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Background:  We previously found that activation of the glial cell line‐derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) reduces ethanol‐drinking behaviors. In this study, we set out to assess the contribution of endogenous GDNF or its receptor GFRα1 to the regulation of ethanol‐related behaviors.Methods:  GDNF and GFRα1 heterozygote mice (HET) and their wild‐type littermate controls (WT) were used for the studies. Ethanol‐induced hyperlocomotion, sensitization, and conditioned place preference (CPP), as well as ethanol consumption before and after a period of abstinence were evaluated. Blood ethanol concentration (BEC) was also measured.Results:  We observed no differences between the GDNF HET and WT mice in the level of locomotor activity or in sensitization to ethanol‐induced hyperlocomotion after systemic injection of a nonhypnotic dose of ethanol and in BEC. However, GDNF and GFRα1 mice exhibited increased place preference to ethanol as compared with their WT littermates. The levels of voluntary ethanol or quinine consumption were similar in the GDNF HET and WT mice, however, a small but significant increase in saccharin intake was observed in the GDNF HET mice. No changes were detected in voluntary ethanol, saccharin or quinine consumption of GFRα1 HET mice as compared with their WT littermates. Interestingly, however, both the GDNF and GFRα1 HET mice consumed much larger quantities of ethanol after a period of abstinence from ethanol as compared with their WT littermates. Furthermore, the increase in ethanol consumption after abstinence was found to be specific for ethanol as similar levels of saccharin intake were measured in the GDNF and GFRα1 HET and WT mice after abstinence.Conclusions:  Our results suggest that endogenous GDNF negatively regulates the rewarding effect of ethanol and ethanol‐drinking behaviors after a period of abstinence.

Aims The aim of this study was to determine whether the sequential application of povidone iodine-alcohol (PVI) followed by chlorhexidine gluconate-alcohol (CHG) would reduce surgical wound contamination to a greater extent than PVI applied twice in patients undergoing spinal surgery. Patients and Methods A single-centre, interventional, two arm, parallel group randomised controlled trial was undertaken, involving 407 patients who underwent elective spinal surgery. For 203 patients, the skin was disinfected before surgery using PVI (10% [w/w (1% w/w available iodine)] in 95% industrial denatured alcohol, povidone iodine; Videne Alcoholic Tincture) twice, and for 204 patients using PVI once followed by CHG (2% [w/v] chlorhexidine gluconate in 70% [v/v] isopropyl alcohol; Chloraprep with tint). The primary outcome measure was contamination of the wound determined by aerobic and anaerobic bacterial growth from samples taken after disinfection. Results The detection of viable bacteria in any one of the samples taken after disinfection (culture-positive) was significantly lower in the group treated with both PVI and CHG than in the group treated with PVI alone (59 (29.1%) versus 85 (41.7%), p = 0.009; odds ratio 0.574; 95% confidence interval, 0.380 to 0.866). Conclusions Antisepsis of the skin with the sequential application of PVI and CHG more effectively reduces the contamination of a surgical wound than PVI alone. Cite this article: Bone Joint J 2017;99-B:1354–65.

To discuss current evidence of global climate change and its implications for allergic rhinitis and other allergic respiratory diseases.Global climate change is evidenced by increasing average earth temperature, increasing anthropogenic greenhouse gas levels, and elevated pollen levels. Pollutants of interest include carbon dioxide (CO2), ozone (O3), and nitrous oxide (NO2) because they can enhance the allergic response and lead to increased symptoms of allergic respiratory diseases. Heightened CO2 levels stimulate pollen production via photosynthesis and increased growth in multiple plant species investigated. Although worsened air quality appears to increase prevalence of allergic rhinitis, the effects of increased temperature are less certain. The findings of increased aeroallergen levels likely contribute to increases in presentation of allergic diseases, although more healthcare impact studies are necessary.Although recent literature indicates and strongly supports changes in temperature, pollution levels, and aeroallergen levels, more longitudinal epidemiologic surveillance of allergic diseases in relation to climate change as well as pathophysiologic studies on changing aeroallergen effects on allergic diseases are needed.

ABSTRACTPrenatal ethanol exposure causes a variety of cognitive deficits that have a persistent impact on quality of life, some of which may be explained by ethanol-induced alterations in interneuron function. Studies from several laboratories, including our own, have demonstrated that a single binge-like ethanol exposure during the equivalent to the third trimester of human pregnancy leads to acute apoptosis and long-term loss of interneurons in the rodent retrosplenial cortex (RSC). The RSC is interconnected with the hippocampus, thalamus, and other neocortical regions and plays distinct roles in visuospatial processing and storage, as well as retrieval of hippocampal-dependent episodic memories. Here we used slice electrophysiology to characterize the acute effects of ethanol on GABAergic neurotransmission in the RSC of neonatal mice, as well as the long-term effects of neonatal ethanol exposure on parvalbumin-interneuron mediated neurotransmission in adolescent mice. Mice were exposed to ethanol using vapor inhalation chambers. In postnatal day (P) 7 mouse pups, ethanol unexpectedly failed to potentiate GABAAreceptor-mediated synaptic transmission. Binge-like ethanol exposure of P7 mice expressing channel rhodopsin in parvalbumin-positive interneurons enhanced the peak amplitudes, asynchronous activity and total charge, while decreasing the rise-times of optically-evoked GABAAreceptor-mediated inhibitory postsynaptic currents in adolescent animals. These effects could partially explain the learning and memory deficits that have been documented in adolescent and young adult mice exposed to ethanol during the third trimester-equivalent developmental period.

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.

Ethanol is associated with oxidative stress. Exposure to ethanol during childhood may lead to neurological disorders. Congenital disorders induced by alcohol are mainly caused by an oxidative-inflammatory cascade due to extensive apoptotic neurodegeneration in the brain, particularly in the hippocampus. Simvastatin, which acts as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), is widely used to manage cardiovascular diseases. Recently, the neuroprotective effects of simvastatin against nervous system disorders have been introduced. In this study, we examined the protective effects of simvastatin on ethanol-related neurotoxicity in the hippocampus of rat pups. Ethanol (5.27 g/kg) in a milk solution (27.8 mL/kg) was administered to male rat pups via intragastric intubation at 2-10 days after birth. Also, 10 and 20 mg/kg of simvastatin were injected to the animals. By using Morris water maze task, the hippocampus-dependent memory and spatial learning was evaluated 36 days after birth. An ELISA assay was performed to investigate the antioxidant and anti-inflammatory effects of simvastatin by measuring the levels of tumor necrosis factor-α (TNF-α), and antioxidant enzymes. To assess the expression levels of Iba1 immunohistochemical staining and caspase-3 immunofluorescence staining was performed. The current study demonstrated that administration of simvastatin significantly attenuates spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also simvastatin could considerably increase the total superoxide dismutaseand glutathione levels (P < 0.01). Moreover, it was associated with a greater reduction in malondialdehyde (P < 0.05) and TNF-α levels, compared to the ethanol group (P < 0.01). Furthermore, in the simvastatin group, the hippocampal level of caspase-3 and the level of Iba1-positive cells, reduced (P < 0.01). This study demonstrated that apoptotic signaling, mediated by the oxidative-inflammatory cascade, could be inhibited by simvastatin in rat pups with ethanol exposure in the postnatal period.

To evaluate the therapeutic efficacy of a new liquid embolic material, Embol, in embolization of the renal artery.Embol is a new embolic material obtained by partial hydrolysis of polyvinyl acetate mixed in absolute ethanol and Iopromide 370 and manufactured by Schering Korea, Kyonggido, Korea. Six patients who underwent embolization of the renal artery using Embol were evaluated. Four were male and two were female and their ages ranged from 11 to 70 (mean, 53) years. Clinical and radiologic diagnoses referred for renal artery embolization were renal cell carcinoma (n = 3), renal angiomyolipoma (n = 2) and pseudoaneurysm of the renal artery (n = 1). After selective renal angiography, Embol was injected through various catheters, either with or without a balloon occlusion catheter. Changes in symptoms and blood chemistry which may have been related to renal artery embolization with Embol were analyzed.The six patients showed immediate total occlusion of their renal vascular lesions. One of the three in whom renal cell carcinoma was embolized with Embol underwent radical nephrectomy, and the specimen thus obtained revealed 40% tumor necrosis. In the two patients with angiomyolipomas, the tumors decreased in size and abdominal pain subsided. Bleeding from pseudoaneurysm of the renal artery was successfully controlled. Four patients showed symptoms of post-embolization syndrome, and one of these also showed increased levels of blood urea nitrogen and creatinine. One patient experienced transient hypertension.Embol is easy to use, its radiopacity is adequate and it is a safe and effective embolic material which provides immediate and total occlusion of renal vascular lesions.