According to current knowledge, hypoxia is a key mechanism mediating the detrimental effects of prenatal alcohol exposure on the nervous tissue. However, comparative analysis of these interrelated conditions has only been partially addressed. We conducted a morphometric analysis of fetal brain tissue affected by chronic alcohol exposure and hypoxia. A decrease in the specific area of neuroblasts, glioblasts, and microvascular elements was found. Hypoxia promoted enlargement of neuroblasts and their differentiation into immature neurons, whereas alcohol exposure led only to a decrease in their number. In the brain subjected to hypoxia, glioblasts were characterized by size variability with a general trend toward reduction, while alcohol had no significant effect on their size. Both experimental groups showed a decline in vascular density.

Steatotic liver disease (SLD) has emerged as a heterogeneous condition with distinct subtypes defined by metabolic dysfunction and alcohol exposure. We aimed to investigate the associations of SLD subtypes-metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with elevated alcohol intake (MetALD), and alcohol-related liver disease (ALD)-with the risk of gastric cancer (GC) and esophageal cancer (EC) in a nationwide cohort. We analyzed a cohort of 362,285 individuals aged ≥ 40 years using the Korean National Health Insurance Service claims data. Participants underwent screening in 2009-2010 with follow-up through 2019. They were categorized into no SLD, MASLD, MetALD, or ALD. Cox proportional hazards models adjusted for demographic, clinical, and lifestyle factors estimated hazard ratios (HRs) for GC and EC. Subgroup analyses were conducted by alcohol intake levels and cardiometabolic burden. Over 10 years, 4,842 participants (1.98%) developed GC or EC. The risk of GC increased progressively across SLD subtypes, with HRs of 1.09 (95% CI: 1.02-1.16) for MASLD, 1.31 (1.16-1.48) for MetALD, and 1.40 (1.16-1.68) for ALD. For EC, MASLD was not significant associated (HR 0.81, 95% CI: 0.63-1.05), whereas risks were significantly elevated in MetALD (1.68, 1.17-2.42) and ALD (2.18, 1.36-3.49). GC risk is modestly increased in MASLD and more pronounced in alcohol-related SLD subtypes, whereas EC risk is primarily driven by alcohol exposure. These findings indicate that GC is influenced by both metabolic dysfunction and alcohol, while alcohol plays the predominant role in EC.

Alcohol-induced neuropathy associated downregulation of Kv7 channels in primary nociceptors.

Prenatal alcohol exposure (PAE) increases the risk for serious adverse birth outcomes and long-term neurodevelopmental, physical, and mental health outcomes, known under the umbrella term of fetal alcohol spectrum disorders (FASD). Despite its well-documented adverse effects, PAE continues to be prevalent in the United States (U.S.), where an estimated 13.5% of women report alcohol consumption during pregnancy. Brief interventions to reduce PAE delivered during prenatal care have obtained mixed results, in part due to obstetricians' high workload and short prenatal care visits. To overcome this challenge and address the need, Safe Start is a clinical trial to evaluate the efficacy of a hybrid intervention to reduce alcohol-exposed pregnancies delivered on a digital platform and by prenatal care nurses. Women attending obstetrics clinics for pregnancy confirmation or an initial prenatal care visit are screened for eligibility. To qualify, participants must be at least 18years old; have a gestational age of less than 28weeks; report any alcohol use in the past 30days; and provide consent to participate. Recruited participants are randomized in 1:1 proportion to the Safe Start intervention plus usual prenatal care or usual prenatal care alone. Over three visits, participants receive two digitally- and three nurse-delivered sessions based on motivational enhancement principles. Sessions are scheduled during prenatal care appointments to minimize participant burden and increase retention. Using an intent-to-treat analysis, weighted generalized estimating equations will be used to evaluate the intervention's efficacy, relative to usual care, in enhancing the proportion of women with a laboratory-confirmed negative phosphatidylethanol, a biomarker for alcohol use, at each visit. Additional analyses will evaluate intervention effects on the prevalence of adverse birth outcomes (preterm birth and low birth weight). This intervention is embedded within a prenatal care clinic in a large urban setting serving primarily low-income racially minoritized women. If efficacious, this theory-driven, rigorously tested intervention may represent a scalable strategy suitable for adoption in maternity care across the U.S. to reduce PAE and alcohol-related adverse birth outcomes, including FASD. The study is registered on clinicaltrials.org; Clinical Trials Registration Number: NCT05766761; Registration Date: 2023-02-27.

General Background: Pediatric Non-Alcoholic Fatty Liver Disease (NAFLD) represents a critical chronic liver condition in children globally, characterized by hepatic fat accumulation without alcohol exposure, potentially progressing to steatohepatitis, fibrosis, and cirrhosis. Specific Background: Rapid socioeconomic transitions in Asia have escalated childhood obesity rates, with India reporting prevalence estimates of 12–63% among overweight children, while Uzbekistan demonstrates 50–66% prevalence in similar cohorts, though comprehensive epidemiological data remain limited. Knowledge Gap: No comparative analysis exists examining pediatric NAFLD patterns between Uzbekistan and India, particularly regarding temporal trends and population-based prevalence. Aims: This study compares burden, risk factors, and clinical characteristics of pediatric NAFLD across both nations through systematic literature review. Results: Both countries exhibit increasing prevalence driven by obesity and insulin resistance, with male preponderance and age-dependent patterns; however, Uzbekistan lacks population-based studies unlike India's more established epidemiological framework. Novelty: This represents the first cross-country comparison of pediatric NAFLD between Central and South Asian contexts. Implications: Findings underscore urgent need for standardized screening protocols, culturally adapted lifestyle interventions, and population-based research in Uzbekistan to inform national health policies.Keywords : Pediatric NAFLD, Childhood Obesity, Non-Alcoholic Fatty Liver Disease, Metabolic Syndrome, Insulin ResistanceHighlight : Prevalence reaches 42-47% among overweight Indian children, with boys consistently more affected. Uzbekistan shows 50-100% rates in obese cohorts but lacks comprehensive population-based studies. Both nations face growing burden from dietary transitions, urbanization, and sedentary lifestyles.

Prenatal alcohol exposure impacts fetal development, leading to Fetal Alcohol Spectrum Disorders (FASD) characterized by cognitive, behavioral, and physical impairments. This pre-post, open-label, non-randomized pilot study explores Epigallocatechin-3-Gallate (EGCG), a potent antioxidant and neuronal plasticity modulator, as a therapeutic intervention for FASD improvement. In a 12-month pilot study, patients with 40 FASD (mean age 10 ± 3 years) received 9mg/kg/day of EGCG, with outcomes assessed through RNA sequencing and neurocognitive evaluations (WISC-IV, CBCL 6-18, and NEPSY-II). Reduced levels of oxidative stress were observed after 6 and 12 months of treatment with EGCG. Significant neurocognitive improvements were shown after one year of treatment in Perceptual Reasoning Index (PRI) and Working Memory Index (WMI) using the WISC-IV test. CBCL test revealed an improvement in aggressive behavior scores after EGCG treatment. NEPSY-II assessment showed improvements in face memory and delayed face memory. Interestingly, no significant improvements were observed in intelligence quotient, attention, anxiety, or depression, which affect a proportion of individuals diagnosed with FASD. Additionally, EGCG modulates molecular pathways associated with neuroinflammation, immune response, and neurogenesis. This study highlights EGCG as a potential therapeutic candidate to ameliorate cognitive and behavioral deficits in children affected by FASD, revealing potential pathways and biomarkers that contribute to these improvements.ClinicalTrials.gov identifier:NCT02558933 (registered 22 September 2015).

Chronic adolescent alcohol exposure induces long-term neurofunctional and metabolic dysregulation in adult rats.

Astrocytes and Alcohol Throughout the Lifespan.

Understanding similarities and differences of FASD in three zebrafish populations.

An overview of family-focused interventions for supporting children with fetal alcohol spectrum disorder: A scoping review.

Leveraging court appointed special advocates to improve outcomes for children involved in the child welfare system with prenatal alcohol exposure

ABSTRACTBackgroundAlcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal‐related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may modulate alcohol‐related behaviors. We investigated the effects of pitolisant, an FDA‐approved H3R antagonist, on ethanol (EtOH)‐related behaviors in mice.MethodAdult male C57BL/6J mice underwent acute or chronic (2 or > 8 weeks) intermittent alcohol exposure. Pitolisant pretreatment was administered, and then pharmacological behavior, histologic, and molecular assays were conducted.ResultPitolisant administration reduced acute EtOH‐induced locomotor activation, conditioned place preference, and sedative effects, and also curtailed EtOH intake. It alleviated anxiety and depression‐like behavior during 24‐h withdrawal (Post‐EtOH). Mechanistically, the Post‐EtOH condition was featured by complicated brain cFos expression mapping, including elevated cFos, [HA] and [glutamine]/[glutamate] ratio in the lateral habenula (LHb). However, systemic pitolisant treatment significantly increased [norepinephrine]/[normetanephrine] ratio, and restored the diminished phosphorylated CREB and BDNF levels in the LHb. Intra‐LHb H2R antagonist cimetidine infusion partly blocked the pitolisant therapeutic effect on alcohol‐related behavior.ConclusionThese findings highlight the HAergic system as a critical regulator of alcohol‐related behaviors. The LHb HA signaling and norepinephrine neurotransmission might underlie pitolisant's potential novel therapeutic strategy for AUD.

The evaluation and care of children with suspected fetal alcohol spectrum disorders in the pediatric medical home: The importance of therapeutic alliance, longitudinal surveillance and trauma-informed care.

Gender-specific gut microbiota alterations in adolescent C57BL/6 mice following prenatal alcohol exposure.

Fetal alcohol spectrum disorder (FASD) encompasses a broad range of central nervous system (CNS)-related disabilities representing a mild-to-severe continuum of neurodevelopmental disorders that include mood and sensory function. The prevalence of FASD is estimated at ~5% in school-aged children who are prone to develop inappropriate responses to stressful stimuli leading to higher rates of anxiety and low touch tolerance. Low touch tolerance has been self-reported in 33.6% of FASD-affected individuals. The FASD manifestations of sensory abnormalities like pathological light-touch hypersensitivity, a hallmark of chronic pain may be a result of abnormal neurological relays the spinal cord, and from spinal cord to brain. Animal modeling of FASD that utilize prenatal alcohol exposure (PAE) demonstrate mood disorders such as anxiety-like behavior and low touch tolerance, which support these clinical observations of mood and tactile dysregulation.In an effort to contextualize central nervous system (CNS) processing of stress and resultant mood disorders that are exacerbated by PAE, this review outlines the fundamentals of the neurocircuitry of stress from the perspective of the central autonomic network (CAN), differentiating physiological vs. psychological stressors with a focus on elements of the limbic system, including the medial prefrontal cortex (mPFC), amygdala (AMG), hippocampus (HIPP), hypothalamus, cingulate cortex, and brainstem periaqueductal gray (PAG), locus coeruleus (LC), and the nucleus of the solitary tract (NTS) of the medulla. The review addresses stress-sensitized CNS circuits and the underlying immune signaling molecules that may be responsible for heightened stress responses. Adolescence will be discussed as a critical corticolimbic developmental period that is itself highly susceptible to stressors, which is further impacted by PAE leading to stress-related anxiety with lifelong consequences.Linking the heightened neuroimmune response of offspring with PAE, a discussion is included of rodent models demonstrating PAE as a risk factor for developing painful tactile neuropathies following sciatic nerve injury mediated by sensitized and over-active spinal glial cytokine actions. Included in this discussion is the role oflimbic forebrain, subcortical and even brainstem circuits that process and regulate mood and stress also engage the emotional and sensory-discriminative aspects of pain processing. Lastly, the impact of PAE on sensitized neuroimmune factors that link stress to touch allodynia in the absence of nerve injury is briefly discussed. These topics aim to help the reader gauge the profound impact of PAE on the CAN, and immune signaling molecules in limbic areas and spinal cord that drive sensitized stress sequelae, which should now include exaggerated pain states as well as anxiety disorders.

Background: In clinical research, multiple outcomes are often measured within the same cohort, leading to statistical dependencies that violate assumptions of traditional meta-analytic methods. While advanced models can accommodate such correlations, they typically require programming expertise, limiting accessibility for many physician-researchers. Objective: We present a user-friendly, interactive Shiny web application designed to perform meta-analyses of correlated outcomes, with particular relevance for cohort-based clinical datasets. Methods: The application implements a modified multivariate meta-analytic framework that accounts for the correlation structure of outcomes within cohorts. Users can upload their data, define correlation matrices, and filter observations by any variable (e.g., age, domain, exposure) without writing code. The application provides graphical output (forest plots) along with estimates of overall effect size, heterogeneity (τ²), and p-values. Results: A demonstration dataset on prenatal alcohol exposure and neurodevelopmental outcomes is simulated to illustrate the application’s functionality. The application automatically generates correlation matrices where needed, adjusts for intra-cohort dependencies, and produces interpretable results suitable for clinical research reports. Conclusion: This open-access application bridges the gap between complex statistical modeling and clinical usability. It enables physicians to conduct robust meta-analyses of correlated outcomes with ease, supporting evidence-based practice and local research initiatives. The tool is particularly valuable in multi-domain or multi-cohort studies where outcome correlation is non-negligible.

Alcohol relapse is associated with corticotropin-releasing factor (CRF) signaling and altered reward pathway function, though the precise mechanisms remain unclear. Here, we investigated how CRF modulates cholinergic interneurons (CINs) in the dorsal striatum, a region critical in mediating cognitive flexibility and action selection. Using monosynaptic and retrograde circuit tracing, we identified direct inputs from CRF-expressing (CRF⁺) neurons in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) to dorsal striatal CINs. We showed that CINs express CRF receptor 1 (CRFR1) and established their functional connectivity with CeA/BNST CRF⁺ projections. Functional recordings revealed that CRF enhanced CIN excitability and promoted acetylcholine release in the dorsal striatum. However, acute alcohol exposure and withdrawal attenuated the excitatory effect of CRF on CIN firing, suggesting a mechanism by which alcohol disrupts CRF-dependent neuromodulation. These findings reveal a previously unrecognized CRF-CIN pathway linking the extended amygdala to the dorsal striatum and provide new insight into how CRF and alcohol interact to impair striatal function. This work highlights CRF signaling as a potential target for understanding stress-induced changes to the reward pathway.HighlightsDorsal striatal CINs receive monosynaptic CRF+inputs from CeA and BNST neurons.CRFR1 is expressed in striatal CINs, and CRF+fibers are present in the dorsal striatum.CRF enhances dorsal striatal CIN activity via CRFR1 signaling.Acute alcohol exposure impairs CRF-induced cholinergic activity.Significance StatementThe dorsal striatum regulates goal-directed behavior and is implicated in alcohol use disorder (AUD). Within this region, cholinergic interneurons (CINs) support cognitive flexibility and receive input from limbic areas, including the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this study, we identified direct projections from CRF-producing neurons in the CeA and BNST to dorsal striatal CINs, a subset of which express CRF receptor 1 (CRFR1). Electrophysiological recordings confirmed these projections provide functional input that is disrupted by acute alcohol exposure. These findings lay the groundwork for future studies on how CRF and alcohol interact to impair striatal function.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Recent findings suggest that long-term and heavy alcohol consumption can aggravate several pathological processes associated with AD, whereas the impact of light or moderate consumption remains uncertain. Excessive alcohol exposure impairs the structure and function of key brain regions involved in cognition, particularly the hippocampus, prefrontal cortex, amygdala, cerebellum, Basolateral amygdala (BLA), and hypothalamus. Several studies indicate that chronic alcohol consumption affects the brain by multiple mechanisms like increased oxidative stress, microglial activation, neuroinflammation, microtubule instability, tau hyperphosphorylation, and modified amyloid-β turnover. Disruption of cholinergic transmission further contributes to memory deficits and neuronal susceptibility. These alcohol-related alterations closely resemble core features of AD pathology and may accelerate disease progression. Although some epidemiological studies report the potential benefits of low alcohol intake, their interpretation is limited by inconsistent definitions of drinking patterns and the influence of confounding variables. Overall, current evidence supports a dose-dependent relationship in which alcoholism increases vulnerability to AD-related neurodegeneration. Reducing harmful alcohol use may therefore represent a practical approach to lowering long-term dementia risk. This review summarizes the current mechanisms of alcohol induced neuronal damage across different brain regions. Prolonged alcohol consumption accelerates cerebral aging by enhancing oxidative stress, neuroinflammation, disrupting tau protein degradations, and other neuronal damages that intersect with the pathogenesis of AD.

Adolescence is a critical developmental window during which exposure to stress and alcohol can induce long-lasting neurobiological alterations. Binge-like alcohol consumption is particularly disruptive to corticostriatal circuits, but the extent to which prior stress history modulates these effects remains poorly understood. Here, we investigated how acute versus repeated restraint stress before intermittent alcohol exposure during adolescence shapes transcriptional changes in the dorsal striatum of male rats. Animals were exposed either to a single (acute) or five-day (repeated) restraint stress at postnatal day (PND) 32-36, followed by four weeks of intermittent intragastric ethanol (3 g/kg) or saline administration. At adult age, striatal mRNA expression of dopaminergic (Drd1, Drd2, Th), glutamatergic (Gls, Gls2, Gria2, Grin2a, Grin2b), endocannabinoid (Cnr1, Cnr2, Napepld, Faah, Dagla, Daglb, Mgll), neurotrophic (Bdnf, Ntrk2), and glial (Gfap, Aif1) genes was quantified. Alcohol exposure upregulated genes associated with glutamate synthesis and receptor signaling, endocannabinoid metabolism, and astrocytic activation. Acute stress amplified alcohol-induced expression of Gls, Gls2, Gria2, Napepld, Faah, Daglb, Ntrk2, and Gfap, while repeated stress blunted these effects and selectively enhanced Drd1, Drd2, Grin2a, and Bdnf expression. Microglial activation (Aif1) was increased by alcohol independently of stress. These results suggest that acute stress sensitizes glutamatergic and endocannabinoid pathways to alcohol, whereas repeated stress engages adaptive mechanisms consistent with the stress inoculation hypothesis. Overall, stress history critically determines the neurobiological outcomes of adolescent alcohol exposure, with implications for resilience and vulnerability to alcohol-induced psychopathology.

Adolescent binge drinking has detrimental effects on brain function, leading to long-lasting impairments in synaptic plasticity, cognition, and behavior. These effects are mediated, in part, by disruption of the endocannabinoid system (ECS) and its cannabinoid type-1 (CB1) receptor. Alcohol consumption also depletes omega-3 fatty acids, which are essential for maintaining cell membrane integrity and supporting brain function. This depletion impairs synaptic plasticity by disrupting endocannabinoid signaling and reducing CB1 receptor expression and function. Conversely, enhancement of the ECS can restore brain function and reverse the loss of endocannabinoid-dependent synaptic plasticity associated with omega-3 deficiency. Notably, omega-3 supplementation has been shown to restore CB1 receptor expression in specific brain regions in adult mice following adolescent alcohol exposure. However, despite the established interplay between alcohol, omega-3, and the ECS, the direct impact of omega-3 supplementation on the subcellular localization of CB1 receptors after alcohol exposure remains poorly understood. In this study, we used immunoelectron microscopy to investigate whether omega-3 supplementation influences CB1 receptor distribution in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice. Our results demonstrate that omega-3 partially restore the excitatory/inhibitory balance disrupted by alcohol, as evidenced by an increased number of excitatory terminals and a significant reduction in inhibitory terminals. However, the distribution and density of CB1 receptors within neuronal and glial compartments remain unchanged following alcohol exposure and omega-3 supplementation. These findings highlight novel structural effects of omega-3 in mitigating alcohol-induced brain damage.