bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Contraceptives Worsen Endotoxin‐Induced Liver Injury in Rats
Authors: Konno Akira , Enomoto Nobuyuki , Takei Yoshiyuki , Hirose Miyoko , Ikejima Kenichi , Sato Nobuhiro 
Published: April 2006

Background Oral contraceptives are widely used; however, these drugs occasionally cause liver injury. Recently, it was reported that estriol worsens alcoholic liver injury by the mechanism involving activation of Kupffer cells as a result of gut‐derived endotoxin. However, the relationship between oral contraceptives and endotoxin‐induced liver injury has not been elucidated. Here we show that oral contraceptives sensitize Kupffer cells via a mechanism dependent on increased gut permeability to endotoxin.Methods Female Wistar rats (200–250 g) were given intraperitoneally a combination of estradiol (35 ng/kg of 17α‐Ethynylestradiol) and progesterone (2 μg/kg of Norethindrone), each dose being similar to that contained in oral contraceptives (EP treatment). After 24 hr, a sublethal dose of lipopolysaccharide (LPS; 5 mg/kg) was injected via the tail vein. In some experiments, antibiotics (150 mg/kg/day of polymyxin B and 450 mg/kg/day of neomycin) were administered orally for 4 days before EP treatment. Gut permeability was measured in isolated segments of ileum by translocation of horseradish peroxidase. Kupffer cells were isolated and cultured in RPMI 1640 + 10% fetal bovine serum for 24 hr. After addition of LPS (100 ng/ml) to the culture medium, intracellular calcium concentration ([Ca2+]i) was measured with fura‐2.Results Liver histology in rats given EP treatment intraperitoneally followed by an injection of LPS (5 mg/kg) 24 hr later revealed pronounced liver damage with massive necrosis. Whereas mean values of alanine aminotransferase (ALT) in the control, nontreated rats were 30 ± 6 IU/liter, ALT increased to 75 ± 21 IU/liter 24 hr after LPS injection. This increase was aggravated 6‐fold (483 ± 118 IU/liter;p < 0.05) by EP treatment. The EP treatment‐induced increase in ALT was completely blocked by antibiotics (82 ± 26 IU/liter;p < 0.05). Gut permeability was increased approximately 10‐fold with EP treatment. This increase in gut permeability was not altered by treatment with nonabsorbable antibiotics. In isolated Kupffer cells, LPS increased [Ca2+]i of Kupffer cells in control rats from basal levels (36 ± 8 nmol/liter) to 100 ± 8 nmol/liter. In contrast, the LPS‐induced [Ca2+]i elevation was approximately 3‐fold greater in the group given EP treatment before 24 hr (305 ± 17 nmol/liter;p < 0.05). This increase was also blocked completely by treatment with antibiotics (128 ± 13 nmol/liter). Similar results were obtained for LPS‐induced tumor necrosis factor‐α production by Kupffer cells from either control or EP treatment group. The increased tumor necrosis factor‐α production as a result of EP treatment was blocked completely by antibiotics.Conclusions These results indicate that EP treatment in vivo sensitizes Kupffer cells to LPS via a mechanism dependent on the portal increase of gut‐derived endotoxin. This event suggests that oral contraceptives exacerbate alcoholic liver injury.
Effect of Alcohol on the Secretion of Tumor Necrosis Factor‐α by Macrophages in the Presence of Rat Serum
Authors: Nakatani Yoshihiro , Fukui Hiroshi , Kitazawa Toshiyuki , Fujimoto Masao , Yamao Junichi , Uemura Masahito 
Published: April 2006

Background It is suggested that endotoxin, proinflammatory cytokines, and lipopolysaccharide‐binding protein (LBP) play an important role in the development of alcoholic liver disease. Our previous study showed that splenic macrophages were important for endotoxin uptake and excessive production of tumor necrosis factor (TNF) in rats given large amounts of alcohol. To determine the pathophysiological roles of macrophages in alcoholic liver disease, we examined the effect of ethanol on TNF‐α secretion of rat Kupffer cells, alveolar macrophages, and peritoneal macrophages in the presence or absence of LBP.Methods Kupffer cells, alveolar macrophages, and peritoneal macrophages were isolated from male Sprague Dawley rats. After the preculture in the medium containing 0, 10, 50, and 100 mmol/liter of ethanol, TNF‐α secretion by these cells incubated with 100 ng/ml of endotoxin in the presence or absence of LBP (1% rat serum) was determined.Results In the absence of LBP, an addition of ethanol to the medium suppressed TNF‐α secretion of alveolar macrophages. Kupffer cells and peritoneal macrophages were less affected. Addition of LBP led to marked enhancement (7‐ to 24‐fold) of TNF‐α secretion of macrophages either with or without ethanol in the medium. Although ethanol tended to suppress TNF‐α secretion of these cells, alveolar macrophages were less affected in the presence of LBP.Conclusions Serum LBP enhances the secretion of TNF‐α by macrophages. Alveolar macrophages may be important for excessive production of TNF‐α in chronic alcoholics with endotoxemia.
Experimental Studies on the Relationship Between Immune Responses and Liver Damage Induced by Ethanol After Immunization With Homologous Acetaldehyde Adducts
Authors: Shimada Seika , Yamauchi Masayoshi , Takamatsu Masashi , Uetake Shinichiro , Ohata Mitsuru , Saito Saburo 
Published: April 2006

Background It has been considered that acetaldehyde (AcH) adducts induce liver injury through an immune response. Previous experimental studies showed that hepatic necrosis, inflammatory cell infiltration, and hepatic fibrosis were induced in guinea pigs immunized with heterologous human AcH adducts and ethanol feeding. AcH modification of foreign protein may markedly increase immunogenicity of the protein itself, leading to enhanced formation of immune complex and possible liver injury. The present study investigated whether immune responses and alcoholic liver disease would be induced in mice by immunization with mouse albumin‐AcH adducts and ethanol feeding.Methods 6B6 mice were divided into six groups with or without immunization and ethanol feeding. Mice were immunized with mouse albumin‐AcH adducts three times at 2‐week intervals and fed ethanol for 10 weeks. The stimulation index of [3H]thymidine uptake into lymphocytes cultured with mouse albumin or mouse albumin‐AcH adducts was measured. Histologic findings of the liver were examined, and the plasma levels of aspartate transaminase and alanine aminotransferase were also measured.Results The stimulation index was increased remarkably in ethanol‐fed mice that were immunized with mouse albumin‐AcH adducts. However, neither inflammatory cell infiltration nor hepatic necrosis was observed in the liver. There were also no differences in the plasma activities of aspartate transaminase and alanine aminotransferase between the group of mice regardless of ethanol feeding or immunization.Conclusion Although marked immune responses were observed, no liver damage was induced by long‐term ethanol feeding in our mouse model using AcH‐homologous albumin adducts. These results suggest that homologous protein adducts may not induce liver injury by long‐term ethanol feeding or may have lower immunogenicity than heterologous protein adducts. These results also suggest that nonreduced AcH adducts and/or a larger amount of ethanol may be needed for liver injury in this model.
NPY leu7pro and Alcohol Dependence in Finnish and Swedish Populations
Authors: Zhu Guanshan , Pollak Lotta , Mottagui‐Tabar Salim , Wahlestedt Claes , Taubman Julie , Virkkunen Matti , Goldman David , Heilig Markus 
Published: April 2006

Background: Neuropeptide Y (NPY) is a modulator of alcohol intake in animal models of alcoholism, and is potentially involved in alcohol dependence. A coding Leu7Pro polymorphism in the signal peptide of preproNPY has been described, and the Pro7 allele has been reported to correlate with increased alcohol consumption in non‐dependent Finnish males. Recently, this polymorphism was also reported to be associated with an actual diagnosis of alcohol dependence.Methods: We compared Pro7 allele frequencies in one Finnish (n= 135) and one Swedish (n= 472) population of alcohol dependent individuals, and ethnically matched controls (Finns:n= 213; Swedes:n= 177) in whom alcohol dependence was established, or any diagnosis of substance disorder was excluded, respectively, through the use of structured face‐to‐face interviews.Results: Pro7 frequencies in alcoholics were 5.2 and 4.1% in Finns and Swedes, respectively, similar to the 5.0‐5.5% recently reported in European Americans in a Yale study. However, corresponding frequencies in the control populations were similar, at 6.1 and 5.9% in Finns and Swedes, respectively, yielding no association, in contrast with the Yale study, where an association was reported based on a 2.0% Pro7 frequency in European American controls. A meta‐analysis of available data yields Pro7 frequencies of 4.7% both in Caucasian alcoholics and Caucasian controls.Conclusions: Pro7 does not seem to be associated with a diagnosis of alcoholism in Caucasian populations.
Maternal Separation Alters Acquisition of Ethanol Intake in Male Ethanol‐Preferring AA Rats
Authors: Roman Erika , Hyytiä Petri , Nylander Ingrid 
Published: April 2006

Background: Prolonged daily maternal separation can increase the risk for developing substance abuse, whereas brief maternal separation has been reported to induce positive behavioral effects, decrease voluntary ethanol intake and induce long‐lasting changes in brain opioid peptides. The ethanol‐preferring AA (Alko, Alcohol) rats have altered basal levels of endogenous opioid peptides that may relate to their high voluntary ethanol intake. The purpose of this study was to investigate whether maternal separation could affect acquisition of ethanol intake in AA rats.Methods: The rat pups were exposed to 15 min (MS15) or 360 min (MS360) of maternal separation during postnatal day 1‐21, while control rats were exposed to normal animal facility rearing. As adults, the male rats were gradually introduced to increasing concentrations of ethanol. Furthermore, the effect of restraint stress on voluntary ethanol intake was investigated.Results: The MS15 rats reached a high voluntary ethanol intake later than MS360 and control rats. The MS15 rats had a lower ethanol intake and preference at 8% ethanol compared to MS360 rats and lower ethanol intake compared to control rats. MS15 rats also had a lower 10% ethanol intake in comparison with MS360 rats. Restraint stress decreased the ethanol intake in MS15 and MS360 rats, whereas the ethanol intake in control rats was unaffected.Conclusions: We have previously shown that prolonged periods of maternal separation in Wistar rats result in an increased ethanol intake later in life. This was not repeated in this study, using AA rats with an inherent high ethanol intake. However, it is shown that brief maternal separation can delay acquisition of high ethanol intake and in addition decrease voluntary ethanol intake and preference in AA rats. Maternal separation for 15 min is therefore suggested to protect against high voluntary ethanol intake later in life.
Behavioral Undercontrol and Subjective Stimulant and Sedative Effects of Alcohol Intoxication: Independent Predictors of Drinking Habits?
Authors: Erblich Joel , Earleywine Mitchell 
Published: April 2006

Background: Previous studies have demonstrated relations between behavioral undercontrol (e.g., sensation seeking) and higher levels of alcohol use. The mechanism underlying this relation is not yet understood. In this article, we investigate the role of subjective stimulant and sedative effects of intoxication on drinking habits, and we test the possibility that these effects mediate or moderate relations between behavioral undercontrol and drinking habits.Methods: College drinkers (n= 91) consumed 0.85 ml/kg of alcohol (approximately four drinks) and completed self‐report measures of stimulation and sedation at three time points: (1) before drinking; (2) 15 min after consumption, on the ascending limb of the blood alcohol curve; and (3) 45 min after consumption, on the descending limb of the curve. In addition, participants completed the MacAndrew Alcoholism and Sensation Seeking Scales, indices of behavioral undercontrol, and a self‐report questionnaire of drinking habits (quantity, frequency, and maximum).Results: As expected, undercontrol was strongly related to drinking habits (p < 0.0005). Undercontrol was also significantly related to ascending limb stimulation (p < 0.005), which, in turn, was related to drinking habits (p < 0.005). Finally, stimulation was found to moderate the relations between undercontrol and drinking habits such that relations were stronger at higher levels of stimulation.Conclusions: These findings may help to better understand the variability in drinking behavior, and this may be critical in eventually developing and appropriately targeting prevention efforts.
Strategies for Reduction and Cessation of Alcohol Use: Adolescent Preferences
Authors: Metrik Jane , Frissell Kevin C. , McCarthy Denis M. , D'Amico Elizabeth J. , Brown Sandra A. 
Published: April 2006

Background: Although the majority of youth and adults resolve alcohol problems without formal treatment, we know little about the strategies used by youth in their efforts to decrease alcohol use. Recent studies have begun to address change efforts that adolescents report being helpful in cutting down or stopping alcohol use. The current study seeks to improve our understanding of adolescent change processes in alcohol use by examining the perceptions of high school students.Methods: As part of a secondary alcohol intervention study of high school students (ages 12–18; 51% male), 1069 participants completed an anonymous supplemental questionnaire on change strategies for cutting down and stopping alcohol use. Based on content analysis of youth‐generated responses, a classification system consisting of nine broad categories was developed (e.g., informal‐interpersonal supports, formal aids, alternative activities). Participant responses were independently coded by two raters trained to criterion. Cases with full agreement (n= 934; 96%) were used for data analyses of methods for cutting down drinking, stopping drinking, and strategies recommended for a friend.Results: The five most frequently youth‐generated change strategies to alter drinking were environmental exposure management (e.g., avoid drinking situations, 19%); informal interpersonal supports (e.g., talk to a friend, 18%); formal aids (e.g., peer support group, counselor, 17%); behavioral self‐management (e.g., limit consumption, 14%); and alternative activities (e.g., recreation, sports, 10%). Whereas informal interpersonal supports were consistently endorsed for all change situations, behavioral self‐management strategies were viewed as more useful for reduction of drinking and formal aids more critical for cessation efforts. Some differences were observed in youth‐generated strategies for changing their own drinking compared with efforts to help friends, with environmental changes (e.g., reducing exposure to risk situations and people, formal aids) more often considered when changing youth's own behavior, and strategies reflecting a need for personal change (e.g., education) recommended to others.Conclusions: Our findings support theoretical conceptualizations of alcohol and drug problem resolution that accommodates multiple pathways to recovery. The normative information about specific change strategies generated by youth may further aid in the design of interventions more acceptable for adolescents.
Rates and Correlates of Alcohol Use Among Pregnant Women in Obstetrics Clinics
Authors: Flynn Heather A. , Marcus Sheila M. , Barry Kristen L. , Blow Frederic C. 
Published: April 2006

Background: The purpose of this study was to demonstrate feasibility of screening and to identify rates and correlates of alcohol use in a large, demographically representative sample of pregnant women across a number of obstetrics clinics, extending previous studies of single or high‐risk settings. Identification of harmful alcohol use during pregnancy and of associated factors is critical for the design and implementation of secondary prevention strategies.Methods: A total of 1131 pregnant women age 18 and older were screened in the waiting areas of eight obstetrics clinics in Southeastern Michigan using a brief (10 min) screening questionnaire. This survey consisted of direct and indirect (TWEAK) measures of alcohol use, as well items assessing demographic characteristics, use of tobacco, and whether participants’ physicians discussed alcohol use behavior with them. Women ranged in age from 18 to 46, with a mean age of 28.7 (SD = 5.3). The racial/ethnic distribution of our sample suitably reflects the various racial segments of the Michigan population.Results: We found that 15.1% of the total sample (n= 169) reported any alcohol use during pregnancy, with the majority of those women reporting relatively low levels of alcohol use. One hundred and forty‐seven women (13%) scored above the cutoff on the TWEAK (i.e., above a score of 2). Based on multivariate analyses, higher risk alcohol use (defined as binge drinking or greater than one standard drink per week) during pregnancy was predicted by smoking and earlier stage of pregnancy. Caucasian race, smoking, psychological distress, and greater number of drinks during pregnancy predicted scores above a cutoff of 2 on the TWEAK.Conclusion: This study demonstrated that screening in busy obstetrics clinics is feasible and acceptable to women and that it may be optimal to use both indirect and direct measures of alcohol use. In addition, brief assessments should be conducted throughout pregnancy and may be targeted or intensified for smokers and for women earlier in their pregnancy.
Average Volume of Alcohol Consumption and All‐Cause Mortality in African Americans: The NHEFS Cohort
Authors: Sempos Christopher T. , Rehm Jürgen , Wu Tiejian , Crespo Carlos J. , Trevisan Maurizio 
Published: April 2006

Aim: To analyze the relationship between average volume of alcohol consumption and all‐cause mortality in African Americans.Design: Prospective cohort study—the NHANES Epidemiologic Follow‐Up Study (NHEFS)—with baseline data collected 1971 through 1975 as part of the first National Health and Nutrition Examination Survey (NHANES I) and follow‐up through 1992.Participants: The analytic data set consisted of 2054 African American men (n= 768) and women (n= 1,286), 25 to 75 years of age, who were followed for approximately 19 years.Measurement: Alcohol was measured with a quantity‐frequency measure at baseline.Outcome: All‐cause mortality.Results: No J‐shaped curve was found in the relationship between average volume of alcohol consumption and mortality for male or female African Americans. Instead, no beneficial effect appeared and mortality increased with increasing average consumption for more than one drink a day. The reason for not finding the J‐shape in African Americans may be the result of the more detrimental drinking patterns in this ethnicity and consequently the lack of protective effects of alcohol on coronary heart disease. Taking into account sampling design did not substantially change the results from the models, which assumed a simple random sample.Conclusions: If this result can be confirmed in other samples, alcohol policy, especially prevention, should better incorporate patterns of drinking into programs.
Induction of Transferrin Receptor by Ethanol in Rat Primary Hepatocyte Culture
Authors: Suzuki Masako , Fujimoto Yoshinori , Suzuki Yasuaki , Hosoki Yayoi , Saito Hiroyuki , Nakayama Kenji , Ohtake Takaaki , Kohgo Yutaka 
Published: April 2006

Background: It is not uncommon for alcoholics to have iron accumulation in the liver, a condition that may contribute to the development of alcoholic liver disease. Recently, we reported that the expression of transferrin receptor, which mediates cellular iron uptake, was increased in hepatocytes in patients with alcoholic liver disease. To elucidate the mechanism of the iron accumulation in hepatocytes in such disease, we examined whether ethanol exposure induced the transferrin receptor expression and increased the cellular iron uptake.Methods: Rat primary hepatocytes were isolated and cultured in the presence of 20 μmol/liter of iron and 25 mmol/liter of ethanol.Results: Ethanol exposure to the hepatocytes demonstrated an ˜2‐fold increase in transferrin receptor expression for 24 hr, shown by Western blot analysis and 35S‐methionine metabolic labeling, 19% increase in 59Fe‐transferrin uptake by hepatocytes, and 20% increase in activity of iron regulatory protein examined by band shift assay.Conclusion: Ethanol exposure induced the transferrin receptor expression, partially through the activation of iron regulatory protein, and increased the transferrin‐bound iron uptake in rat hepatocyte cultures. The induction of transferrin receptor by ethanol might be one of the mechanisms of iron accumulation in the hepatocytes in alcoholic liver disease.
Polymorphisms of Interleukin‐1β and β3‐Adrenergic Receptor in Japanese Patients With Nonalcoholic Steatohepatitis
Authors: Nozaki Yasuko , Saibara Toshiji , Nemoto Yoshihisa , Ono Masafumi , Akisawa Naoaki , Iwasaki Shinji , Hayashi Yoshihiro , Hiroi Makoto , Enzan Hideaki , Onishi Saburo 
Published: April 2006

Background: Obesity, hypertriglyceridemia, and diabetes have been reported as frequent complications observed in patients with nonalcoholic steatohepatitis (NASH) in Western countries. The aim of this study was to investigate the genetic predisposition on NASH pathogenesis in the Japanese population.Methods: Genotypes of two previously described functional polymorphisms—β3‐adrenergic receptor 190 T/A polymorphism, which results in Trp64Arg (W64R) amino acid replacement, and interleukin‐1β‐511 T/C polymorphism in the promoter sequence—were determined in 63 Japanese NASH patients and 100 healthy volunteers using polymerase chain reaction and restriction fragment length polymorphism.Results: β3‐adrenergic receptor R allele frequency and the R/− (W/R and R/R) genotype frequency were significantly higher in NASH patients than those in control subjects. Interleukin‐1β‐511 T allele frequency and the T/T genotype frequency were significantly higher in NASH patients than those in control subjects. Obesity, hypertriglyceridemia, and hyperinsulinemia were associated with NASH patients with the R/− genotype, whereas an increase in fasting plasma glucose level and a decrease in insulinogenic index were associated with NASH patients with the W/W genotype.Conclusion: This study confirmed the contribution of obesity, glucose intolerance, and hypertriglyceridemia to NASH development in the Japanese population. In addition to these factors, genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH.