was treated with intravenous methylprednisolone, 1,000 mg daily for 5 consecutive days. [Extracted from the article]

Abstract: The issue of central bank communication on fiscal policy has so far received very little attention in the literature. This article aims to shed light on the determinants of central bank communication on fiscal policy by analysing the intensity of central banks’ fiscal communication for five central banks (the Federal Reserve, the ECB, the Bank of Japan, the Bank of England and the Swedish Riksbank) over the period 1999–2011. The ECB communicates intensively on fiscal policies, in a normative way. The other central banks emphasise foreign fiscal developments, fiscal policy as input to forecasts, or the use of government debt instruments in monetary policy operations. The empirical analysis indicates that the financial crisis has overall increased the intensity of central bank communication on fiscal policy. The evolution of the government deficit ratio is a driver of the intensity of fiscal communication in the euro area, the US and Japan, and for Sweden since the start of the crisis, while in the UK its intensity is related to government debt developments as of the start of the crisis. [Copyright &y& Elsevier]

OBJECTIVE To assess the potentiation of erectile responses induced by electrical stimulation (ES) of the dorsal penile nerve (DPN) in the urethane-anaesthetized rat by the selective melanocortin receptor 4 agonist MB243. MATERIALS AND METHODS Intracavernosal and blood pressures (ICP and BP, respectively) were monitored in urethane-anaesthetized rats after complete spinal cord transection at the thoracic level. Erectile responses were induced by ES of the DPN (train of square wave pulses of 1 ms and 6 V for 20 s at 1, 2 and 5 Hz) after i.v. injection of either saline or MB243, 3 mg/kg, in two groups of six rats. The maximal and mean ICP, and the area under the curve (AUC) of the ICP response, corrected for the corresponding BP, were measured and used as an index of erectile function (ICPmax/BP, ICPmean/BP and AUC/BP, respectively). RESULTS MB243 increased the number of spontaneous erections between the injection and the first ES when compared with the vehicle group, but this difference was not statistically significant. ES of the DPN induced frequency-dependent erectile responses, the mean (sem) ICPmean/BP was 0.26 (0.02), 0.34 (0.04) and 0.39 (0.05) after administration of saline (vehicle) at 1, 2 and 5 Hz, respectively. All the variables, except the ICPmax/BP at 5 Hz, were significantly increased in the group injected with MB243 when compared with the vehicle group ( P < 0.05 for ICPmax/BP and ICPmean/BP; P < 0.01 for AUC/BP). The AUC/BP showed the greatest increases of (+79%, +60% and +44% at 1, 2 and 5 Hz, respectively) in the group injected with MB243 compared with the vehicle group. CONCLUSION Erectile responses induced by ES of the DPN in spinalized, urethane-anaesthetized rat are suitable for evaluating the proerectile facilitator activity of selective peripherally restricted melanocortin receptor 4 agonists. This model represents a valuable alternative to the classically used cavernous/pelvic nerve stimulated model. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) can be delayed by the use of angiotensin-converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal. To investigate the impact of bradykinin B2 receptor (B2R) activation during ACE inhibition, type II diabetic mice (C57BLKS db/db) received for 20 wk: 1) ACEi (ramipril) alone, 2) ACEi + HOE-140 (a specific B2R antagonist), 3) HOE-l40 alone, or 4) no treatment. The development of DN, defined by an increase in albuniinuria and glomerulosclerosis, was largely prevented by ACEi treatment (albu- minuria: 980 ± 130 vs. 2,160 ± 330 mg/g creatinine; mesangial area: 22.5 ± 0.5 vs. 27.6 ± 0.3%). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria: 2,790 ± 680 mg/g creatinine; mesangial area: 30.4 ± 1.1%), whereas HOE-l40 alone significantly increased albuminuria. Despite such benefits, gb- merular filtration rate remained unchanged, probably because of the combination of the hypotensive effect of diabetes in this model and the renal hemodynamic action of ramipril. Finally, the renal protective effect of ACEi was associated with a marked decrease in gbomerular overexpression of insulin-like growth factor-I (IGF- I) and transform- ing growth factor-13 pathways, but also in advanced glycation end product receptors and lipid peroxidation assessed by 4-hydroxy-2- nonenal (4-HNE) adducts. Concomitant blockade of B2R partly re- stored glomerular overexpression of IGF- I receptor 13 and 4-HNE complexes. These results support the critical role of B2R activation.in the mediation of ACEi renal protection against DN and provide the rationale to examine the benefit of B2R activation by itself as a new therapeutic approach for DN. [ABSTRACT FROM AUTHOR]

Estrogens are known to modulate lower urinary tract (LUT) trophicity and neuronal nitric oxide synthase (nNOS) expression in several organs. The aim of this study was to explore the effects of endogenous and supraestrus levels of 17β-estradiol (E2) on LUT and urethral nNOS expression and function. LUT function and histology and urethral nNOS expression were studied in adult female mice subjected either to sham surgery, surgical castration, or castration plus chronic E2 supplementation (80 µg·kg-1·day-1, i.e., pregnancy level). The micturition pattern was profoundly altered by long-term supraestrus levels of E2 with decreased frequency paralleled by increased residual volumes higher than those of ovariectomized mice. Urethral resistance was increased twofold in E2-treated mice, with no structural changes in urethra, supporting a pure tonic mechanism. Acute nNOS inhibition by 7-nitroindazole decreased frequency and increased residual volumes in ovariectomized mice but had no additive effect on the micturition pattern of long-term supraestrus mice, showing that long-term supraestrus E2 levels and acute inhibition of nNOS activity had similar functional effects. Finally, E2 decreased urethral nNOS expression in ovariectomized mice. Long-term supraestrus levels of E2 increased urethral tone through inhibition of nNOS expression, whereas physiological levels of E2 had no effect. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor- β1 (TGF-β-RII), platelet-derived growth factor (PDGF- R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACE!) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACE! on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-β- RI! and activation of IRS 1, Erk ½, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACE! stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACE! were abolished by HOE- 140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACE! to reduce albuminuria was also prevented by HOE- 140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation. [ABSTRACT FROM AUTHOR]

Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. During intercourse, the spinal ejaculation generator integrates the sensory inputs that are necessary to trigger ejaculation. At the time of ejaculation, it coordinates the sympathetic, parasympathetic, and somatic outflow to induce the two phases of ejaculation, i.e. emission and expulsion. It also provides the brain with signals related to the occurrence of ejaculation. Experimental and clinical data evidenced that these functions were devoted to neurons located in the lumbosacral cord. We recently characterized a population of spinothalamic neurons in the lumbar spinal cord of male rats (LSt cells) that constitutes an integral part of the spinal ejaculation generator. LSt cells send projections to the autonomic nuclei and motoneurons involved in the emission and expulsion phase, and they receive sensory projections from the pelvis. LSt cells are activated with ejaculation, but not following other components of sexual behavior, and lesions of LSt cells completely ablate ejaculatory function. These data support a pivotal role for the LSt cells in the control of ejaculation. [ABSTRACT FROM AUTHOR]

Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. This spinal ejaculation generator coordinates sympathetic, parasympathetic and motor outflow to induce the two phases of ejaculation, i.e., emission and expulsion. In addition, the spinal ejaculation generator integrates this outflow with inputs that are related to the summation of sexual activity prior to ejaculation that are required to trigger ejaculation. Recently, a group of spinothalamic neurons in the lumbar spinal cord (LSt cells) were demonstrated to comprise an integral part of the spinal ejaculation generator. Specifically, lesions of LSt cells completely ablate ejaculatory function. Moreover, LSt cells are activated following ejaculation, but not following other components of sexual behavior. Furthermore, based on their relationship with autonomic nuclei, motoneurons and genital sensory inputs, LSt cells are also in the ideal anatomical position to integrate sensory inputs and autonomic and motor outflow. Additionally, the spinal ejaculation generator is under inhibitory and excitatory influence of supraspinal sites, including the nucleus paragigantocellularis (nPGi), the paraventricular nucleus of the hypothalamus (PVN) and the medial preoptic area (MPOA). Finally, sensory information related to ejaculation is processed in the spinal cord and brain, possibly contributing to the rewarding properties of ejaculation. One candidate pathway for relay of ejaculation-related cues consists of LSt cells and their projections to the parvocellular subparafascicular thalamic nucleus. Moreover, neural activation specifically related to ejaculation is observed in the brain and may reflect of processing of ejaculation-related sensory cues. [Copyright &y& Elsevier]

Assesses the vaginal vascular events on stimulation of the pelvic nerves to establish a female rat model of vaginal sexual arousal. Qualitative description of the vaginal response; Analysis of the vaginal wall tension and intracavernous pressure; Effect of additional sympathetic chain stimulation.

Characterizes the physiological changes in vaginal sexual arousal of rat models. Effect of temperature and pelvic nerves stimulation on vaginal muscular activity; Role of major neural pathways; Result of administering atropine sulfate.

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl- l -carnitine, palmitoyl-CoA + l -carnitine, or octanoyl- l -carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential, and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition. [ABSTRACT FROM AUTHOR]

St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100 µM and depleted ATP at 20 µM. In HepaRG cells, ATP depletion started at 5 µM. In comparison, hyperforin and citalopram were not toxic up to 100 µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2 µM and mitochondrial ATP formation starting at 10 µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations. [Display omitted] • Exposure to hypericin induces cytotoxicity in hepatic HepG2 and HepaRG cells. • Hypericin decreases mitochondrial ATP production in HepG2 cells. • Hypericin inhibited the activity of complex I, II and IV of the ETS in HepG2 cells. • Hypericin induces mitochondrial oxidative stress in HepG2 cells. • Hypericin diminishes the mitochondrial DNA copy number and causes cell necrosis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the precision of methods used to assess renal function in patients with neurogenic voiding dysfunction. Materials and Methods: This multicenter prospective study, which was set in Toulouse and Lyon, France, included 60 patients (mean age, 48.9 ± 15.2 years) with neurogenic bladder and sphincter dysfunction. The correlation and the concordance with the inulin clearance of each method of renal function evaluation were assessed. Results: The correlation of serum creatinine with inulin clearance was low when using serum creatinine-based equations such as the Modification of Diet in Renal Disease (simplified and complete) and Cockcroft-Gault equations. The r and r 2 coefficients were higher for creatinine-based methods, such as 24-hour (r = 0.72) and 3-hour creatinine clearance (r = 0.78). The strongest correlation was found for serum cystatin C–based equations: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine/cystatin C combined equation (r = 0.78) and the CKD-EPI cystatin C equation (r = 0.80). Mean bias of serum creatinine–based equations estimating glomerular filtration rate, the Cockcroft-Gault, and the simplified and complete Modification of Diet in Renal Disease equations, was 27.5 ± 28.6, 17.48 ± 29.40, and 21.98 ± 30.40 mL/min, respectively. Mean bias of creatinine clearance was 19.89 ± 15.30 mL/min at 3 hours and 19.00 ± 31.08 mL/min at 24 hours. Mean bias of the CKD-EPI cystatin C and the CKD-EPI creatinine/cystatin C combined equations was 11.98 ± 17.68 mL/min and 18.62 ± 17.85 mL/min, respectively. Limitations are the numerous types of neurologic diseases. Conclusion: The CKD-EPI equation using cystatin C was the most precise method of renal function evaluation in patients with neurogenic bladder. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction. Nitric oxide synthases (NOSs) and estrogen receptors are expressed in the female urethra. Aim. We aimed to assess the impact of sildenafil on micturition behavior, urethral tone according to the hormonal status and to determine the implications of the neuronal isoform of NOS (nNOS). Methods. Four-week-old C57/BL6 female mice were sham-operated or ovariectomized. Six weeks later, they were injected intraperitoneally by any combination of sildenafil, 7-nitroindazole (7-NI)-a potent selective nNOS inhibitor-or the corresponding vehicles. The mice were then subjected to micturition behavior and leak point pressure studies. Urethral histomorphometry was performed. Main Outcome Measures. The main outcome measures were micturition behavior, leak point pressure, and histomorphometry. Results. In sham-operated and ovariectomized animals, sildenafil did not impact micturition, although it decreased urethral resistance 10-fold. nNOS inhibition by 7-NI reduced the number of micturitions and increased residual volume and leak point pressure. It abrogated sildenafil-induced drop in urethral resistances. Hormonal status did not influence the structure of the urethral layers. Conclusions. Irrespective of the hormonal status, sildenafil decreased leak point pressure by a nNOS-mediated mechanism. Gamé X, Bouali O, Allard J, Gourdy P, Escourrou G, Tack I, Rischmann P, Arnal J-F, and Malavaud B. Influence of sildenafil on micturition and urethral tone in ovariectomized and non-ovariectomized mice. J Sex Med 2012;9:466-471. [ABSTRACT FROM AUTHOR]

Vaginal sexual arousal is a vasocongestive and neuromuscular event controlled by facilitatory parasympathetic and inhibitory sympathetic inputs. Autonomic preganglionic parasympathetic and inhibitory sympathetic fibers to the vagina and clitoris originate in the spinal cord in the sacral parasympathetic nucleus at the sacral level and in the dorsal gray commissure and the intermediolateral cell column at the thoracolumbar level, respectively. Parasympathetic fibers are conveyed by the pelvic nerve, and sympathetic fibers are conveyed by the hypogastric nerve and the paravertebral sympathetic chain. The activity of these spinal nuclei is controlled by descending projections from the brain and sensory afferens (conveyed in the pudendal, hypogastric, pelvic, and vagus nerves) from the genitalia. A key but unresolved issue concerns the neurotransmitters involved in the control of genital sexual arousal. At the peripheral level, acetylcholine plays a minor role in the regulation of vaginal blood flow, however, recent data suggests that it may be involved in the control of vaginal smooth muscle contractions. Vasoactive intestinal peptide and nitric oxide may be responsible for the increase in vaginal blood flow during sexual arousal, whereas noradrenaline is likely inhibitory. Within the central nervous system, serotoninergic projections from the brain to the spinal cord likely inhibit the induction of genital arousal by peripheral infor mations (spinal reflex). Although some neurotransmitters regulating the display of sexual behavior have been identified (for example, dopamine), their involvement in the control of genital sexual arousal has not been invested. Anatomical and electrophysiological data point to a contribution of the paraventricular nucleus of he hypothalamus and the median preoptic area, respectively, as key elements in the control of genital arousal. The recent development of models allowing the assessment of vaginal sexual arousal in anesthetized female rats should assist in deciphering the neurochemical pathways controlling vaginal sexual arousal and the development of suitable pharmacological treatment for female sexual dysfunctions. [ABSTRACT FROM AUTHOR]

Background Long-term studies have demonstrated a slight increased risk for end-stage renal disease (ESRD) for living kidney donors (LKD). In France, living kidney donation doubled within the past 10 years. We investigated the change in characteristics of LKD between 2007 and 2017 and the adequacy of follow-up. Methods Data were obtained from the national registry for LKD. We compared characteristics of LKD between two study periods: 2007–11 and 2012–17, and stratified donors by age and relation to recipient. We aggregated four characteristics associated with higher ESRD risk [young age, first-degree relation to recipient, obesity, low glomerular filtration rate (GFR) for age] in a single risk indicator ranging from 0 to 4. Results We included 3483 donors. The proportion of unrelated donors >56 years of age increased significantly. The proportion of related donors <56 years of age decreased significantly. The body mass index and proportion of obese donors did not change significantly. The proportion of donors with low estimated GFR for age decreased significantly from 5% to 2.2% (P < 0.001). The proportion of donors with adequate follow-up after donation increased from 19.6% to 42.5% (P < 0.001). No donor had a risk indicator equal to 4, and the proportion of donors with a risk indicator equal to 0 increased significantly from 19.2% to 24.9% (P < 0.001). Conclusions An increase in living kidney donation in France does not seem to be associated with the selection of donors at higher risk of ESRD and the proportion of donors with adequate annual follow-up significantly increased. [ABSTRACT FROM AUTHOR]

Purpose: The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations. Methods: In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak > 8*MIC and a trough < 1 mg/L for MIC values between 0.25 and 4 mg/L. Results: A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1 mg/L at 96 h for 92% and 34% respectively. Conclusion: The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3–8 mg/kg/day just before dialysis, taking into account the type of infection. [ABSTRACT FROM AUTHOR]

Introduction Nitric oxide synthases ( NOSs) and estrogen receptors are expressed in the vagina. Aim We aimed to assess the impact of sildenafil on vaginal lubrication according to the hormonal status and to determine the role of the neuronal isoform of NOS ( nNOS). Methods Four-week-old C57/ BL6 female mice were sham operated or ovariectomized. At 10 weeks of age, they were injected intraperitoneally by any combination of sildenafil, 7-nitroindazole (7- NI)-a potent selective nNOS inhibitor-or the corresponding vehicles. Vaginal lubrication was induced in a physiological manner by cervical vaginal probing and quantified depending on the hormonal and pharmacological conditions. The animals were then sacrificed for vaginal histomorphometry. Main Outcome Measures The main outcome measure is the quantification of vaginal transudate after cervicovaginal stimulation and vaginal histomorphometry. Results Sildenafil increased cervicovaginal probing-induced vaginal lubrication in ovariectomized and sham-operated animals. Ovariectomized mice exhibited decreased vaginal lubrication as compared with sham-operated mice. When taking into account the presence of severe vaginal atrophy, a threefold increase in transudate per gram of vagina wet weight was revealed in ovariectomized animals. Castration markedly reduced the thickness of the vaginal wall. nNOS inhibition by 7- NI had no impact on vaginal lubrication. Conclusions Irrespective of the hormonal status, sildenafil increased vaginal lubrication. The vaginal effect of sildenafil was independent of the nNOS pathway and more pronounced in ovariectomized animals. [ABSTRACT FROM AUTHOR]

The article studies the morphologic and functional renal impact of acute kidney injury following prolonged hemorrhagic shock using a mice model. According to the authors, apparent recovery of renal function following acute kidney injury can mask existing dysfunctions and damages to tissues that can lead to chronic kidney disease. They add that prolonged hemorrhagic shock in mice produced data that can be useful in the pathophysiological study of hemorrhagic shock in acute kidney injuries.