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Browsing by Author "Crabb, David"
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Item Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study(Wiley, 2017) Li, Wei; Amet, Tohti; Xing, Yanyan; Yang, Dennis; Liangpunsakul, Suthat; Puri, Puneet; Kamath, Patrick; Sanyal, Arun; Shah, Vijay; Katz, Barry; Radaeva, Svetlana; Crabb, David; Chalasani, Naga; Yu, Qigui; Department of Microbiology and Immunology, IU School of MedicineAlcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma–induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. Conclusion: AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities.Item Chronic free-choice drinking in crossed HAP (cHAP) mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage(Wiley, 2013-02) Matson, Liana; Liangpunsakul, Suthat; Crabb, David; Buckingham, Amy; Ross, Ruth Ann; Halcomb, Meredith; Grahame, Nicholas; Department of Psychology, School of ScienceBackground Crossed High Alcohol Preferring (cHAP) mice were selectively bred from a cross of the HAP1xHAP2 replicate lines, and demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP 2E1) induction plays a prominent role in driving both metabolic tolerance and ethanol-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an ethanol liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. Methods In Experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of ethanol accumulation in these mice. In Experiments 1 and 2, mice were injected with ethanol following 3–4 weeks of access to water or 10% ethanol and water, and blood samples were taken to assess metabolic tolerance. In Experiment 3, 24 mice had 4 weeks access to 10% ethanol and water or water alone, followed by necropsy and hepatological assessment. Results In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points, and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, ethanol-exposed mice metabolized ethanol faster than ethanol-naïve mice, demonstrating metabolic tolerance (p < .05). In experiment 3, ethanol-drinking mice showed greater expression of hepatic CYP 2E1 than water controls, consistent with the development of metabolic tolerance (p < .05). Ethanol access altered neither hepatic histology nor levels of ADH and ALDH. Conclusions These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP 2E1 induction. Together these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism.Item Predictors of Acceptance: Exploring Healthcare-Related Master's-Level Social Workers' Attitudes on Alcohol Use Disorder, Opioid Use Disorder, and Medication-Assisted Treatment(2022-08) Bartholomew, Joseph Brooks; Carlson, Joan M.; Lay, Kathy; Agley, Jon; Crabb, David; Kim, Hea-WonHeavy alcohol consumption and opioid overdose rates continue to increase in the United States (U.S.). Social workers provide approximately 70% of the behavioral healthcare in the U.S. Medication-assisted treatment (MAT) combines FDA-approved medications with psychosocial interventions to provide a comprehensive approach to recovery for alcohol use disorder (AUD) and opioid use disorder (OUD). However, stigmatized attitudes toward individuals with AUD, OUD, and MAT limit MAT’s use. Guided by critical social theory, this study explores factors that predict master’s-level social workers’ (MSWs) attitudes toward AUD and OUD and, by extension, factors that predict their acceptance of MAT. A repeated measures analysis of variance (ANOVA) identified MSWs from Indiana, Kentucky, and Ohio (N = 140) having more favorable statistically significant (p < 0.001) attitudes toward individuals with AUD than those with OUD. Multiple regression models used age, gender identity, political ideology, years working in addiction (tenure), social work licensure, and 12-step facilitation beliefs to predict AUD and OUD attitudes, with AUD and OUD attitudes included in the regression models for MAT acceptance. Increased years working in addiction (tenure) was a statistically significant predictor in elevating attitudes toward individuals with AUD (p < 0.05) and OUD (p < 0.01). A more liberal political ideology (p < 0.001), increased years working in addiction (tenure) (p < 0.05), and more favorable attitudes toward individuals with AUD and OUD (p < 0.001) were statistically significant predictors in MAT acceptance. These results warrant increasing MSWs’ education on addiction and research on factors that impact their acceptance of MAT. Increasing MSWs’ education on addiction may lower stigmatized attitudes toward individuals with AUD and OUD and increase MAT acceptance. MSWs’ increased acceptance of MAT could improve patient health outcomes.Item Sex Differences in Motivation to Self‐Administer Alcohol After 2 Weeks of Abstinence in Young‐Adult Heavy Drinkers(Wiley, 2018) Plawecki, Martin Henry; White, Kurt; Kosobud, Ann E. K.; Grahame, Nicholas; Zimmermann, Ulrich S.; Crabb, David; O'Connor, Sean; Psychiatry, School of MedicineBackground Studies in animal models document that forced abstinence from usual consumption of alcohol changes subsequent seeking and consumption, with increases or decreases depending on the species, duration of abstinence, number of deprivations, and sex. Human laboratory‐based alcohol deprivation studies are rare. Methods We conducted a 2‐session, within‐participant, randomized‐order comparison of intravenous, progressive ratio, alcohol self‐administration during 2.5 hours of progressive work for alcohol and/or vehicle; once while the participants pursued their usual drinking habits and once after 2 weeks of closely monitored, voluntary outpatient abstinence from alcohol. The schedule of work for rewards and the incremental increases in breath alcohol concentration following completion of an alcohol work‐set were identical across participants. Fifty young‐adult (27 men), heavy‐drinking participants completed both sessions. Our primary hypothesis was that motivation to work for alcohol after 2 weeks of abstinence would be greater in participants with a weekly binge pattern of drinking, compared to those who regularly drink heavily, and we intended to explore associations with biological family history of alcoholism and sex. Results We detected no change in work for alcohol associated with recent drinking history. However, females, on average, increased their work for alcohol upon resumption after 2 weeks of abstinence (mean ± SEM = +16.3 ± 9.6%), while males decreased that work (−24.8 ± 13.8%). The sex difference was substantial and significant (p < 0.03), with a medium effect size (Cohen's d = 0.63). Conclusions We believe a more comprehensive study of mechanisms underlying the sex differences in the human postabstinence response is warranted.