Heavy Alcohol Intake Research Articles

Restoring CFTR function with Orkambi decreases the severity of alcohol-induced acute pancreatitis.

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100mm) for 12h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

To Drink or Not to Drink? Investigating Alcohol’s Impact on Prostate Cancer Risk

Background/Objectives: Prostate cancer (PCa) is a significant global health issue. The relationship between alcohol consumption and PCa risk has been the subject of extensive research, yet findings remain inconsistent. This review aims to clarify the association between alcohol intake and PCa risk, its aggressiveness, and the potential metabolic pathways involved in PCa onset. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed and MEDLINE, focusing on epidemiological studies, meta-analyses, cohort studies, and case–control studies. Studies evaluating alcohol consumption, prostate-specific antigen (PSA) levels, and PCa risk were included. The review also explored the roles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in alcohol metabolism. Results: The analysis reveals a complex relationship between alcohol consumption and PCa. Heavy alcohol intake is associated with an increased risk of PCa, particularly more aggressive forms, and higher mortality rates. However, studies also show weak or no association between moderate alcohol consumption and PCa. The variability in findings may be attributed to differences in alcohol types, regional factors, and study methodologies. Conclusions: The link between alcohol consumption and PCa risk is multifaceted. While heavy drinking appears to increase the risk of aggressive PCa, the overall relationship remains unclear. Further research is needed to better understand these associations and inform public health recommendations and cancer prevention strategies.

Extended Review and Updates of Nonalcoholic Fatty Pancreas Disease

Abstract Non-alcoholic fatty pancreatic disease (NAFPD), also known as pancreatic steatosis, is a benign condition characterized by deposition of lipids in the pancreas and is associated with insulin resistance, malnutrition, obesity, metabolic syndrome, aging, and absence of heavy alcohol intake or infection. Similar to nonalcoholic fatty liver disease, NAFPD is a phenotypic entity that includes fat buildup in the pancreas, pancreatic inflammation, and subsequent fibrosis. The extent to which pancreatic fat infiltration is clinically important remains unclear. Despite these clinical associations, most of the clinical effects of NAFPD are not known. NAFPD may be identified by transabdominal and elastography ultrasound, computed tomography scan, or magnetic resonance imaging modalities, but a confirmatory diagnosis can only be made through tissue histology. In addition to complications such as acute and chronic pancreatitis, NAFPD may progress to pancreatic ductal adenocarcinoma. However, further research is required to fully understand the associations, pathophysiology, and effects of NAFPD. This review provides a narrative synthesis of the current literature on the epidemiology, pathophysiology, complications, diagnostic and imaging tools, and management of NAFPD.

Cancer in people who identify as lesbian, gay, bisexual, transgender, queer, or gender-nonconforming.

Individuals who identify as lesbian, gay, bisexual, transgender, queer, intersex, or gender-nonconforming (LGBTQ+) experience discrimination and minority stress that may lead to elevated cancer risk. In the absence of population-based cancer occurrence information for this population, this article comprehensively examines contemporary, age-adjusted cancer risk factor and screening prevalence using data from the National Health Interview Survey, Behavioral Risk Factor Surveillance System, and National Youth Tobacco Survey, and provides a literature review of cancer incidence and barriers to care. Lesbian, gay, and bisexual adults are more likely to smoke cigarettes than heterosexual adults (16% compared to 12% in 2021-2022), with the largest disparity among bisexual women. For example, 34% of bisexual women aged 40-49 years and 24% of those 50 and older smoke compared to 12% and 11%, respectively, of heterosexual women. Smoking is also elevated among youth who identify as lesbian, gay, or bisexual (4%) or transgender (5%) compared to heterosexual or cisgender (1%). Excess body weight is elevated among lesbian and bisexual women (68% vs. 61% among heterosexual women), largely due to higher obesity prevalence among bisexual women (43% vs. 38% among lesbian women and 33% among heterosexual women). Bisexual women also have a higher prevalence of no leisure-time physical activity (35% vs. 28% among heterosexual women), as do transgender individuals (30%-31% vs. 21%-25% among cisgender individuals). Heavier alcohol intake among lesbian, gay, and bisexual individuals is confined to bisexual women, with 14% consuming more than 7 drinks/week versus 6% of heterosexual women. Incontrast, prevalence of cancer screening and risk reducing vaccinations in LGBTQ+ individuals is similar to or higher than their heterosexual/cisgender counterparts except for lower cervical and colorectal cancer screening among transgender men. People within the LGBTQ+ population have a higher prevalence of smoking, obesity, and alcohol consumption compared to heterosexual and cisgender people, suggesting a higher cancer burden. Health systems have an opportunity to help inform these disparities through the routine collection of information on sexual orientation and gender identity to facilitate cancer surveillance and to mitigate them through education to increase awareness of LGBTQ+ health needs.

A national cross-sectional study on breakfast skipping-related factors and comparison of nutritional status according to breakfast skipping in older adults based on the 8th Korea National Health and Nutrition Examination Survey (KNHANES, 2020)

ObjectivesThis study aimed to compare the distinct socio-ecological characteristics, nutritional status, and nutrient intake quality of the older adults based on breakfast skipping (EBF, eating breakfast vs. SBF, skipping breakfast). This study also investigated the association between breakfast skipping, socioecological features, and quality of nutrient consumption. MethodFrom the 8th Korea National Health and Nutrition Examination Survey (KNHANES, 2020), data of 92,093 subjects aged ≥ 65 years old (male: 43,910 and female: 48,183) having data with eating habits, such as nutrient intake and skipping breakfast were analyzed. ResultsThe average age of SBF was markedly lower than EBF. EBF had a lower employed status, education level, heavy alcohol intake frequency, smoking, and eating out regularly than SBF. Compared to EBF, SBF showed a significantly higher BMI and waist circumference. Moreover, EBF showed a markedly higher average intake in energy, protein, fiber, calcium, and iron compared with SBF, while SBF had a noticeably higher mean intake in fat, saturated fat, and sugar. In addition, SBF had a significantly reduced mean adequacy ratio (MAR, adjusted OR: 0.260 [95% CI: 0.245−0.276]) and the value of index nutritional quality (INQ, adjusted OR: 0.847 [95% CI: 0.799−0.898]) compared with EBF. DiscussionThere were distinct socioecological features and nutritional conditions of older adults relying on breakfast skipping; and a strong association between breakfast skipping, socioecological parameters, and nutrient intake quality. These observations provide the significance of breakfast skipping in the nutritional status of older adults and offer fundamental information for nutritional education and implications for older adults.

The use of surgical sealant to repair intubation-related tracheal injury.

This case study describes the management of a tracheal injury following emergency intubation in a 56-year-old man. After collapsing from heavy alcohol ingestion, intubation was performed using a bougie, leading to a punctate tracheal wound. Initial conservative treatment with antibiotics was followed by bronchoscopy, revealing a tracheal laceration. Rigid bronchoscopy was then performed, and the wound was closed using BioGlue® surgical sealant. The patient made a full recovery, with follow-up bronchoscopy confirming complete healing. This case highlights the effectiveness of BioGlue® as a minimally invasive alternative for tracheal wound closure, reducing the need for more complex interventions.

Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding

BackgroundHepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aβ) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing. MethodsEight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7–11/group). Brain and liver Aβ were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aβ regulator), blood-brain barrier (BBB) function (vascular Aβ regulator), and microglia (major brain Aβ regulator) using immunoassays. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aβ were measured. ResultsAlcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aβ (p < 0.05) by ELISA and 6E10-positive Aβ load by immunostaining (p < 0.05). Increased brain Aβ corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aβ and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. ConclusionChronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aβ. The hepato-specific LRP-1 silencing similarly increased brain Aβ which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Impact of targeted drug administration and intermittent preventive treatment for forest goers using artesunate–pyronaridine to control malaria outbreaks in Cambodia

IntroductionThe national malaria programme of Cambodia targets the rapid elimination of all human malaria by 2025. As clinical cases decline to near-elimination levels, a key strategy is the rapid identification of malaria outbreaks triggering effective action to interrupt local transmission. We report a comprehensive, multipronged management approach in response to a 2022 Plasmodium falciparum outbreak in Kravanh district, western Cambodia.MethodsThe provincial health department of Pursat in conjunction with the Center for Parasitology, Entomology and Malaria Control (CNM) identified villages where transmission was occurring using clinical records, and initiated various interventions, including the distribution of insecticide-treated bed nets, running awareness campaigns, and implementing fever screening with targeted drug administration. Health stations were set up at forest entry points, and later, targeted drug administrations with artesunate–pyronaridine (Pyramax) and intermittent preventive treatment for forest goers (IPTf) were implemented in specific village foci. Data related to adherence and adverse events from IPTf and TDA were collected. The coverage rates of interventions were calculated, and local malaria infections were monitored.ResultsA total of 942 individuals were screened through active fever surveillance in villages where IPTf and TDA were conducted. The study demonstrated high coverage and adherence rates in the targeted villages, with 92% (553/600) coverage in round one and 65% (387/600) in round two. Adherence rate was 99% (551/553) in round one and 98% (377/387) in round two. The study found that forest goers preferred taking Pyramax over repeated testing consistent with the coverage rates: 92% in round one compared to 65% in round two. All individuals reachable through health stations or mobile teams reported complete IPTf uptake. No severe adverse events were reported. Only six individuals reported mild adverse events, such as loss of energy, fever, abdominal pain, diarrhoea, and muscle aches. Two individuals attributed their symptoms to heavy alcohol intake following prophylaxis.ConclusionsThe targeted malaria outbreak response demonstrated high acceptability, safety, and feasibility of the selected interventions. Malaria transmission was rapidly controlled using the available community resources. This experience suggests the effectiveness of the programmatic response for future outbreaks.

Alcoholic cardiomyopathy: an update.

Alcohol-induced cardiomyopathy (AC) is an acquired form of dilated cardiomyopathy (DCM) caused by prolonged and heavy alcohol intake in the absence of other causes. The amount of alcohol required to produce AC is generally considered as >80 g/day over 5 years, but there is still some controversy regarding this definition. This review on AC focuses on pathogenesis, which involves different mechanisms. Firstly, the direct toxic effect of ethanol promotes oxidative stress in the myocardium and activation of the renin-angiotensin system. Moreover, acetaldehyde, the best-studied metabolite of alcohol, can contribute to myocardial damage impairing actin-myosin interaction and producing mitochondrial dysfunction. Genetic factors are also involved in the pathogenesis of AC, with DCM-causing genetic variants in patients with AC, especially titin-truncating variants. These findings support a double-hit hypothesis in AC, combining genetics and environmental factors. The synergistic effect of alcohol with concomitant conditions such as hypertension or liver cirrhosis can be another contributing factor leading to AC. There are no specific cardiac signs and symptoms in AC as compared with other forms of DCM. However, natural history of AC differs from DCM and relies directly on alcohol withdrawal, as left ventricular ejection fraction recovery in abstainers is associated with an excellent prognosis. Thus, abstinence from alcohol is the most crucial step in treating AC, and specific therapies are available for this purpose. Otherwise, AC should be treated according to current guidelines of heart failure with reduced ejection fraction. Targeted therapies based on AC pathogenesis are currently being developed and could potentially improve AC treatment in the future.

Porphyria cutanea tarda in Scotland: underlying associations and treatment approaches.

Despite its rarity, porphyria cutanea tarda (PCT) is globally recognized as the most common form of cutaneous porphyria. This study aims to review the underlying associations and treatment of PCT in Scotland. We retrospectively reviewed data on 27 patients diagnosed with PCT between 1987 and 2022 at the Scottish Cutaneous Porphyria Service. Males slightly predominated (66.7%). The mean ± standard deviation (SD) age at diagnosis was 55.6 ± 12.5 years. Common associated factors were heavy alcohol intake (88.5%), genetic hemochromatosis (72%), smoking (45.5%), and hepatitis C virus infection (16%). Most had multiple associated factors (70.4%). Patients with genetic hemochromatosis with the C282Y genotype exhibited higher median transferrin saturation (69.5 vs. 35, P = 0.004) and ferritin levels (observed in males only) (1175 vs. 339; P = 0.014) than those with the H636D genotype. Most (52%) received combination therapy of venesection and antimalarials, followed by venesection monotherapy (32%) and antimalarial monotherapy (16%). Overall, 95.2% achieved biochemical improvement. Median time to improvement was 7, 5, and 9 months with venesection, antimalarial, and combined treatments, respectively (P = 0.173). Biochemical remission was achieved in 50% of patients. Remission occurred in 2/4 of patients with antimalarial monotherapy (median time 19 months) and 9/13 patients with combined treatment (median time 26 months). Biochemical relapse was found in three patients, all of whom received combination therapy. Excess alcohol intake and genetic hemochromatosis were the most common underlying associations with PCT in our Scottish cohort. Treatment for PCT should be individualized, and long-term follow-up is needed to monitor for disease relapse.

Alcohol-associated liver cancer.

Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated HCC (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop post alcohol-associated cirrhosis, but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of pre-clinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis are also discussed.

A review on comparative study of effectiveness of pregabalin and carbamazepine in painful diabetic peripheral neuropathy using mc gill's pain questionnaire

Diabetic neuropathy is a unique degenerative disorder of the peripheral nervous system that preferentially targets sensory axons and autonomic axons. The loss of sensory function that begins distally in the lower extremities is known as Diabetic neuropathy. It is characterized by burning pain, paresthesias and numbness in stocking glove pattern that progress proximally from the feet and hands. Diabetic neuropathy is a highly prevalent condition that substantially affects patients by increasing falls causing pain and reducing quality of life. The major risk factors for diabetic neuropathy is hyperglycemia. In addition to poor glycemic control, more-severe symptoms of diabetic neuropathy are associated with advanced age, hypertension, the duration of diabetes, dyslipidemia, smoking and heavy alcohol intake. Diabetic neuropathy is a major cause for disability of feet and hands globally. Anti-convulsants like pregabalin and carbamazepine are the medications used in the treatment of painful diabetic neuropathy.

Abstract P397: Choline Metabolites Are Associated With Non-Alcoholic Fatty Liver Disease: A Coronary Artery Risk Development in Young Adults (CARDIA) Study

Background: Non-alcoholic fatty liver disease (NAFLD), a common cause of chronic liver disease, has become increasingly prevalent. Choline deficiency has long been a model for the study of accelerated NAFLD, in preclinical and small-scale human studies. More recently, NAFLD has been associated with choline metabolites betaine (inversely) and trimethylamine N-oxide (TMAO) (positively). There has been a paucity of research on circulating choline metabolites and NAFLD in diverse and population-based cohort studies. Methods: We used data from 2,413 CARDIA participants who did not self-report liver disease or heavy alcohol intake at Y15, had stored plasma available from Y15, and chest computed tomography (CT) measures from Y25. NAFLD was defined as a mean CT-derived liver attenuation score &lt;51 Hounsfield units; severe NAFLD was &lt;40 Hounsfield units. Liquid chromatography mass spectrometry was used to quantify choline, betaine, and TMAO concentrations from stored plasma samples. Plasma metabolite concentrations were standardized for analysis. Plasma TMAO was natural log transformed for normality. Multivariable-adjusted logistic regression models quantified associations between plasma choline metabolites and NAFLD. Results (Table): In fully adjusted models, plasma betaine was inversely associated with NAFLD, and plasma TMAO was positively associated with NAFLD. Plasma choline was not associated with NAFLD in fully adjusted models. Conclusions: Our findings support an inverse association between plasma betaine and NAFLD in a diverse, population-based US cohort, and a positive association between plasma TMAO and NAFLD. Circulating betaine reflects dietary intake of betaine, as well as conversion from choline. TMAO reflects an alternative fate of choline, through metabolism by the gut microbiota. These results contribute to a growing literature on choline metabolism and cardiometabolic risk.

Risk of Hepatocellular Carcinoma by Steatotic Liver Disease and Its Newly Proposed Subclassification

Introduction: Steatotic liver disease (SLD) is a new overarching term proposed to replace nonalcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease. Subclassification includes metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and cryptogenic SLD. This study aimed to investigate whether SLD and its subclassification could stratify hepatocellular carcinoma (HCC) risk. Methods: A cohort of 85,119 adults without viral hepatitis or heavy alcohol intake was analyzed for the risk of HCC according to SLD and its subclassification. The fibrosis-4 (FIB-4) index was used to estimate the degree of liver fibrosis. Results: During a median follow-up of 11.9 years, HCC was diagnosed in 123 individuals. The incidence rate of HCC per 1,000 person-years was higher in individuals with SLD than in those without SLD (0.197 vs. 0.071, p Conclusions: HCC risk was different by SLD and its subclassification. The utilization of SLD and its subclassification can aid in stratifying HCC risk and facilitate the identification of individuals requiring interventions to mitigate the risk of HCC.

Prevalence and prediction of hepatocellular carcinoma in alcohol-associated liver disease: a retrospective study of 136 571 patients with chronic liver diseases

Background and aimsTo explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated...

Non-Adherence to Antihypertensive Medications Among the US Population: A Pooled Analysis of 22 Million Patients

BackgroundNon-adherence is a barrier to the control of hypertension. This study aimed to analyze the factors and interventions affecting adherence rates in the US. MethodsPubMed, Scopus, Web of Science, and Embase were searched on January 21 st, 2022 for studies on the adherence to anti-hypertensives in the US. R software (4.2.1) and RevMan (5.4) were used for the analysis. ResultsOur analysis showed that non-adherence to antihypertensives was higher in Hispanics compared with Blacks (OR= 1.25, p-value= 0.0335) with further analysis showing lower non-adherence rates among Whites compared with Blacks (OR= 0.63, p-value= 0.0049). Younger individuals had higher non-adherence rates (53%) compared with individuals older than 60 (46%), however, no statistically significant difference was detected between both groups. Unemployment was associated with decreased adherence (OR= 0.40, p-value< 0.00001), while gender and marital status yielded insignificant associations. Patients who suffered from multiple comorbidities (OR= 0.43, p-value= 0.004), depression (OR= 0.65, p-value <0.00001), and poor mental health (OR= 0.38, p-value< 0.00001) had lower adherence rates. Heavy alcohol consumption was associated with a decline in adherence, conversely, obesity didn't significantly affect the adherence rates. Regarding interventions, Fixed-dose combination had lower non-adherence rates compared with the control group (OR= 0.83, p-value= 0.0029), while telepharmacy didn't prove to be as effective. Lastly, exercise was associated with higher adherence (OR= 3.08, p-value< 0.00001). ConclusionRace and unemployment play a role in adherence to anti-hypertensives. Patients who suffer from depression, multiple comorbidities, and heavy alcohol intake had lower adherence rates. Accordingly, interventions such as fixed-dose combinations and exercise should be targeted at susceptible groups.

Effects of binge alcohol administration on tauopathy and neuroinflammation in PS19 mice

AbstractBackgroundIt is estimated that 50 million people worldwide are suffering from dementia, the most common being Alzheimer’s disease (AD). Even as the population ages and the incidence of AD increases, there are limited disease‐modifying treatments to date. Alcohol use disorders (AUD) have been identified as a modifiable risk factors for developing AD. Heavy alcohol intake in elderly individuals is associated with more rapid progression of AD pathology and an elevated neuroinflammatory state. The objective of this study was to investigate the interaction of high ethanol ‘binge’ treatments in a mouse model of tauopathy.MethodPS19 mice, a widely used tauopathy model, were subjected to a 5‐week binge paradigm of IP ethanol administration, 3.0g/kg, three times per week, beginning at 6 months of age. Prior to initiation of the binge ethanol regimen, mice received subcutaneous biotransponder implantations to record body temperature changes in response to ethanol. Blood ethanol concentrations were determined in a subset of mice at 30 minutes following the last ethanol administration. Frailty measures were completed one week after ethanol administration. NanoString unbiased gene expression, MesoScale Discovery ELISA, Western blotting, and Immunohistochemistry were performed to examine neuroimmune changes and markers of tau pathology.ResultOverall, ethanol treatment resulted in reduced body weight, which was further exacerbated in female PS19 mice.. Measures of frailty (i.e. cerebellar ataxia and grip strength) were impaired in PS19 mice, however, female PS19 mice receiving ethanol treatment had the greatest impairments compared to WT controls. Alterations in inflammatory signaling pathways were observed in the PS19 animals receiving alcohol treatment compared to PS19 or WT mice.ConclusionWe have examined the result of intermittent alcohol exposure on tau pathogenesis. In the present study we found that alcohol can induce biometric and behavioral changes in mice, which are further exacerbated by alcohol. Transcriptomic analysis indicated changes in both innate and inflammatory signaling, suggesting a increased inflammatory response in the ethanol treated animals. Taken together, these results suggest that intermittent environmental influences, such as ethanol, can result in more rapid progression of AD pathogenesis.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice.

Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking. The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a key mediator of the stress response. Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or nonlocal origin is currently unknown. Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57BL/6J mice exposed to a chronic, intermittent access to ethanol. While pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor-expressing cells were unchanged by chronic alcohol, the levels of a peptide closely related to PACAP, the calcitonin gene-related neuropeptide, were found to also be increased in the BNST. Finally, using a retrograde chemogenetic approach in PACAP-ires-Cre mice, we found that the inhibition of PACAP neuronal afferents to the BNST reduced heavy ethanol drinking. Our data suggest that the PACAP system of the BNST is recruited by chronic, voluntary alcohol drinking in mice and that nonlocally originating PACAP projections to the BNST regulate heavy alcohol intake, indicating that this system may represent a promising target for novel AUD therapies.

Spur Cell Anemia: A Rare and Under-Diagnosed Cause of Anemia in Alcoholic Patients with Advanced Liver Disease

Anemia in patients with alcohol use disorder (AUD) has a wide range of differential diagnoses, which can be challenging to interpret. It is often multifactorial, such as due to blood loss with or without coagulopathy, direct toxic effect of alcohol on hematopoietic cells, chronic inflammation, abnormalities in red blood cells (RBC) membranes, and nutritional deficiencies. Alcohol-induced liver disease may contribute to anemia through coagulopathy, splenomegaly, and hypersplenism. Macrocytosis is a common finding in patients with AUD due to B12 or folate deficiency or RBC membrane abnormality due to changes in lipid composition of RBC membranes. Patients with cirrhosis may have low haptoglobin due to impaired synthetic liver function. However, non-autoimmune hemolytic anemia and concomitant alcohol-induced liver damage should raise suspicion for spur cell anemia (SCA) and Zieve's syndrome. These medical conditions tend to be underreported or misdiagnosed. We describe a 44 year old male patient with a past medical history of AUD who presented with alcohol intoxication and was found to have newly diagnosed decompensated cirrhosis with severe macrocytic anemia with Hgb of 5.9 g/dl. Patient denied overt bleeding. Initial workup revealed high absolute reticulocyte count of 10.8% with retic index of 3, low haptoglobin of &amp;lt;15 mg/dl, elevated LDH of 275 u/l, negative Coombs test consistent with non-autoimmune hemolytic anemia, normal folate and B12 levels, and mixed direct and indirect hyperbilirubinemia. Peripheral blood smear showed anisopoikilocytosis, macrocytes, many spur cells, increased reticulocytes, but no schistocytes. Endo-colonoscopy showed grade 1 esophageal varices without evidence of recent bleeding. Given the history of heavy alcohol intake and cirrhosis, combined with Coombs-negative hemolytic anemia and peripheral blood smear findings of numerous spiculated red cells, our patient was diagnosed with SCA. At the time, due to active alcohol use, the patient was deemed not to be a candidate for liver transplant. This case report aims to aid physicians with the recognition of acute hemolytic anemia in patients with alcoholic liver injury and consideration of SCA and Zieve's syndrome as potential underlying causes. Prompt recognition and differentiation between these medical conditions are crucial as prognosis and treatment are different. Early recognition of SCA and timely consideration of liver transplantation can significantly improve patient outcomes.

Investigating Diabetic Foot Pathophysiology and Amputation Prevention Strategies through Behavioral Modification

Diabetic foot complications stem from intricate interactions between macrovascular and microvascular changes, neuropathy, inflammation, immune responses, hyperglycemia, oxidative stress, and infection susceptibility. Macrovascular factors like atherosclerosis lead to tissue ischemia, while microvascular dysfunction worsens perfusion deficits. Neuropathy contributes significantly to such complications, causing sensory loss, motor problems, and autonomic dysfunction. This results in unnoticed injuries, muscle atrophy, deformities, and dry skin, elevating the risk of non-healing wounds and infections. Inflammation and immune responses amplify tissue damage and hinder healing. Chronic hyperglycemia generates advanced glycation end products, stiffening tissues, while oxidative stress exacerbates damage. Mitochondrial dysfunction further compromises cellular energy production, worsening tissue repair challenges. These multifaceted factors collectively contribute to diabetic foot complications. The impact of modifiable behavior factors such as smoking, heavy alcohol consumption, and exercise on the risk of lower extremity amputation (LEA) in diabetic patients is also not to be ignored. Substantial data had identified increased LEA risk from smoking and heavy alcohol intake and reduced risk from regular exercise. The cumulative impact of these behaviors underscores the significance of behavior modification in preventing LEA and enhancing the well-being of diabetic patients. Understanding these mechanisms is vital for developing effective preventive strategies, diagnostics, and treatments, addressing the impact of diabetic foot complications on individuals and healthcare systems.