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Heidelberg, Germany

Neuman M.G.,In Vitro Drug Safety and Biotechnology | Neuman M.G.,University of Toronto | Malnick S.,Health Science University | Maor Y.,Health Science University | And 18 more authors.
Experimental and Molecular Pathology | Year: 2015

The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical research, translational research, pathogenesis and therapies. A special accent is placed on alcohol misuse, as alcohol is a legally commercialized and taxable product. Drinking alcohol, particularly from a young age, is a major health problem. Alcoholism is known to contribute to morbidity and mortality. A systematic literature search was performed in order to obtain updated data (2008-2015). The review is focused on genetic polymorphisms of alcohol metabolizing enzymes and the role of cytochrome p450 2E1 and iron in ALD. Alcohol-mediated hepatocarcinogenesis is also discussed in the presence or absence of co-morbidities such as viral hepatitis C as well as therapeutic the role of innate immunity in ALD-HCV. Moreover, emphasis was placed on alcohol and drug interactions, as well as liver transplantation for end-stage ALD. Finally, the time came to eradicate alcohol-induced liver and intestinal damage by using betaine. © 2015 Elsevier Inc. Source


Heaton M.B.,University of Florida | Heaton M.B.,McKnight Brain Institute | Heaton M.B.,Center for Alcohol Research | Paiva M.,University of Florida | And 8 more authors.
Brain Research | Year: 2012

These studies investigated ethanol effects on upstream cellular elements and interactions which contribute to Bax-related apoptosis in neonatal rat cerebellum at ages of peak ethanol sensitivity (postnatal day 4 [P4]), compared to later ages of relative resistance (P7). Analyses were made of basal levels of the pro-apoptotic c-jun N-terminal kinase (JNK), Bax, and the 14-3-3 anchoring proteins, as well as the responsiveness of these substances to ethanol at P4 versus P7. Dimerization of Bax with 14-3-3 was also investigated at the two ages following ethanol treatment, a process which sequesters Bax in the cytosol, thus inhibiting its mitochondrial translocation and disruption of the mitochondrial membrane potential. Cultured cerebellar granule cells were used to examine the protective potential of JNK inhibition on ethanol-mediated cell death. Basal levels of JNK were significantly higher at P4 than P7, but no differences in the other proteins were found. Activated JNK, and cytosolic and mitochondrially-translocated Bax were increased in P4 but not P7 animals following ethanol exposure, while protective 14-3-3 proteins were increased only at P7. Ethanol treatment resulted in decreases in Bax:14-3-3 heterodimers at P4, but not at P7. Inhibition of JNK activity in vitro provided partial protection against ethanol neurotoxicity. Thus, differential temporal vulnerability to ethanol in this CNS region correlates with differences in both levels of apoptosis-related substances (e.g., JNK), and differential cellular responsiveness, favoring apoptosis at the most sensitive age and survival at the resistant age. The upstream elements contributing to this vulnerability can be targets for future therapeutic strategies. © 2011 Elsevier B.V. Source


Andersen A.-M.N.,Copenhagen University | Andersen P.K.,Section of Biostatistics | Olsen J.,University of Aarhus | Gronbaek M.,Center for Alcohol Research | And 2 more authors.
International Journal of Epidemiology | Year: 2012

Background: Controversies still exist regarding the existence of a 'safe' level of alcohol intake during pregnancy. The aim of this study was to assess the risk of fetal death (spontaneous abortion and stillbirth) according to maternal alcohol consumption in a large Danish pregnancy cohort. Methods: A cohort study carried out within the framework of the Danish National Birth Cohort. A total of the 92 719 participants enrolled in the Danish National Birth Cohort who provided information about lifestyle during first trimester of pregnancy were included in the study. Information about average weekly consumption of alcohol during pregnancy, smoking, coffee drinking, occupational status and reproductive history were obtained by means of computer-assisted telephone interviews. Pregnancy outcomes (spontaneous abortion, stillbirth, live birth and other pregnancy outcome) and gestational age at end of pregnancy were obtained through register linkage with the Civil Registration System and the National Discharge Registry. Data were analysed using Cox regression models, taking the varying gestational age at recruitment and time-dependent co-variables into account. Results: Fifty-five per cent of the participants abstained from alcohol drinking during pregnancy and only 2.2% reported four or more drinks per week. The adjusted hazard ratios for fetal death in first trimester were 1.66 [95% confidence interval (CI) 1.43-1.92] and 2.82 (95% CI 2.27-3.49) for women who reported 2-31/2 drinks per week and 4 or more drinks per week, respectively, and 1.57 (95% CI 1.30-1.90) and 1.73 (95% CI 1.24-2.41) for fetal death during pregnancy weeks 13-16. No increased risk was found for fetal death after 16 weeks of pregnancy. Conclusions: Even low amounts of alcohol consumption during early pregnancy increased the risk of spontaneous abortion substantially. The results indicate that the fetus is particularly susceptible to alcohol exposure early in pregnancy. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved. Source


Millonig G.,Center for Alcohol Research | Friedrich S.,Center for Alcohol Research | Adolf S.,Center for Alcohol Research | Fonouni H.,University of Heidelberg | And 7 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fibrosis. Methods & results: Using landrace pigs, we studied the direct relationship between the central venous pressure and LS measured by Fibroscan. Clamping of the inferior caval vein increased LS from 3.1 to 27.8 kPa while reopening reversed LS within 5 min to almost normal values of 5.1 kPa. We then studied LS as a function of venous pressure in the isolated pig liver by clamping the upper and lower caval, portal vein and hepatic artery. The stepwise increase of intravenous pressure to 36 cm of water column (3.5 kPa) linearly and reversibly increased LS to the upper detection limit of 75 kPa. We finally measured LS in 10 patients with decompensated congestive heart failure before and after recompensation. Initial LS was elevated in all patients, in 8 of them to a degree that suggested liver cirrhosis (median 40.7 kPa). Upon recompensation with a median weight loss of 3.0 kg, LS decreased in all 10 patients down to a median LS of 17.8 kPa. Inflammation could not account for increased LS since initial liver enzyme counts were only slightly elevated and did not change significantly. Conclusion: LS is a direct function of central venous pressure which should be considered when assessing the degree of fibrosis. © 2009 European Association for the Study of the Liver. Source

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