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BackgroundWe previously showed that, by activating innate immune receptors Toll‐like 4 (TLR4), adolescent intermittent ethanol (EtOH) exposure causes neuroinflammation, myelin damage, and behavioral dysfunctions. Recent findings reveal that clinically used opioid antagonists naltrexone (NT) and naloxone (NX) inhibit opioid‐induced TLR4 signaling and that NT, NX, and nalmefene (NF), the 6‐methylene derivative of NX, are able to reduce alcohol drinking escalation.MethodsNF (0.1 mg/kg, intraperitoneally) was injected 1 hour prior to EtOH (3 g/kg, intraperitoneally) following intermittent treatment in female (PND35) adolescent mice. Inflammatory molecules, myelin proteins, and apoptotic markers were assessed in the prefrontal cortex (PFC) and striatum/nucleus accumbens (STR/NAcc). The effect of NF on alcohol drinking preference was evaluated in both the wild‐type and TLR4 knockout (KO) adolescent mice. Using astroglial cells, the inhibitory potential of NT, NX, and NF on lipopolysaccharide (LPS), or the EtOH‐triggered TLR4 response, was compared.ResultsOur findings indicate that NF prevents the up‐regulation of cytokines (IL‐1β, IL‐17A, TNF‐α), chemokines (MCP‐1, MIP‐1, KC), and pro‐inflammatory mediators (iNOS, COX‐2), along with myelin damage and apoptotic events, in both PFC and STR/NAcc. NF also abolishes EtOH‐induced escalation of alcohol preference/consumption, but has no effect when administered to TLR4‐KO mice. In vitro experiments indicate that NX and NF inhibit TLR4 activation upon LPS or EtOH stimulation. Immunofluorescence studies and lipid rafts isolation show that NF is able to prevent TLR4 translocation to lipid rafts/caveolae in astrocytes.ConclusionsThese results suggest that NF prevents neuroinflammation and brain damage by blocking the TLR4 response and also support the role of central pro‐inflammatory immune signaling in the modulation of alcohol consumption/addiction.

AbstractThe co‐occurrence of chronic pain and alcohol use disorders (AUDs) involves complex interactions between genetic and neurophysiological aspects, and the research has reported mixed findings when they both co‐occur. There is also an indication of a gender‐dependent effect; males are more likely to use alcohol to cope with chronic pain problems than females. Recently, a new conceptualization has emerged, proposing that the negative affective component of pain drives and maintains alcohol‐related behaviors. We studied in a longitudinal fashion alterations in alcohol drinking patterns and pain thresholds in a mouse model of chronic neuropathic pain in a sex‐dependent manner. Following partial denervation (spared nerve injury [SNI]), stimulus‐evoked pain responses were measured before chronic alcohol consumption, during drinking, during a deprivation phase, and following an episode of excessive drinking. During the course of alcohol drinking, we observed pronounced sex differences in pain thresholds. Male mice showed a strong increase in pain thresholds, suggesting an analgesic effect induced by alcohol over time, an effect that was not observed in female mice. SNI mice did not differ from sham‐operated controls in baseline alcohol consumption. However, following a deprivation phase and the reintroduction of ethanol, male SNI mice but not female mice showed more pronounced excessive drinking than controls. Finally, we observed decreased central ethanol sensitivity in male SNI mice but not in females. Together with our finding, that ethanol is able to decrease a pain‐induced negative affective memory we come to following conclusion. We propose that a lower sensitivity to the intoxicating effects of alcohol together with the ability of alcohol to reduce the negative affective component of pain may explain the higher co‐occurrence of AUD in male chronic pain patients.

ABSTRACTThe aquifer system of Doñana (SW Spain) represents the most important freshwater source in the Doñana Natural Area. Its spatiotemporal dynamics favours the hydrological connection between surface and subsurface ecosystems, and promotes matter fluxes among the different terrestrial and aquatic systems present here. This aquifer has been intensively studied from a hydrogeological point of view but little is known from an ecological perspective. In order to understand the ecological roles played by microbial communities in this system, we conducted a long‐term seasonal study of bacterial abundance, cell biomass, bacterial biomass and functional activities over a 2‐year period. Bacterial abundance ranged between 2.11 ± 1.79 × 105 and 8.58 ± 6.99 × 107 bacteria mL−1 groundwater, average cell biomass was estimated to be 77.01 ± 31.56 fgC and bacterial biomass varied between 8.99 ± 4.10 × 10−2 and 5.65 ± 0.70 µgC mL−1. Iron‐related bacteria showed the highest activities among the functional groups studied. Moreover, among the variables that usually control spatial distributions of microbial communities in aquifer systems, depth did not have a relevant effect on this aquifer, at least in the range of depths studied, but grain size, probably due to its direct effects on hydrogeological parameters, such as permeability or porosity, appeared to exert moderate control, principally in terms of bacterial abundance. Finally, significant seasonal differences in the means of these microbiological variables were also observed; temperature seems to be the main factor controlling the temporal distribution of microbial communities in this aquifer system.

The oxidative metabolism of ethanol by the cytochrome P450 2E1 (CYP2E1) has been recognized to contribute to the ethanol-induced deleterious effects through the induction of oxidative stress. This study compared the effect of ethanol and acetaldehyde in the induction of oxidative stress and activation of transcription factors nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) in HepG2 cells, which do not express CYP2E1, and HepG2 cells transfected with CYP2E1 (E47 cells). Neither ethanol (80 mmol/L) nor acetaldehyde (25-200 μmol/L) caused oxidative stress in HepG2 cells, an effect that was independent of blocking reduced glutathione (GSH) synthesis with buthionine-l -sulfoximine (BSO). However, BSO preincubation caused an overproduction of peroxides and activation of NF-κB and AP-1 in E47 cells even in the absence of ethanol. Furthermore, the incubation of E47 cells with ethanol (80 mmol/L for up to 5 days) depleted cellular GSH stores in both cytosol and mitochondria, reflecting the induction of oxidative stress. Ethanol activated NF-κB and AP-1 in E47 cells, an effect that was prevented by 4-methylpyrazole, potentiated by cyanamide, and attenuated by trolox C. Interestingly, however, despite the inability of acetaldehyde to induce oxidative stress in HepG2, acetaldehyde activated NF-κB and AP-1; in contrast, ethanol failed to activate these transcription factors in HepG2. Thus, our findings indicate that activation of NF-κB and AP-1 by ethanol and acetaldehyde occurs through distinct mechanisms. CYP2E1 is indispensable in the induction of oxidative stress from ethanol, whereas the activation of NF-κB and AP-1 by acetaldehyde is independent of oxidative stress.

Ethanol is the most common human teratogen, and its consumption during pregnancy can produce a wide range of abnormalities in infants known as fetal alcohol spectrum disorder (FASD). The major characteristics of FASD can be divided into: (i) growth retardation, (ii) craniofacial abnormalities, and (iii) central nervous system (CNS) dysfunction. FASD is the most common cause of nongenetic mental retardation in Western countries. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, the induction of oxidative stress is believed to be one central process linked to the development of the disease. Currently, there is no known effective strategy for prevention (other than alcohol avoidance) or treatment. In the present review we will provide the state of art in the evidence for the use of antioxidants as a potential therapeutic strategy for the treatment using whole‐embryo and culture cells models of FASD. We conclude that the imbalance of the intracellular redox state contributes to the pathogenesis observed in FASD models, and we suggest that antioxidant therapy can be considered a new efficient strategy to mitigate the effects of prenatal ethanol exposure. Birth Defects Research (Part A) 103:163–177, 2015. © 2014 Wiley Periodicals, Inc.

Background and ObjectiveThe root surface topography exerts a major influence on clinical attachment and bacterial recolonization after root planing. In‐vitro topographic studies have yielded variable results, and clinical studies are necessary to compare root surface topography after planing with current ultrasonic devices and with traditional manual instrumentation. The aim of this study was to compare the topography of untreated single‐rooted teeth planed in vivo with a curette, a piezoelectric ultrasonic (PU) scraper or a vertically oscillating ultrasonic (VOU) scraper.Material and MethodsIn a randomized experimental trial of 19 patients, 44 single‐rooted teeth were randomly assigned to one of four groups for: no treatment; manual root planing with a curette; root planing with a PU scraper; or root planing with a VOU scraper. Post‐treatment, the teeth were extracted and their topography was analyzed in 124 observations with white‐light confocal microscopy, measuring the roughness parameters arithmetic average height, root‐mean‐square roughness, maximum height of peaks, maximum depth of valleys, absolute height, skewness and kurtosis.ResultsThe roughness values arithmetic average height and root‐mean‐square roughness were similar after each treatment and lower than after no treatment ( p < 0.05). Absolute height was lower in the VOU group than in the untreated ( p = 0.0026) and PU (p = 0.045) groups. Surface morphology was similar after the three treatments and was less irregular than in the untreated group. Values for the remaining roughness parameters were similar among all treatment groups ( p > 0.05).ConclusionBoth ultrasonic devices reduce the roughness, producing a similar topography to that observed after manual instrumentation with a curette, to which they appear to represent a valid alternative.

AbstractRising atmospheric [CO2] and associated climate change are expected to modify primary productivity across a range of ecosystems globally. Increasing aridity is predicted to reduce grassland productivity, although rising [CO2] and associated increases in plant water use efficiency may partially offset the effect of drying on growth. Difficulties arise in predicting the direction and magnitude of future changes in ecosystem productivity, due to limited field experimentation investigating climate and CO2 interactions. We use repeat near‐surface digital photography to quantify the effects of water availability and experimentally manipulated elevated [CO2] (eCO2) on understorey live foliage cover and biomass over three growing seasons in a temperate grassy woodland in south‐eastern Australia. We hypothesised that (i) understorey herbaceous productivity is dependent upon soil water availability, and (ii) that eCO2 will increase productivity, with greatest stimulation occurring under conditions of low water availability. Soil volumetric water content (VWC) determined foliage cover and growth rates over the length of the growing season (August to March), with low VWC (<0.1 m3 m−3) reducing productivity. However, eCO2 did not increase herbaceous cover and biomass over the duration of the experiment, or mitigate the effects of low water availability on understorey growth rates and cover. Our findings suggest that projected increases in aridity in temperate woodlands are likely to lead to reduced understorey productivity, with little scope for eCO2 to offset these changes.

In theoretical ecology, recent field experiments on terrestrial vertebrates observe that the predator-prey interaction can not only be curtailed by direct consumption but also governed by some indirect effects such as the fear of predator which may reduce the reproduction rate of prey individuals. Based on this fact, we have developed and explored the predator-prey interaction with the influence of both cost and benefit of fear effect (felt by prey). A Holling type III functional response with the effect of habitat complexity has been taken to consume the prey biomass. Positivity and boundedness of the studied system prove that the model is well-behaved. The uniform persistence of the studied system is derived analytically under some parametric restrictions. The feasibility conditions and stability criteria of each equilibrium points have been discussed. Next, we have exhibited the existence of Hopf-bifurcation around the interior equilibrium point. Our mathematical analyses show that habitat complexity and fear effect both have a great impact on the persistence of the predator biomass. Furthermore, we have investigated the effect of breeding delay parameter such that the system loses its stability behaviour and enters into a limit cycle oscillations through Hopf-bifurcation. Numerical simulations are illustrated to verify our analytical outcomes. Numerically, we have perturbed the death rates of prey and predator species with Gaussian white noise terms due to the effects of environmental fluctuations.