Combined Insults of a MASH Diet and Alcohol Binges Activate Intercellular Communication and Neutrophil Recruitment via the NLRP3-IL-1ß Axis in the Liver.

Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1ß via NLRP3 activation and that IL-1ß acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.

In Vivo Administration of Phosphatidic Acid, a Direct Alcohol Target Rescues Fetal Growth Restriction and Maternal Uterine Artery Dysfunction in Rat FASD Model.

Fetal growth restriction is a hallmark of Fetal Alcohol Syndrome (FAS) and is accompanied by maternal uterine circulatory maladaptation. FAS is the most severe form of Fetal Alcohol Spectrum Disorder (FASD), a term for the range of conditions that can develop in a fetus when their pregnant mother consumes alcohol. Alcohol exerts specific direct effects on lipids that control fundamental developmental processes. We previously demonstrated that direct in vitro application of phosphatidic acid (PA, the simplest phospholipid and a direct target of alcohol exposure) to excised uterine arteries from alcohol-exposed rats improved vascular function, but it is unknown if PA can rescue end organ phenotypes in our FASD animal model. Pregnant Sprague-Dawley rats (n = 40 total dams) were gavaged daily from gestational day (GD) 5 to GD 19 with alcohol or maltose dextrin, with and without PA supplementation, for a total of four unique groups. To translate and assess the beneficial effects of PA, we hypothesized that in vivo administration of PA concomitant with chronic binge alcohol would reverse uterine artery dysfunction and fetal growth deficits in our FASD model. Mean fetal weights and placental efficiency were significantly lower in the binge alcohol group compared with those in the control (p < 0.05). However, these differences between the alcohol and the control groups were completely abolished by auxiliary in vivo PA administration with alcohol, indicating a reversal of the classic FAS growth restriction phenotype. Acetylcholine (ACh)-induced uterine artery relaxation was significantly impaired in the uterine arteries of chronic in vivo binge alcohol-administered rats compared to the controls (p < 0.05). Supplementation of PA in vivo throughout pregnancy reversed the alcohol-induced vasodilatory deficit; no differences were detected following in vivo PA administration between the pair-fed control and PA alcohol groups. Maximal ACh-induced vasodilation was significantly lower in the alcohol group compared to all the other treatments, including control, control PA, and alcohol PA groups (p < 0.05). When analyzing excitatory vasodilatory p1177-eNOS, alcohol-induced downregulation of p1177-eNOS was completely reversed following in vivo PA supplementation. In summary, these novel data utilize a specific alcohol target pathway (PA) to demonstrate a lipid-based preventive strategy and provide critical insights important for the development of translatable interventions.

Adolescent social isolation increases binge-like alcohol drinking in male but not female high-alcohol-preferring mice.

AIMS: This study examined how adolescent social isolation affects adult binge-like alcohol drinking and stress-axis function, via basal levels of circulating corticosterone (CORT), in male and female mice with a genetic predisposition toward high alcohol preference (HAP). METHODS: Male and female HAP2 mice were randomly assigned to a group-housed or social isolation (ISO) group. Social isolation began at postnatal Days 40-42 and lasted for 21 days prior to assessment of binge-like alcohol drinking using a 4-day drinking-in-the-dark (DID) procedure. Blood samples to assess basal CORT were taken 6 days after social isolation ended and 24 h before DID started, and again 60 h after DID ended, during the light portion of the light cycle. RESULTS: Adolescent social isolation increased adult binge-like alcohol drinking in male but not female mice. All groups showed significantly lower CORT after DID compared to before DID. Pearson bivariate correlation coefficients between the first 2 h of grams-per-kilogram alcohol intake on Day 4 and CORT levels indicated a significant positive correlation in ISO males only after DID and negative correlations in ISO females before and after DID. CONCLUSIONS: These findings demonstrate that adolescent social isolation increased binge-like alcohol drinking in male but not female adult HAP2 mice. Stress-axis adaptations in male HAP2 mice may be associated with the social-isolation-induced increase in binge-like alcohol drinking.

Longitudinal associations among experiences of sexual assault, posttraumatic stress disorder symptoms, and heavy drinking in young adults.

Prior research with young adults has demonstrated clear associations between experiences of sexual assault, symptoms of posttraumatic stress disorder (PTSD), and alcohol use, but most studies have been cross-sectional or have not considered multiple theoretical pathways to understand these associations. Using six waves of data from a longitudinal cohort sample of 1,719 young adults, we examined associations among experiences of past-year sexual assault (i.e., rape, unwanted sexual touching, and physical intimidation in a sexual way), PTSD symptoms, and the frequency of binge drinking over time, allowing for the exploration of symptom-induced, interpersonal risk, and substance-induced pathways for male and female participants. For both male, ßs = 2.84 to 6.55, and female participants, ßs = 2.96 to 10.1, higher prior levels of PTSD symptoms were associated with larger increases in binge drinking over time. For female participants, higher prior levels of sexual assault were associated with larger increases in PTSD symptoms over time, ßs = 3.48 to 4.25, whereas for male participants, higher prior levels of past-year binge drinking were associated with decreases in PTSD symptoms over time, ßs = -2.75 to -0.53. Continued efforts are needed to prevent sexual assault among young adults and address PTSD symptoms among those who experience sexual assault. Interventions that target binge drinking are also needed for individuals who experience PTSD symptoms, especially young adults, to address potentially hazardous drinking before problems escalate and become chronic.

Arranjos assistenciais em uma rede atenção psicossocial no sul do Brasil / Arreglos asistenciales en una red de apoyo psicosocial en sur de Brasil / Care arrangements on a psychosocial care network in southern Brazil

RESUMO. A implementação da reforma psiquiátrica é tema de recorrentes discussões no campo da saúde mental. Essa implementação não é padrão para todas as localidades brasileiras, uma vez que depende dos recursos materiais, humanos e aspectos culturais de cada região. A esta singularidade retoma-se a noção de arranjo assistencial. Este trabalho se propôs a conhecer a implementação numa regional de saúde da região Sul. Foi realizado um mapeamento descritivo, seguindo método empírico-fenomenológico. Descrevem-se serviços que acolhem todos os públicos, mas que encontram dificuldades no trabalho com a população usuária de álcool e outras drogas. Foram elencados sete dispositivos assistenciais: acolhimento, grupos terapêuticos, oficinas, atendimentos individuais, uso da medicação, encaminhamentos e reuniões de equipe. Expõe-se a ideia de que a estrutura de um serviço de saúde mental não pode ser estanque. Os arranjos assistenciais estão relacionados às vivências e soluções criativas e humanas como também práticas irrefletidas e normatizadoras na atenção do sofrimento mental.

RESUMEN. La implementación de la reforma psiquiátrica no se encuentra estandarizada para todas las regiones brasileras, una vez que eso depende de recursos materiales, humanos y de aspectos culturales. Por cuenta de esta singularidad, se retoma la noción de arreglo asistencial. En este trabajo se propone conocer la implementación en una regional de salud de sur de Brasil. Se realizó un mapeo descriptivo, siguiendo el método empírico-fenomenológico. Se describen servicios que acogen a todos los públicos, pero que encuentran dificultades en el trabajo con usuarios de alcohol y drogas. Fueran enumerados siete dispositivos asistenciales: Acogimiento, grupos terapéuticos, talleres, atendimientos individuales, uso de medicación, encaminamientos y reuniones de equipo. Se expone la idea de que la estructura de un servicio de Salud Mental no puede ser hermética. Los arreglos asistenciales están relacionados con las vivencias y soluciones creativas y humanas como también prácticas irreflexivas y normalizadoras en la atención del sufrimiento mental.

ABSTRACT. The psychiatric reform is not standard in all Brazilian places, as it depends on different factors such as material, human and cultural aspects of each region. As for its singularity, it is seen as a care arrangement. This article aims to study the psychosocial care network on a regional health department in south Brazil. A descriptive mapping has been performed, following the empirical-phenomenological method. The services described welcome the entire community, people from all walks of life, but when it comes Drug and Alcohol addicted, the approach becomes more challenging. There have been seven care services listed: Hosting, Therapeutic Groups, Workshops, Individual Treatment, Medication usage, Referrals and Support Group Meetings. The approach for care arrangement is related to the creative experiences and human solutions as well as thoughtless and normative practices in the attention of mental suffering.

Factors associated with unexplained sudden deaths among adults aged 18-45 years in India - A multicentric matched case-control study.

BACKGROUND OBJECTIVES: In view of anecdotal reports of sudden unexplained deaths in India's apparently healthy young adults, linking to coronavirus disease 2019 (COVID-19) infection or vaccination, we determined the factors associated with such deaths in individuals aged 18-45 years through a multicentric matched case-control study. METHODS: This study was conducted through participation of 47 tertiary care hospitals across India. Cases were apparently healthy individuals aged 18-45 years without any known co-morbidity, who suddenly (<24 h of hospitalization or seen apparently healthy 24 h before death) died of unexplained causes during 1 st October 2021-31 st March 2023. Four controls were included per case matched for age, gender and neighborhood. We interviewed/perused records to collect data on COVID-19 vaccination/infection and post-COVID-19 conditions, family history of sudden death, smoking, recreational drug use, alcohol frequency and binge drinking and vigorous-intensity physical activity two days before death/interviews. We developed regression models considering COVID-19 vaccination ≤42 days before outcome, any vaccine received anytime and vaccine doses to compute an adjusted matched odds ratio (aOR) with 95 per cent confidence interval (CI). RESULTS: Seven hundred twenty nine cases and 2916 controls were included in the analysis. Receipt of at least one dose of COVID-19 vaccine lowered the odds [aOR (95% CI)] for unexplained sudden death [0.58 (0.37, 0.92)], whereas past COVID-19 hospitalization [3.8 (1.36, 10.61)], family history of sudden death [2.53 (1.52, 4.21)], binge drinking 48 h before death/interview [5.29 (2.57, 10.89)], use of recreational drug/substance [2.92 (1.1, 7.71)] and performing vigorous-intensity physical activity 48 h before death/interview [3.7 (1.36, 10.05)] were positively associated. Two doses lowered the odds of unexplained sudden death [0.51 (0.28, 0.91)], whereas single dose did not. INTERPRETATION CONCLUSIONS: COVID-19 vaccination did not increase the risk of unexplained sudden death among young adults in India. Past COVID-19 hospitalization, family history of sudden death and certain lifestyle behaviors increased the likelihood of unexplained sudden death.

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation-related markers.

BACKGROUND: Frequent binge drinking is a known contributor to alcohol-related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease. AIM: To investigate the effects of acute alcohol intoxication on inflammation-related markers in hepatic and systemic venous plasma in people with alcohol-related liver disease (ArLD), non-alcoholic fatty liver disease (NAFLD) and healthy controls. METHODS: Thirty-eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy-two inflammation-related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention. RESULTS: Alcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis. CONCLUSION: Acute alcohol intoxication induced changes in multiple inflammation-related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment. CLINICAL TRIAL NUMBER: NCT03018990.

Single ethanol binge causes severe liver injury in mice fed Western diet.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) and NAFLD often coexist in Western societies that consume energy-rich and cholesterol-containing Western diets. Increased rates of ALD mortality in young people in these societies are likely attributable to binge drinking. It is largely unknown how alcohol binge causes liver damage in the setting of Western diets. APPROACH AND RESULTS: In this study, we showed that a single ethanol binge (5 g/kg body weight) induced severe liver injury as shown by marked increases in serum activities of the 2 aminotransferases AST and ALT in C57BL/6J mice that have been fed a Western diet for 3 weeks. The Western diet plus binge ethanol-fed mice also displayed severe lipid droplet deposition and high contents of triglycerides and cholesterol in the liver, which were associated with increased lipogenic and reduced fatty acid oxidative gene expression. These animals had the highest Cxcl1 mRNA expression and myeloperoxidase (MPO)-positive neutrophils in the liver. Their hepatic ROS and lipid peroxidation were the highest, but their hepatic levels of mitochondrial oxidative phosphorylation proteins remained largely unaltered. Hepatic levels of several ER stress markers, including mRNAs for CHOP, ERO1A, ERO1B, BIM, and BIP, as well as Xbp1 splicing and proteins for BIP/GRP78 and IRE-α were also the highest in these animals. Interestingly, Western diet feeding for 3 weeks or ethanol binge dramatically increased hepatic caspase 3 cleavage, and the combination of the 2 did not further increase it. Thus, we successfully established a murine model of acute liver injury by mimicking human diets and binge drinking. CONCLUSIONS: This simple Western diet plus single ethanol binge model recapitulates major hepatic phenotypes of ALD, including steatosis and steatohepatitis characterized by neutrophil infiltration, oxidative stress, and ER stress.

Effects of binge drinking and depression on cognitive-control processes during an emotional Go/No-Go task in emerging adults.

INTRODUCTION: The goal of the current study was to examine differences in neurocognitive processes across groups marked by binge drinking and depression to identify patterns of cognitive and affective processing impairments. METHODS: Undergraduate students (N = 104; 64% female) were recruited based on self-reported symptoms of depression and alcohol use. They completed an emotional Go/No-Go task while undergoing EEG. Mean amplitudes for N2 and P3 components were examined with 2 (Depressed/Non-depressed) X 2 (Binge/Non-binge drinkers) X 4 (Happy/Sad/Angry/Calm) X 3 (Left/Middle/Right) X 2 (Go/No-Go) repeated measures ANOVAs. RESULTS: There were significant Trial Type X Valence X Depression X Binge Drinking interactions for N2 (F(3, 80) = 6.62, p < .01) and P3 (F(3, 80) = 4.65, p < .01) components. There was a significant Valence X Depression X Binge Drinking interaction for response bias (F(3, 65) = 3.11, p < .05). LIMITATIONS: The source of our sample may be a limitation, as all participants were university students, potentially making the results less generalizable. Further, we cannot be certain that social desirability did not interfere with honest reporting of alcohol use in this population. CONCLUSIONS: Differences in early inhibitory control were observed across emotions based on trial type among depressed non-binge drinkers, and these differences were attenuated in the presence of binge drinking. Further, the effects of depression on later inhibitory control were specific to non-binge drinkers. Results help to clarify the nature of underlying patterns of neurocognitive and affective risk processes that could be targeted by prevention and intervention programs.

Maternal alcohol consumption and the risk of miscarriage in the first and second trimesters: A systematic review and dose-response meta-analysis.

INTRODUCTION: According to a precautionary principle, it is recommended that pregnant women and women trying to conceive abstain from alcohol consumption. In this dose-response meta-analysis, we aimed to examine the association between alcohol consumption and binge drinking and the risk of miscarriage in the first and second trimesters. MATERIAL AND METHODS: The literature search was conducted in MEDLINE, Embase and the Cochrane Library in May 2022, without any language, geographic or time limitations. Cohort or case-control studies reporting dose-specific effects adjusting for maternal age and using separate risk assessments for first- and second-trimester miscarriages were included. Study quality was assessed using the Newcastle-Ottawa Scale. This study is registered with PROSPERO, registration number CRD42020221070. RESULTS: A total of 2124 articles were identified. Five articles met the inclusion criteria. Adjusted data from 153 619 women were included in the first-trimester analysis and data from 458 154 women in the second-trimester analysis. In the first and second trimesters, the risk of miscarriage increased by 7% (odds ratio [OR] 1.07, 95% confidence interval [CI] 0.96-1.20) and 3% (OR 1.03, 95% CI 0.99-1.08) for each additional drink per week, respectively, but not to a statistically significant degree. One article regarding binge drinking and the risk of miscarriage was found, which revealed no association between the variables in either the first or second trimester (OR 0.84 [95% CI 0.62-1.14] and OR 1.04 [95% CI 0.78-1.38]). CONCLUSIONS: This meta-analysis revealed no dose-dependent association between miscarriage risk and alcohol consumption, but further focused research is recommended. The research gap regarding miscarriage and binge drinking needs further investigation.

Risk Factors for Stroke in the Young (18-45 Years): A Case-Control Analysis of INTERSTROKE Data from 32 Countries.

BACKGROUND: It is not clear whether conventional vascular risk factors are responsible for most strokes in patients younger than 45 years of age. Our objective was to evaluate the association of common risk factors with stroke in individuals under 45 years. METHODS: INTERSTROKE was a case-control study carried out in 32 countries between 2007 and 2015. Patients presenting within 5 days of symptom onset of a first stroke were enrolled as cases. Controls were age and sex matched to cases and had no history of stroke. Cases and controls underwent similar evaluations. Odds ratios (ORs) and population attributable risks (PARs) were calculated to determine the association of various risk factors with all stroke, ischemic stroke, and intracranial hemorrhage, for patients 45 years of age or younger. FINDINGS: 1,582 case-control pairs were included in this analysis. The mean age of this cohort was 38.5 years (SD 6.32). Overall, 71% strokes were ischemic. Cardiac causes {OR: 8.42 (95% confidence interval [CI]: 3.01-23.5)}; binge drinking of alcohol (OR: 5.44 [95% CI: 1.81-16.4]); hypertension (OR: 5.41 [95% CI: 3.40-8.58]); ApoB/ApoA1 ratio (OR: 2.74 [95% CI: 1.69-4.46]); psychosocial stress (OR: 2.33 [95% CI: 1.01-5.41]); smoking (OR: 1.85 [95% CI: 1.17-2.94]); and increased waist-to-hip ratio (OR: 1.69 [95% CI: 1.04-2.75]) were the most important risk factors for ischemic stroke in these young cases. For intracerebral hemorrhage, only hypertension (OR: 9.08 [95% CI: 5.46-15.1]) and binge drinking (OR: 4.06 [95% CI: 1.27-13.0]) were significant risk factors. The strength of association and population attributable risk (PAR) for hypertension increased with age (PAR 23.3% in those <35 years of age, 50.7% in 35-45 years of age). INTERPRETATION: Conventional risk factors such as hypertension, smoking, binge drinking of alcohol, central obesity, cardiac causes, dyslipidemia, and psychosocial stress are important risk factors for stroke in those younger than 45 years of age. Hypertension is the most significant risk factor in all age groups and across all regions and both stroke subtypes. These risk factors should be identified and modified in early adulthood to prevent strokes in young individuals.

Differential Regulation of Tachykinin and Opioid System Gene Expression in Brain and Immune Cells of Chronic Binge Alcohol-Treated Simian Immunodeficiency Virus-Infected Macaques.

People living with HIV have a high likelihood of at-risk alcohol use and are at increased risk for neurocognitive decline. The underlying mechanisms involved in HIV-associated neurocognitive disorder (HAND) are not completely understood. Previously, we showed that chronic binge alcohol (CBA) administration produced behavioral deficits in non antiretroviral therapy (ART)-treated simian immunodeficiency virus (SIV)-infected macaques. Moreover, we observed that CBA/SIV enhanced neuroinflammatory gene expression and attenuated growth factor signaling in the frontal cortex (FC) and basal ganglia, effects that were partially ameliorated by ART. We hypothesized that the neuroinflammatory and growth factor changes observed could be associated with alterations in opioid, tachykinin, and endocannabinoid gene expression. Furthermore, we proposed that gene expression patterns in peripheral blood mononuclear cells (PBMCs) could serve as an indicator of expression changes in the brain (FC). We examined gene expression patterns of opioid, tachykinin, and endocannabinoid systems in FC and PBMCs isolated from CBA/SIV macaques. Expression of targeted genes as determined by reverse transcription-quantitative polymerase chain reaction was analyzed in relation to CBA, ART, plasma, and brain viral loads (PVL and BVL, respectively) and compared with baseline (PBMC) or FC from SIV- controls. FC expression of ORM1, POMC, and TACR1 was negatively associated with PVL (p = .03, .002, .05 respectively). FC expression of TAC1 was positively associated with CBA exposure (p = .05). PBMC expression of DAGLA was positively associated with CBA exposure; but negatively associated with combined CBA/ART exposure (p = .03). Our findings reflect the complex interactions of SIV, CBA, and ART in modulating opioid and tachykinin system gene expression. Contrary to our prediction, results did not reveal parallel changes (in magnitude or direction) in PBMC and FC gene expression. Further studies are warranted to determine the relevance of these transcriptional changes in modulating HAND-related behaviors resulting from at-risk alcohol use and HIV/SIV exposure.

Adolescent intermittent ethanol exposure enhances adult stress effects in male rats.

Binge patterns of alcohol use, prevalent among adolescents, are associated with a higher probability of developing alcohol use disorders (AUD) and other psychiatric disorders, like anxiety and depression. Additionally, adverse life events strongly predict AUD and other psychiatric disorders. As such, the combined fields of stress and AUD have been well established, and animal models indicate that both binge-like alcohol exposure and stress exposure elevate anxiety-like behaviors. However, few have investigated the interaction of adolescent intermittent ethanol (AIE) and adult stressors. We hypothesized that AIE would increase vulnerability to restraint-induced stress (RS), manifested as increased anxiety-like behavior. After AIE exposure, in adulthood, animals were tested on forced swim (FST) and saccharin preference (SP) and then exposed to either RS (90 min/5 days) or home-cage control. Twenty-four hours after the last RS session, animals began testing on the elevated plus maze (EPM), and were re-tested on FST and SP. A separate group of animals were sacrificed in adulthood after AIE and RS, and brains were harvested for immunoblot analysis of dorsal and ventral hippocampus. Consistent with previous reports, AIE had no significant effect on closed arm time in the EPM (anxiety-like behavior). However, in male rats the interaction of AIE and adult RS increased time spent in the closed arms. No effect was observed among female animals. AIE and RS-specific alterations were found in glial and synaptic markers (GLT-1, FMRP and PSD-95) in male animals. These findings indicate AIE has sex-specific effects on both SP and the interaction of AIE and adult RS, which induces a propensity toward anxiety-like behavior in males. Also, AIE produces persistent hippocampal deficits that may interact with adult RS to cause increased anxiety-like behaviors. Understanding the mechanisms behind this AIE-induced increase in stress vulnerability may provide insight into treatment and prevention strategies for alcohol use disorders.

Binge drinking alongside alcoholic chronic abuse.

Here is reported the case of an adult patient with ethylic cirrhosis associated with spur cell anemia. Moreover, acute vacuolation of leukocytes was observed in relationship with recent binge drinking.

Alcohol Binge Drinking-Induced ST-Segment-Elevation Acute Coronary Syndrome.

We present the case of a 26-year-old man, without any apparent cardiovascular risk factors, who experienced an ST-segment-elevation acute coronary syndrome after binge drinking high-proof alcohol, which was successfully managed with primary percutaneous coronary intervention and comprehensive, guideline-directed medical therapy.

Stabilizing Cardiac Ryanodine Receptor With Dantrolene Treatment Prevents Binge Alcohol-Enhanced Atrial Fibrillation in Rats.

ABSTRACT: Binge drinking is a risk factor for cardiac arrhythmias, known as the holiday heart syndrome. Atrial fibrillation (AF) is the most frequently diagnosed arrhythmia in this condition. Recent reports indicated that cardiac ryanodine receptor (RyR2) dysfunction and Ca 2+ leak contribute to alcohol-enhanced AF. In this study, we investigated whether stabilizing RyR2 with dantrolene treatment can prevent alcohol-enhanced AF in rats. A binge drinking rat model was established with alcohol (2 g /kg, IP) delivered once every other day for 4 times. The study consisted of following 3 groups: control group (n = 9), binge alcohol group (n = 10), and binge alcohol + dantrolene (A+D) group (dantrolene, 10 mg/kg, IP before each alcohol injection, n = 9). Echocardiography, left ventricular hemodynamics, in vivo atrial electrophysiology and AF inducibility test, RyR2 phosphorylation level, and blood norepinephrine level were studied 24 hours after the last injection. Ca 2+ leak in isolated atrial myocytes from control and binge alcohol rats was examined. Binge alcohol significantly increased AF inducibility (1/9 in control vs. 8/9 in binge alcohol group, P < 0.05) and AF duration. Dantrolene treatment significantly reduced both AF inducibility (2/9 in dantrolene group, P < 0.05) and AF duration. Binge alcohol significantly increased Ca 2+ leak in isolated atrial myocytes, which was reduced by dantrolene treatment. Blood norepinephrine,7 RyR2 phosphorylation level, cardiac echocardiography, and left ventricular hemodynamics were not significantly affected 24 hours after binge drinking. In conclusion, stabilizing RyR2 with dantrolene treatment significantly attenuated binge drinking-enhanced AF, suggesting that therapeutic strategies stabilizing RyR2 could be a preventive measure to blunt binge drinking-enhanced AF arrhythmogenesis.

Acute binge alcohol alters whole body metabolism and the time-dependent expression of skeletal muscle-specific metabolic markers for multiple days in mice.

Alcohol is a myotoxin that disrupts skeletal muscle function and metabolism, but specific metabolic alternations following a binge and the time course of recovery remain undefined. The purpose of this work was to determine the metabolic response to binge alcohol, the role of corticosterone in this response, and whether nutrient availability mediates the response. Female mice received saline (control) or alcohol (EtOH) (5 g/kg) via intraperitoneal injection at the start of the dark cycle. Whole body metabolism was assessed for 5 days. In a separate cohort, gastrocnemius muscles and liver were collected every 4 h for 48 h following intoxication. Metyrapone was administered before alcohol and gastrocnemius was collected 4 h later. Lastly, alcohol-treated mice were compared with fed or fasted controls. Alcohol disrupted whole body metabolism for multiple days. Alcohol altered the expression of genes and proteins in the gastrocnemius related to the promotion of fat oxidation (Pparα, Pparδ/ß, AMPK, and Cd36) and protein breakdown (Murf1, Klf15, Bcat2). Changes to select metabolic genes in the liver did not parallel those in skeletal muscle. An alcohol-induced increase in circulating corticosterone was responsible for the initial change in protein breakdown factors but not the induction of FoxO1, Cebpß, Pparα, and FoxO3. Alcohol led to a similar, but distinct metabolic response when compared with fasting animals. Overall, these data show that an acute alcohol binge rapidly disrupts macronutrient metabolism including sustained disruption to the metabolic gene signature of skeletal muscle in a manner similar to fasting at some time points.NEW & NOTEWORTHY Herein, we demonstrate that acute alcohol intoxication immediately alters whole body metabolism coinciding with rapid changes in the skeletal muscle macronutrient gene signature for at least 48 h postbinge and that this response diverges from hepatic effects and those of a fasted animal.

Binge alcohol consumption exacerbates high-fat diet-induced neurobehavioral anomalies: Possible underlying mechanisms.

The current study aimed to validate the mice model of alcohol (ALC), high-fat diet (HFD), and HFD + ALC combination affecting neurobehavioral and neurochemical anomalies via inflammatory cascade, lowered neurogenesis, enhanced microgliosis, reactive astrogliosis, activated IDO-1 (indoleamine 2,3-dioxygenase), and reduce CHAT (choline acetyltransferase) signaling in the hippocampus (HIP). The adult male Swiss albino mice were provided with ALC (3-15%) and in-house prepared HFD for continuous 12 weeks. The HFD and HFD + ALC consumption impacted the liver and mediated HIP damage. The liver biomarkers (AST, ALT, γ-GT, TG, HDL-C, and LDL-C), oxidative stress, and proinflammatory cytokines (IL-1ß and TNF-α) level were found significantly higher in the liver and HIP tissue of HFD + ALC. Furthermore, the neurobehavioral deficits that include cognitive dysfunction, depressive, and, anxiety-like behavior were found severely affected in HFD + ALC consumed mice. The overactivated HPA axis, intense oxidative insults, and increased AChE activity were seen in the HIP of HFD + ALC grouped mice. The gene and protein expression also confirmed disrupted NF-κB-mediated inflammatory and Nrf2-regulated antioxidant balance and dysregulated TrκB/BDNF signaling. Hence, our new findings explain the insight mechanism of chronic alcoholism in exacerbating the deleterious effect of chronic high-fat diet consumption on the HIP.

Periconceptual and prenatal alcohol consumption and neurodevelopment at age two and five years.

OBJECTIVE: Examine the association between alcohol consumption before and during pregnancy and neurodevelopmental outcomes in the offspring at two and five years. STUDY DESIGN: Retrospective analysis of a prospective longitudinal cohort; SCOPE-BASELINE. Data on pre-conception and prenatal alcohol consumption were obtained at 15 weeks' gestation and categorised as abstinent, occasional-low (1-7units/week) and moderate-heavy (≥8units/week). Binge drinking was defined as ≥6 units/session. Outcome measures (Child Behaviour Checklist and Kaufman Brief Intelligence Test) were obtained at two and five years. Linear regression examined an alcohol consumption and Child Behaviour Checklist and Kaufman Brief Intelligence Test relationship, adjusting for several potential confounders. RESULTS: Data on alcohol consumption was available for 1,507 women. Adjusted linear regression suggested few associations: pre-pregnancy occasional-low alcohol consumption was associated with lower log externalizing Child Behaviour Checklist scores (-0.264, 95% CI: -0.009, -0.520), while pre-pregnancy moderate-high levels of alcohol consumption was associated with lower Kaufman Brief Intelligence Test verbal standard scores (-0.034, 95% CI: -0.001, -0.068) and composite IQ scores (-0.028, 95% CI: -0.056, -0.0004) at five-years. In the first trimester, moderate-high levels of alcohol consumption was associated with lower internalizing Child Behaviour Checklist scores at two-years (-0.252, 95% CI: -0.074, -0.430). No significant associations were observed between number of binge episodes pre-pregnancy or binge drinking in the first trimester and Child Behaviour Checklist or Kaufman Brief Intelligence Test. CONCLUSIONS: We did not find strong evidence of associations between pre-pregnancy and early pregnancy maternal alcohol consumption and adverse neurodevelopmental outcomes at age two and five years overall. Further research examining alcohol consumption (including binge drinking) beyond 15 weeks' gestation and subsequent neurodevelopmental outcomes is needed to examine the potential effect of alcohol consumption in later pregnancy.