Blood Ethanol Research Articles

Intermittent Exposure to a Single Bottle of Ethanol Modulates Stress Sensitivity: Impact of Age at Exposure Initiation.

Alcohol use during adolescence is a serious public health problem, with binge drinking and high-intensity drinking being particularly harmful to the developing adolescent brain. To investigate the adverse consequences of binge drinking and high-intensity adolescent drinking, adolescent rodents were intermittently exposed to ethanol through intragastric gavage, intraperitoneal injection, or vapor inhalation. These models revealed the long-lasting behavioral and neural consequences of adolescent intermittent ethanol (AIE) exposure. The present study was designed to characterize a different AIE model, namely, intermittent exposure to a single bottle of 10% ethanol as the only source of fluids on a 2 days on/2 days off (water days) schedule, and to determine whether this AIE exposure model would produce changes in hormonal and neuroimmune responsiveness to challenges of differing modalities. Assessments of ethanol intake as well as blood and brain ethanol concentrations (BECs and BrECs, respectively) in adult male and female rats (Experiment 1) revealed that BECs and BrECs peaked following access to ethanol for a 2 h period when assessed 1 h into the dark cycle. Experiment 2 revealed age differences in ethanol intake, BECs, and BrECs following a 2 h access to ethanol (1 h into the dark cycle), with adolescents ingesting more ethanol and reaching higher BECs as well as BrECs than adults. In Experiment 3, intermittent exposure to a single bottle of 10% ethanol for 10 cycles of 2 days on/2 days off was initiated either in early or late adolescence, followed by an acute systemic immune challenge with lipopolysaccharide (LPS) in adulthood. LPS increased corticosterone and progesterone levels regardless of sex and prior ethanol history, whereas an LPS-induced increase in cytokine gene expression in the hippocampus was evident only in ethanol-exposed males and females, with females who underwent early exposure to ethanol being more affected than their later-exposed counterparts. In Experiment 4, intermittent ethanol exposure in females was initiated either in adolescence or adulthood and lasted for 12 ethanol exposure cycles. Then, behavioral (freezing behavior), hormonal (corticosterone and progesterone levels), and neuroimmune (cytokine gene expression in the PVN, amygdala, and hippocampus) responses to novel environments (mild stressors) and shock (intense stressors) were assessed. More pronounced behavioral and hormonal changes, as well as changes in cytokine gene expression, were evident in the shock condition than following placement in the novel environment, with prior history of ethanol exposure not playing a substantial role. Interleukin (IL)-1β gene expression was enhanced by shock in the PVN, whereas shock-induced increases in IL-6 gene expression were evident in the hippocampus. Together, these findings demonstrate that our intermittent adolescent exposure model enhances responsiveness to immune but not stress challenges, with females being more vulnerable to this AIE effect than males.

Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease.

In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RARβ agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre-RARβ knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RARβ (RARβ-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RARβ-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RARβ/ATF4-deficient HepG2, suggesting that RARβ is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RARβ as a negative regulator of lipid metabolism and cellular stress in ALD.

Beneficial effects of WON-21 on the symptoms of a hangover and identification of active compounds: experimental studies on antioxidant, anti-inflammation, and alcohol-metabolizing enzymes

Many hangover cure products containing natural ingredients that are also effective against alcohol-related liver damage or improve liver function have recently become available. In addition to curing liver damage, antioxidants, anti-inflammatory agents, and blood ethanol reduction aids are emerging as relief targets that reduce hangover symptoms. We investigated the ameliorating effect of WON-21 herbal medicinal products by studying the mixing ratio of oriental medicine concept with respect to antioxidant potential, anti-inflammation, and aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) enzyme activities. WON-21 and its components exerted antioxidant and anti-inflammatory effects. Rutin, taxifolin, and quercetin showed superior antioxidant effects compared to the other components. WON-12 effectively reduced iNOS and COX-2 in LPS-stimulated macrophages. Quercetin and apigenin were 2 compounds effective for the inhibition of iNOS and COX-2. WON-21 and quercetin also significantly increased the activities of ALDH and ADH enzymes in a concentration-dependent manner.

ASSESSING THE EFFECTIVENESS OF PROANECY HEPA MILK FOR PREVENTING AN INCREASE OF BLOOD ETHANOL CONCENTRATION

Aims: This study aimed to investigate whether consuming 6ml/kg of Proanecy Hepa milk prior to alcohol consumption could limit the increase in blood alcohol concentration (BAC). Methods: A self-controlled clinical trial with 6 ethanol pharmacokinetic crossover trials was performed. Ten fasting students were divided into six groups, each receiving different substances before consuming 0.5g of ethanol/kg. The substances administered included Pure water, Alcohol antidote, Proanecy Hepa milk, Proanecy Hepa milk without Silymarin, Silymarin, and Liver support milk. BAC was measured at five-time points using gas chromatography: baseline (t0), 60 minutes (t1), 120 minutes (t2), 180 minutes (t3), and 240 minutes (t4) after alcohol intake. iAUC of blood ethanol were presented as median (interquartile range). Results: The group that consumed Proanecy Hepa demonstrated a significantly lower increase in BAC, as indicated by the incremental area under the curve (iAUC) (170.9, 50.5-470.8), compared to the other groups (p< 0.001). The median iAUC for the remaining groups were as follows: pure water 2885.1 (2405.7-3005.3), alcohol antidote 2973.9 (2744.2-3369.5), Proanecy Hepa without Silymarin 2295.9 (1222.5-2569.4), Silymarin 3411.8 (3006.2-3922), and Liver support milk 2739.4 (2431.8-3149.4). Furthermore, individuals who consumed 6ml/kg of Proanecy Hepa before alcohol intake maintained BAC below the positive threshold of 10 mg/dl at all measured time points (60, 120, 180, and 240 minutes). In contrast, individuals in the control groups exceeded the positive threshold at those time points except for minute 240. Conclusions: The study suggests that consuming 6 ml/kg of Proanecy Hepa milk 30 minutes before consuming 0.5g of ethanol/kg can help prevent blood alcohol levels from exceeding the positive threshold of 10 mg/dl.

Acute and Chronic Ethanol Effects during Adolescence on Neuroimmune Responses: Consequences and Potential Pharmacologic Interventions.

Heavy ethanol consumption during adolescence has been linked to neuroimmune response dysregulation and cognitive deficits in the developing adolescent brain. During adolescence, the brain is particularly susceptible to the pharmacological effects of ethanol that are induced by acute and chronic bouts of exposure. Numerous preclinical rodent model studies have used different ethanol administration techniques, such as intragastric gavage, self-administration, vapor, intraperitoneal, and free access, and while most models indicated proinflammatory neuroimmune responses in the adolescent brain, there are various factors that appear to influence this observation. This review synthesizes the most recent findings of the effects of adolescent alcohol use on toll-like receptors, cytokines, and chemokines, as well as the activation of astrocytes and microglia with an emphasis on differences associated with the duration of ethanol exposure (acute vs. chronic), the amount of exposure (e.g., dose or blood ethanol concentrations), sex differences, and the timing of the neuroimmune observation (immediate vs. persistent). Finally, this review discusses new therapeutics and interventions that may ameliorate the dysregulation of neuroimmune maladaptations after ethanol exposure.

G protein-coupled receptor 158 modulates sensitivity to the sedative-hypnotic effect of ethanol in male mice.

Sensitivity to ethanol provides an index of the predisposition to recover from unconsciousness induced by a dose of ethanol. The role of the G protein-coupled receptor 158 (GPR158) in modulating sensitivity to the sedative-hypnotic effect of ethanol has not been investigated. Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, Gpr158-/- mice and wild-type (WT) littermates (n = 8/genotype) were tested using LORR induced by a dose of 3.5 g/kg ethanol, an open-field test (OFT), and a measure of blood ethanol concentration. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in Gpr158-/- mice (n = 6/genotype). We also tested CamK2A-Cre;Gpr158fl/fl (n = 9) and Vgat-Cre;Gpr158fl/fl mice (n = 10) using the LORR test and OFT to compare with controls (n = 9 and 8, respectively). Gpr158 deficiency prolonged the LORR duration by 110.6%, t(14) = -5.241, p = 0.0001, without altering spontaneous activity, t(14) = -0.718, p = 0.485, or ethanol metabolism, F(1, 8) = 0.259, p = 0.625. Gpr158 knockout did not change the ethanol effect on locomotion, F(1, 10) = 0.262, p = 0.62. The LORR duration increased by 69% in the conditional knockouts of Gpr158 within calcium/calmodulin-dependent protein kinase II alpha-positive (CamK2A+ ) neurons, t(16) = -2.914, p = 0.01, and by 92% in the vesicular GABA transporter-positive (Vgat+ ) neurons, t(9.802) = -2.519, p = 0.023. Locomotion was not altered in Camk2A-Cre;Gpr158fl/fl , t(16) = 0.49, p = 0.631 or Vgat-Cre;Gpr158fl/fl mice, t(16) = 0.035, p = 0.972. This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative-hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication.

Walnut (Juglans regia L.) Oligopeptides Alleviate Alcohol-Induced Acute Liver Injury through the Inhibition of Inflammation and Oxidative Stress in Rats.

The study was aimed at investigating the effects of walnut oligopeptides (WOPs) on alcohol-induced acute liver injury and its underlying mechanisms. Male Sprague Dawley (SD) rats were randomly assigned to six groups: normal control, alcohol control, whey protein (440 mg/kg.bw), and three WOPs (220 mg/kg.bw, 440 mg/kg.bw, 880 mg/kg.bw) groups. After 30 days of gavage, ethanol with a volume fraction of 50%, administered at a dose of 7 g/kg.bw., caused acute liver injury. A righting reflex experiment and a blood ethanol concentration evaluation were then performed. Serum biochemical parameters, inflammatory cytokines, liver alcohol metabolism enzymes, oxidative stress biomarkers, liver nuclear factor-κB (NF-κB p65), and cytochrome P4502E1 expression were determined. The results revealed that the intervention of 440 mg/kg and 880 mg/kg WOPs could alleviate the degree of intoxication, decrease blood ethanol concentration, alleviate alcohol-induced hepatic steatosis, enhance the activity of hepatic ethanol metabolizing enzymes and antioxidant capacity, reduce lipid oxidation products and pro-inflammatory factor contents, and inhibit the expression of NF-κBp65 in the livers of rats. The outcomes of the study suggest that WOPs have beneficial effects on liver damage caused by acute ethanol binge drinking, with the high-dose WOPs (880 mg/kg.bw) exerting the most pronounced hepatoprotective effect.

A clinical experience-based Chinese herbal formula improves ethanol-induced drunken behavior and hepatic steatohepatitis in mice models

BackgroundBao-Gan-Xing-Jiu-Wan (BGXJW) is a clinical experience-based Chinese herbal formula. Its efficacy, pharmacological safety, targeted function, process quality, and other aspects have met the evaluation standards and the latest requirements of preparations. It could prevent and alleviate the symptoms of drunkenness and alcoholic liver injury clinically. The present work aims to elucidate whether BGXJW could protect against drunkenness and alcoholic liver disease in mice and explore the associated mechanism.Material and methodsWe used acute-on-chronic (NIAAA) mice model to induce alcoholic steatosis, and alcohol binge-drinking model to reappear the drunk condition. BGXJW at indicated doses were administered by oral gavage respectively to analyze its effects on alcoholic liver injury and the associated molecular mechanisms.ResultsBGXJW had no cardiac, hepatic, renal, or intestinal toxicity in mice. Alcoholic liver injury and steatosis in the NIAAA mode were effectively prevented by BGXJW treatment. BGXJW increased the expression of alcohol metabolizing enzymes ADH, CYP2E1, and ALDH2 to enhance alcohol metabolism, inhibited steatosis through regulating lipid metabolism, counteracted alcohol-induced upregulation of lipid synthesis related proteins SREBP1, FASN, and SCD1, meanwhile it enhanced fatty acids β-oxidation related proteins PPAR-α and CPT1A. Alcohol taken enhanced pro-inflammatory TNF-α, IL-6 and down-regulated the anti-inflammatory IL-10 expression in the liver, which were also reversed by BGXJW administration. Moreover, BGXJW significantly decreased the blood ethanol concentration and alleviated drunkenness in the alcohol binge-drinking mice model.ConclusionsBGXJW could effectively relieve drunkenness and prevent alcoholic liver disease by regulating lipid metabolism, inflammatory response, and alcohol metabolism.Graphical

Pengaruh Kadar Etanol Darah Terhadap Kadar Gamma Glutamyl Transferase (GGT) pada Pekerja Pembuatan Etanol di Desa Ngombakan Polokarto

Ethanol is the result of sugarcane fermentation which is converted into molasses (cane drops). Then the distillation process is carried out by heating for a certain time so that a certain level of ethanol is obtained. The process of making ethanol is an activity that has a high risk for its workers. The heating process produces vapors that are harmful to the body, causing health problems for workers. Liver disease is the most common complication caused by exposure to ethanol. Alcoholic fatty liver is a reversible disease that can progress to alcoholic hepatitis which can cause liver cirrhosis and liver failure. This study was conducted to determine blood ethanol levels, Gamma GT levels and the effect of blood ethanol levels on Gamma GT in ethanol production workers. The research was conducted by quota sampling as many as 24 people in 8 traditional ethanol-making industrial houses in Ngombakan, Polokarto. Ethanol examination was carried out using the Gass Chromatography and Mass Spectrometry method and Gamma GT was carried out using the colorimetric enzymatic method. The results obtained are the average ethanol content of the workers is 0.45 mg/dL and Gamma GT is 29 U/L. The results of linear regression analysis showed Sig. 0.257 (0.05) meaning that there was no effect of ethanol content on Gamma GT levels. Based on the coefficient of determination (R2) of 0.058, it means that the effect of ethanol on Gamma GT is 5.8%.

Gender-specific differences in comorbidities, in-hospital complications and outcomes in emergency patients with ethanol intoxication with and without multisubstance use

To analyse gender-specific differences in comorbidities, multisubstance abuse, in-hospital complications, intensive care unit transfers and referrals to psychiatric wards of emergency department patients with ethanol intoxication. Several lines of evidence suggest an influence of gender differences on diagnostic and therapeutic approaches to various diseases. Over a period of 7 years, all patients with signs or symptoms of ethanol intoxication and a positive blood ethanol test admitted for the first time to the emergency department of a Swiss regional tertiary referral hospital were prospectively enrolled. Patients were categorised into two subgroups: patients without additional drug use were considered ethanol-only cases, whereas patients who had also ingested other substances (as determined from bystanders, physicians and urine drug screening) were considered multisubstance cases. A retrospective analysis of this database evaluated gender-specific differences in comorbidities, multisubstance abuse, in-hospital complications, intensive care unit transfers and referrals to psychiatric wards within these two subgroups. Statistical analysis included Fisher's exact test for categorical data and Wilcoxon rank sum test for continuous data. Of 409 enrolled patients, 236 cases were ethanol-only and 173 were multisubstance cases. The three most common comorbidities in multisubstance patients showed significant gender differences: psychiatric disorders (43% males vs 61% females; p = 0.022), chronic ethanol abuse (55% males vs 32% females; p = 0.002) and drug addiction (44% males vs 17% females; p = 0.001). Gender differences were also found for the most frequently co-ingested substances: benzodiazepines (35% males vs 43% females; p = 0.014), cannabis (45% males vs 24% females; p = 0.006) and cocaine (24% males vs 6% females; p = 0.001). Male and female ethanol-only patients were transferred to the intensive care unit in 8% of cases. In multisubstance cases, 32% of male and 43% of female patients were transferred to the intensive care unit (no significant gender difference). The psychiatric ward referral rate in male (30%) and female (48%) patients with multisubstance abuse was significantly different (p = 0.028). No significant gender difference in psychiatric ward referral rates was observed for ethanol-only patients (12% males, 17% females). Among emergency department patients admitted with ethanol intoxication, gender differences in comorbidities, substance use and psychiatric ward referrals were highly significant among patients who presented with multisubstance abuse. Rates of intensive care unit transfer for patients with ethanol intoxication are substantial for both genders, reflecting relevant disease burden and resource demand, as well as the need for further preventive efforts.

Alcohol use trends in Dallas County during the COVID-19 pandemic

Alcohol (ethanol) is the most widely detected drug in forensic toxicology casework and an increase in consumption of alcohol was reported during the COVID-19 pandemic. The increase in consumption could be attributed to rising stress levels and social isolation. To determine whether the pandemic had an impact on ethanol positivity and concentrations in cases analyzed by the Dallas County Southwestern Institute of Forensic Sciences, blood ethanol results were evaluated from January 1, 2019, through December 31, 2021. This time frame captured ethanol prevalence and concentrations before, during, and immediately following the pandemic for comparison. The average ethanol concentration in postmortem casework over the three years for each quarter ranged from 0.116 g/100 mL to 0.142 g/100 mL while the average concentration in driving while intoxicated (DWI) was higher, ranging from 0.173 g/100 mL to 0.188 g/100 mL. The ethanol positivity rate for postmortem casework remained relatively the same at approximately 20% during the time frame, while there was a decrease in ethanol positivity rate for DWI casework during the pandemic in April - June (Q2) 2020. However, the positivity rate returned to pre-pandemic levels by the end of 2020. Despite the self-reported surveys of increased alcohol consumption during the pandemic, a corresponding increase in average ethanol concentrations was not observed in Dallas County and the surrounding area.

Hangover-Relieving Effect of Ginseng Berry Kombucha Fermented by Saccharomyces cerevisiae and Gluconobacter oxydans in Ethanol-Treated Cells and Mice Model.

This study aimed to evaluate the hangover relieving effect of ginseng berry kombucha (GBK) fermented with Saccharomyces cerevisiae and Gluconobacter oxydans in in vitro and in vivo models. The antioxidant activity and oxidative stress inhibitory effect of GBK were evaluated in ethanol-treated human liver HepG2 cells. In addition, biochemical and behavioral analyses of ethanol treated male ICR mice were performed to confirm the anti-hangover effect of GBK. The radical scavenging activity of GBK was increased by fermentation, and the total ginsenoside content of GBK was 70.24 μg/mL. In HepG2 cells, in which oxidative stress was induced using ethanol, GBK significantly increased the expression of antioxidant enzymes by upregulating the Nrf2/Keap1 pathway. Moreover, GBK (15 and 30 mg/kg) significantly reduced blood ethanol and acetaldehyde concentrations in ethanol-treated mice. GBK significantly increased the levels of alcohol-metabolizing enzymes, including alcohol dehydrogenase and acetaldehyde dehydrogenase. The balance beam test and elevated plus maze test revealed that high-dose GBK significantly ameliorated ethanol-induced behavioral changes. Collectively, GBK exerted a protective effect against ethanol-induced liver damage by regulating the Nrf2/Keap1 pathway.

Selective PDE4B and PDE4D inhibitors produce distinct behavioral responses to ethanol and GABAergic drugs in mice

Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABAA receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABAA β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.

Effects of Chronic Alcohol Consumption and Iron Deficiency on Maternal Folate Status and Reproductive Outcome in Mice

The influence of chronic alcohol consumption with or without iron deficiency on reproductive performance and folate status was studied. Female CBA/J mice were fed isocaloric liquid diets prior to and during pregnancy. A 2 × 2 factorial design was employed with ethanol-derived calories (EDC) and iron (Fe) as dietary variables. Groups received 0% EDC and 30 ppm Fe (CA); 0% EDC and 2 ppm Fe (CD); 20% EDC and 30 ppm Fe (EA); and 20% EDC and 2 ppm Fe (ED). Animals were killed on day 18 of gestation. Mean body weights were reduced in CD, EA and ED groups, while daily caloric intakes reduced only in CD and ED groups. Maternal values for hemoglobin, transferrin saturation and red cell folates decreased with iron deficiency and/or 20% EDC; hematocrit, serum iron and serum folates decreased only with iron deficiency. Blood ethanol levels were similar in EA and ED groups. Maternal liver total lipids and alcohol dehydrogenase activity increased only with 20% EDC, while dihydrofolate reductase activity decreased with iron deficiency and/or 20% EDC. Iron deficiency and/or 20% EDC adversely affected gestational performances in mice as indicated by increased resorptions and decreased percentages of live fetuses/litters and live fetal weights. Data indicate that iron deficiency and/or chronic ethanol consumption induce adverse effects on maternal reproductive performance of CBA/J mice possibly via alteration of folate metabolism.

Ethanol combined with energy drinks: Two decades of research in rodents

Many studies raised concerns on alcoholic beverages consumption mixed with energy drinks (AmED), which can induce higher rates of binge drinking and earlier development of alcohol use disorders. After 20 years of research, few studies with laboratory animals have focused on the effects of this mixture and the neurobiological and pharmacological mechanisms underlying them. We found 16 articles on AmED administration to rodents evaluating its effects on voluntary consumption, locomotion, anxiety-like behavior, memory, influence on the onset time of seizures, biochemical and neurochemical measures. Some of these studies indicated energy drinks (ED) can alter the pattern of use and motivation to consume ethanol (EtOH); increase the expression of sensitization to EtOH stimulant effect and the proportion of sensitized mice; decrease the aversiveness of high concentrations of EtOH, among other effects. In addition AmED hastens the loss of righting reflex and its effects on memory are controversial. After acute administration no difference was found in blood ethanol concentration (BEC) of rodents which received EtOH with or without ED, but after 60 days of treatment, AmED group had lower BEC levels than EtOH group. Data on biochemical and neurochemical parameters after AmED are not consistent. Although the AmED group presented higher glucose levels than the EtOH group when drugs were administered by gavage, this was not observed in a self-administration protocol. AmED may induce higher kidney damage, higher levels of plasma urea, uric acid and creatinine when compared to EtOH. Chronic consumption of AmED causes an inflammatory response and oxidative stress, which may induce cell death in the cortex and hypothalamus of adult rats. These controversial results show that AmED diverse effects depend on sex, age and lineage of the animals, duration of the treatment and route of administration. Further research is necessary to evaluate the mechanisms underlying AmED biological effects.

Burn index, burn characteristics and carboxyhemoglobin levels in indoor fire-related deaths: Significance and interpretation of the autopsy findings

IntroductionThe Burn Index (BI) is a significant clinical prognostic parameter for patients with burns. It simultaneously considers major mortality risk factors: age and burns extensivity. Despite the inability to distinguish between ante- and post-mortem burns, their characteristics on autopsy might indicate if a significant thermal injury occurred before the onset of death. We investigated whether autopsy BI, burn extensivity, and severity could tell whether burns were the concurrent cause of fire-related death (FRD), even if the body remained in a fire. Material and methodsTen-year retrospective study analyzed FRD that occurred at the scene in a confined space. Soot aspiration was the main inclusion criterion. Autopsy reports were reviewed for demographic data, burn characteristics (degree, Total Body Surface Area burned- TBSA), coronary artery disease, and blood ethanol. We calculated the BI as a sum of the victim's age and percentage of TBSA affected by 2nd, 3rd and 4th-degree burns. Cases were divided into two groups: those with COHb≤ 30% and with COHb> 30%. Subjects with burned TBSA≤ 40% were analyzed separately afterward. ResultsThe study included 53 males (71.6%) and 21 females (28.4%). No significant difference in age was observed between groups (p > 0.05). COHb≤ 30% had 33, and COHb> 30% had 41 victims. BI and burns extensivity (TBSA) had significant negative correlation with COHb values (ρ = −0.581, p < 0.01 and ρ = −0.439, p < 0.01, respectively). Both were significantly higher in subjects with COHb≤ 30% compared to those with COHb> 30% (140.7 ± 29.57 vs. 95.49 ± 38.49, p < 0.01 and 98 (13−100) vs. 30 (0−100), p < 0.01, BI and TBSA respectively). BI had excellent and TBSA fair performance for detection of subjects with COHb≤ 30% on ROC curve analysis (AUCs 0.821, p < 0.001 and 0.765, p < 0.001), with optimal cut-off values: BI≥ 107 (sensitivity 81.3%, specificity 70.7%) and TBSA≥ 45 (sensitivity 84.8%, specificity 70.7%). On logistic regression analysis BI≥ 107 was independently associated with COHb≤ 30% values (aOR 6; 95%CI 1.55–23.37). The same holds for the presence of 3rd-degree burns (aOR 5.9; 95%CI 1.45–23.99). In the subgroup of subjects with TBSA≤ 40% burned, those with COHb≤ 50% were significantly older than victims with COHb> 50% (p < 0.05). Here BI≥ 85 was a particularly good predictor for detection of subjects with COHb≤ 50% (AUC=0.913, p < 0.001, 95% CI 0.813–1.00; sensitivity 90.9%, specificity 81%). ConclusionThe BI≥ 107, TBSA≥ 45% burned, and 3rd-degree burns observed on autopsy point to a significantly higher odds that limited CO intoxication occurred, and burns should be considered a concurrent cause of indoor FRD. When less than 40% of TBSA was affected, BI≥ 85 indicated sub-lethal CO poisoning.

Interspecies and regional variability of alcohol action on large cerebral arteries: regulation by KCNMB1 proteins.

Alcohol intake leading to blood ethanol concentrations (BEC) ≥ legal intoxication modifies brain blood flow with increases in some regions and decreases in others. Brain regions receive blood from the Willis' circle branches: anterior, middle (MCA) and posterior cerebral (PCA), and basilar (BA) arteries. Rats and mice have been used to identify the targets mediating ethanol-induced effects on cerebral arteries, with conclusions being freely interchanged, albeit data were obtained in different species/arterial branches. We tested whether ethanol action on cerebral arteries differed between male rat and mouse and/or across different brain regions and identified the targets of alcohol action. In both species and all Willis' circle branches, ethanol evoked reversible and concentration-dependent constriction (EC50s ≈ 37-86 mM; below lethal BEC in alcohol-naïve humans). Although showing similar constriction to depolarization, both species displayed differential responses to ethanol: in mice, MCA constriction was highly sensitive to the presence/absence of the endothelium, whereas in rat PCA was significantly more sensitive to ethanol than its mouse counterpart. In the rat, but not the mouse, BA was more ethanol sensitive than other branches. Both interspecies and regional variability were ameliorated by endothelium. Selective large conductance (BK) channel block in de-endothelialized vessels demonstrated that these channels were the effectors of alcohol-induced cerebral artery constriction across regions and species. Variabilities in alcohol actions did not fully matched KCNMB1 expression across vessels. However, immunofluorescence data from KCNMB1-/- mouse arteries electroporated with KCNMB1-coding cDNA demonstrate that KCNMB1 proteins, which regulate smooth muscle (SM) BK channel function and vasodilation, regulate interspecies and regional variability of brain artery responses to alcohol.

Interstrain differences in adolescent fear conditioning after acute alcohol exposure

Adolescent sensitivity to alcohol is a predictor of continued alcohol use and misuse later in life. Thus, it is important to understand the many factors that can impact alcohol sensitivity. Data from our laboratory suggested that susceptibility to alcohol-associated contextual fear learning deficits varied among adolescent and adult mice from two mouse strains. To investigate the extent of genetic background’s influences on adolescent learning after alcohol exposure, we examined how 9 inbred mouse strains differed in vulnerability to alcohol-induced contextual and cued fear conditioning deficits. We demonstrated significant strain- and sex-dependent effects of acute alcohol exposure on adolescent fear learning, with alcohol having most pronounced effects on contextual fear learning. Female adolescents were more susceptible than males to alcohol-induced impairments in contextual, but not cued, fear learning, independent of genetic background. Heritability for contextual and cued fear learning after alcohol exposure was estimated to be 31 % and 18 %, respectively. Learning data were compared to Blood Ethanol Concentrations (BEC) to assess whether strain differences in alcohol metabolism contributed to strain differences in learning after alcohol exposure. There were no clear relationships between BEC and learning outcomes, suggesting that strains differed in learning outcomes for reasons other than strain differences in alcohol metabolism. Genetic analyses revealed polymorphisms across strains in notable genes, such as Chrna7, a promising genetic candidate for susceptibility to alcohol-induced fear conditioning deficits. These results are the first to demonstrate the impact of genetic background on alcohol-associated fear learning deficits during adolescence and suggest that the mechanisms underlying this sensitivity are distinct from alcohol metabolism.

Folate administration ameliorates neurobehavioral effects of prenatal ethanol exposure

ABSTRACT Background: Prenatal ethanol exposure (PEE) induces heightened ethanol intake at adolescence in preclinical studies. Ethanol intake alters the absorption of folate, a methyl-group donor critical for numerous cellular functions. The prenatal administration of folate is, therefore, a promising approach to reduce the effects of PEE. Objectives: Experiment 1 determined if prenatal folate modulated the effects of PEE on ethanol intake, anxiety-like response, and exploratory behaviors (Experiment 1) in Wistar rats. Experiment 2 assessed, in rats not given PEE, if postnatal folate reversed effects of ethanol exposure at postnatal days 28–42. Experiment 3 assessed if folate altered blood ethanol levels (BELs). Methods: Experiment 1 involved 242 (125 male) adolescent Wistar rats derived from dams given folate (20 mg/kg, gestational days – GD- 13-20) + ethanol (2.0 g/kg, GD 17–20), ethanol, or vehicle only at pregnancy. Experiment 2 involved 29 male adolescents administered vehicle or ethanol doses co-administered or not with folate. In Experiment 3 twelve adult females were tested for BELs after folate administration. These tests were applied: intake tests, light dark box (LDB), elevated plus maze, open field and concentric square field. Results: PEE heightened ethanol intake (η2 ps = 0.06–07) and induced hyperactivity and a reduced latency to exit the white area of the LDB (η2 ps = 0.12–17). These effects were partially inhibited by folate (p > .05). Rats exposed to ethanol exposure at adolescence exhibited reduced motor activity (η2 p = .17), regardless of folate treatment. Folate did not affect BELs. Conclusion: Folate administration should be considered as a preventive or acute treatment to attenuate the neurobehavioral effects of PEE.

Derivation of an approximate formula of the Rabotnov fractional-exponential kernel fractional derivative and applied for numerically solving the blood ethanol concentration system

&lt;abstract&gt;&lt;p&gt;The article aimed to develop an accurate approximation of the fractional derivative with a non-singular kernel (the Rabotnov fractional-exponential formula), and show how to use it to solve numerically the blood ethanol concentration system. This model can be represented by a system of fractional differential equations. First, we created a formula for the fractional derivative of a polynomial function $ t^{p} $ using the Rabotnov exponential kernel. We used the shifted Vieta-Lucas polynomials as basis functions on the spectral collocation method in this work. By solving the specified model, this technique generates a system of algebraic equations. We evaluated the absolute and relative errors to estimate the accuracy and efficiency of the given procedure. The results point to the technique's potential as a tool for numerically treating these models.&lt;/p&gt;&lt;/abstract&gt;