bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol‐Induced Augmentation of Annexin IV Expression in Rat C6 Glioma and Human A549 Adenocarcinoma Cells
Authors: Sohma Hitoshi , Ohkawa Hiroko , Hashimoto Eri , Sakai Rie , Saito Toshikazu
Published: April 2006

Background We previously reported that the amount of annexin IV significantly increased in the postmortem brains of alcoholics compared with controls. To investigate further whether ethanol directly affects cellular expression of annexins in a cell, we used cell lines and compared the amounts of annexins between ethanol‐exposed and control cells.

Methods Two kinds of cells (rat glioma C6 cells and human adenocarcinoma A549 cells) were used in the present study. Western blot analysis was performed to quantify expressed amounts of annexins using anti‐annexin I, IV, and V antibodies. The mitochondrial enzyme (dehydrogenase) and caspase 3 activities were measured to assess cell damage (apoptosis) by ethanol.

Results Expressive augmentation of annexin IV was shown in both C6 and A549 cells after a 5‐hr exposure to 200 mM of ethanol, whereas amounts of annexins I and V were not changed. Both the mitochondrial dehydrogenase and caspase 3 activities were altered under the same conditions in C6 cells, indicating the induction of cell damage (apoptosis), whereas both of these enzyme activities were unchanged in A549 cells under the same conditions.

Conclusions The amount of annexin IV seemed to increase before the induction of cell damage by ethanol. Annexin IV might be one of the specific markers for the effect of ethanol.
Outcomes of Small Nodular Lesions in Heavy Drinkers
Authors: Suzuki Michihiro , Maeyama Shiro , Nishikawa Kouji , Okuse Noriaki , Hashizume Kiyoe , Mamada Yukimitu , Kobayashi Yutaro , Okuse Chiaki , Takahashi Yasuhito , Osada Taturo , Hayashi Takeshi , Yotuyanagi Hiroshi , Suzuki Hiroshi , Ogata Seiichiro , Uchikoshi Toshiyuki , Iino Shiro
Published: April 2006

Background Increased detection of nodular lesions in patients not yet definitively diagnosed with hepatocellular carcinoma (HCC) has occurred with the use of advanced imaging techniques. In heavy drinkers, decrease in the size of nodular lesions during on‐going observation, and negation of diagnoses of HCC after surgical resection have been reported, suggesting the need for caution in diagnosis in such cases.

Methods The subjects were eight heavy drinkers with small nodular lesions, 20 mm or less in diameter. All patients were male, with a mean age of 53 years. Five had single and three had multiple nodular lesions. Five of the eight patients were followed up for more than 4 years after an initial biopsy, while three patients were recent cases. Of the three recent cases, two were positive for antibody to hepatitis C virus (HCV) and two had hypervascular nodular lesion. Biopsies were performed percutaneously, under ultrasonography, for histological diagnosis of all cases, and the recent cases were also assessed using a variety of imaging techniques.

Results On initial biopsy, no atypism (NO) was found in two patients, and borderline lesions (Border) were present in six patients. Of the five cases followed up long‐term, only one of the two with NO progressed to HCC, and the three with Border showed disappearance, decrease, and no change, respectively, during the follow‐up period. Of the three recent cases, no changes in size or morphology as revealed by imaging were observed following biopsy.

Conclusions In heavy drinkers, no fixed relationship was observed between initial biopsy finding and clinical course, suggesting that indication for biopsy requires reassessment, refinement, and discussion. Furthermore, tumor staining may occur in hyperplastic nodules, which are histologically similar to early HCC by needle biopsy, and care needs to be exercised for diagnosis in heavy drinkers.
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.
Regional Cerebral Blood Flow Measured by the Resting and Vascular Reserve (RVR) Method in Chronic Alcoholics
Authors: Suzuki Yutaka , Oishi Minoru , Mizutani Tomohiko , Sato Yukimitsu
Published: April 2006

It has been reported that cerebral blood flow is decreased in chronic alcoholics without neurological diseases. We performed SPECT by the resting and vascular reserve (RVR) method in 11 chronic alcoholics (mean age 59.1 ± 10.4, all males) and 11 age‐matched healthy controls (mean age 58.8 ± 10.1, all males). The resting and vascular reserve (RVR) method is a consecutive 99mTc‐ECD SPECT study before and after acetazolamide administration with adjunctive radionuclide angiography, which is easy to perform for a routine clinical study and quite useful for evaluating regional cerebral blood flow and the cerebrovascular response to acetazolamide. Regional cerebral blood flows in almost all regions in the alcoholic group were lower than those in the control group. However, there were no significant differences in increased rates of blood flow in response to acetazolamide in almost all regions between the chronic alcoholic group and the control group. In both groups, the increased rates of blood flow in response to acetazolamide in the supratentorial region, cerebellum, and brain stem were 30–40%, 20–25%, and 42–48%, respectively. The cerebrovascular response to acetazolamide in chronic alcoholics was not impaired, therefore the reduction of brain metabolism may be one of the important factors causing the decreased cerebral blood flow in chronic alcoholics.
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.
Prenatal Alcohol Exposure: Advancing Knowledge Through International Collaborations
Authors: Riley Edward P. , Guerri Consuelo , Calhoun Faye , Charness Michael E. , Foroud Tatiana M. , Li Ting‐Kai , Mattson Sarah N. , May Philip A. , Warren Kenneth R.
Published: April 2006

Fetal alcohol syndrome (FAS) is a major public health issue that is evident on an international scale. The current article summarizes a meeting that was held in Valencia, Spain, in September 2001, that reviewed ongoing international collaborations and the prospects for new collaborative research. The attendees represented nine different countries and many different specialties. Following overviews of existing international collaborations in South Africa, Russia, and Chile, a number of topics for future work were discussed. Issues related to the diagnosis of FAS, its prevalence and how measures might be enhanced and standardized were presented, as obtaining consistency across populations is of prime importance. Another session discussed the current state of basic research and how collaborations in this area might be initiated. The neurobehavioral profile of FAS and how work in this area could be advanced and interpreted in light of findings with different populations generated considerable discussion. There was a review of brain imaging data in FAS and how this might be utilized in assisting the diagnosis of FAS and alcohol‐related neurodevelopmental disorder (ARND). A presentation on the utilization of international collaborations in defining the role of genetics in the etiology of FAS was included. Finally, issues related to the prevention of FAS and how these issues might be modified based upon different populations were presented. International collaborations provide a wealth of resources for the study of FAS, and it was hoped that this meeting might better enhance the work ongoing in this area, and provide opportunities for future work.
Testing Combined Pharmacotherapies and Behavioral Interventions in Alcohol Dependence: Rationale and Methods
Authors:   The COMBINE Study Research Group
Published: April 2006

Increasing knowledge about effective therapies for alcohol dependence calls for new research designs to examine treatment interactions between pharmacotherapies and behavioral interventions. In 1997, the National Institute on Alcohol Abuse and Alcoholism recruited 11 sites and a coordinating center for a large‐scale (1,375 subjects), randomized placebo controlled trial to test 16 weeks of active treatment using naltrexone and acamprosate alone and in combination. Most participants receive 9 brief sessions delivered by medically trained providers to promote sobriety and enhance medication adherence (Medical Management, MM). Half the participants are also randomized to individualized psychotherapy (up to 20 sessions of Combined Behavioral Intervention, CBI), integrating elements of the successful behavioral interventions from Project MATCH. COMBINE seeks to evaluate the efficacy of the two most promising medications (naltrexone and acamprosate) both singly and together, when combined with different intensities of behavioral therapies. COMBINE incorporates a number of innovative design aspects, including a no‐pill psychotherapy‐alone condition, behavioral interventions that are both manual‐guided and individualized, and pharmacotherapy dosing that is greater than in some previous trials. Two COMBINE pilot studies demonstrate the safety and acceptability of the combination pharmacotherapy dosing, and the feasibility of implementing the manualized behavioral interventions. This paper introduces COMBINE's goals, methods and analytic strategies, and their potential to improve multimodal treatment selection.
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.
Effect of Prostaglandin E Receptor Subtype EP4 Selective Agonist on the Secretion of Tumor Necrosis Factor‐α by Macrophages in Acute Ethanol‐Loaded Rats
Authors: Nakatani Yoshihiro , Kitazawa Toshiyuki , Fujimoto Masao , Tamura Nobuhiro , Uemura Masahito , Yamao Junichi , Fukui Hiroshi
Published: April 2006

Background:It is suggested that endotoxin and proinflammatory cytokines play an important role in the development and progression of alcoholic liver disease. Recently, a prostaglandin receptor subtype EP4 agonist with cytoprotective effect has been developed. We examined the efficacy of an EP4 agonist ONO‐AE1‐437 on tumor necrosis factor‐α (TNF‐α) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol‐loaded rats.

Methods:Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from control and acute ethanol‐loaded rats (5 mg/g body weight of ethanol, intraperitoneally). After the preculture in the medium that containing 0, 0.1, 1, 10, or 100 nmol/liter of ONO‐AE1‐437, TNF‐α secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr.

Results:The amount of TNF‐α secreted from alveolar macrophages was largest in both the control and the acute ethanol‐loaded rats. Acute ethanol load enhances TNF‐α secretion of splenic macrophages. The addition of ONO‐AE1‐437 significantly inhibited TNF‐α secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol‐loaded rats. Alveolar macrophages were less affected.

Conclusions:An EP4 agonist ONO‐AE1‐437 suppresses excess TNF‐α secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.
Clinical Characteristics of Portal Hemodynamics in Alcoholic Liver Cirrhosis
Authors: Hirata Mami , Kurose Kiyotaka , Minami Hisaka , Kumagi Teru , Akbar S M. Fazle , Michitaka Koujirou , Horiike Norio , Onji Morikazu
Published: April 2006

Background: Low incidence of reversal blood flow at the portal vein has been reported by measurement in larger and extrahepatic blood vessels but not in intrahepatic blood vessels in patients with liver cirrhosis. Moreover, there is little information regarding the incidence of reversal blood on the basis of the cause of liver cirrhosis. The aim of this study was to measure the reversal blood flow in the portal vein including intrahepatic branches in patients with alcoholic and viral cirrhosis.

Methods: The blood flow in the portal vein and existence of portosystemic shunt were studied in 52 and 27 patients with alcoholic and viral cirrhosis, respectively, by Doppler ultrasonography. The parameters of liver function test and the prevalence of ascites and esophageal varices were compared between patients with and without reversal blood flow.

Results: Reversal blood flow at the portal vein was found only in patients with only alcoholic cirrhosis (17 of 52 patients) but not in any patients with viral cirrhosis (0 of 27 patients; p < 0.05). The incidence of portosystemic ascites and red color of esophageal varices was also higher in patients with alcoholic cirrhosis with reversal blood flow in the portal vein compared with patients without reversal blood flow (p < 0.05).

Conclusions: Reversal blood flow in the portal vein is a characteristic feature of alcoholic cirrhosis. The presence of reversal blood flow indicates severe liver diseases, and this feature may have prognostic importance for patients with alcoholic cirrhosis.
Strategy for Hepatic Hyperplastic Nodules in Heavy Drinkers
Authors: Suzuki Michihiro , Maeyama Shiro , Takahashi Hideaki , Okuse Noriaki , Takahashi Yasuhito , Mizuno Hiroshi , Yotuyanagi Hiroshi , Suzuki Hiroshi , Itoh Fumio , Uchikoshi Toshiyuki
Published: April 2006

Background: Increased detection of nodular lesions that have not yet been definitively diagnosed as hepatocellular carcinoma (HCC) has occured with the use of advanced imaging techniques. In heavy drinkers, the differential diagnosis between a hyperplastic nodule and early HCC on the basis of results of fine‐needle biopsy is often difficult. Negation of diagnosis of HCC after surgical resection has been reported, and nodular lesions have been found to decrease during follow‐up observation. On the basis of findings, a suitable strategy for the management of such lesions is suggested.

Methods: We identified six patients who had hepatic nodular lesions on ultrasonography and were heavy drinkers. This group included five men and one woman with a mean age of 45.3 ± 3.8 years. Two patients had solitary lesions; four had multiple lesions, and of these, two were hepatitis C virus antibody positive (C+). In the five men, the nodular lesions were detected during hospitalization for ruptured or prophylactic treatment of gastroesophageal varices.

Results: Five of the six patients had hypervascular lesions characterized by increased hepatic artery blood flow. However, dynamic computed tomography and magnetic resonance imaging studies during late‐phase imaging could not confirm any decrease in portal blood flow. HCC was diagnosed by detailed imaging studies and liver biopsy in one C+ patient with a solitary nodule. In two of the other four patients, imaging findings were compatible with hypervascular HCC. Findings on liver biopsy do not always permit an easy differential diagnosis between a regenerative lesion (hyperplastic nodule) and a dysplastic or neoplastic lesion. One patient with a hypovascular lesion was C+, and liver biopsy showed a dysplastic nodule.

Conclusion: Heavy drinkers with alcoholic liver disease often develop hypervascular, hyperplastic nodules. The accurate diagnosis of these nodules requires careful consideration of clinical factors, including a combination of images and histologic examination. However, some cases were still difficult to distinguish between HCC by applying advanced imaging techniques and biopsy results.
Comparison of Hepatocellular Carcinoma Patients With Alcoholic Liver Disease and Nonalcoholic Steatohepatitis
Authors: Hashimoto Etsuko , Taniai Makiko , Kaneda Hiroyuki , Tokushige Katsutoshi , Hasegawa Kiyoshi , Okuda Hiroaki , Shiratori Keiko , Takasaki Ken
Published: April 2006

Background: Alcoholic hepatitis and nonalcoholic steatohepatitis (NASH) show different clinical features with similar liver histology, but both disorders may progress to cirrhosis and hepatocellular carcinoma (HCC). HCC arising in alcoholic liver disease (ALD) or NASH, without hepatitis B or C virus infection, has been a rare observation, and there are no studies comparing the characteristics of ALD and NASH patients with HCC. Therefore, we compared the characteristics of ALD and NASH patients with HCC.

Methods: A total of 1202 patients received a diagnosis of HCC at Tokyo Women's Medical University from 1989 to 2003, and their clinical data were collected prospectively. A clinical diagnosis was made to diagnose ALD, and clinical and histological changes were required to diagnose NASH. Of these patients, 88 received a diagnosis of HCC arising from ALD. Among them, a biopsy specimen was obtained in 50 patients (ALD‐HCC group). We compared the clinical and histological characteristics of 50 ALD and 8 NASH patients (NASH‐HCC group) associated with HCC. They all were negative for hepatitis virus infection by serological methods.

Results: The most significant difference between these groups was sex. Women were significantly more common in the NASH‐HCC group (6% vs. 63%; p < 0.0001). The median age was 65 years in the ALD‐HCC group and 68 years in the NASH‐HCC group. The risk factors for NASH all were high in the NASH‐HCC group. However, liver function tests were similar in these groups. In the ALD‐HCC group, 46 (92%) patients showed severe fibrosis; 2 had septal fibrosis and 44 had cirrhosis. All patients in the NASH‐HCC group showed severe fibrosis, and seven had cirrhosis.

Conclusions: Severe fibrosis might be an important risk factor for HCC. Patients who have ALD or NASH with cirrhosis may develop HCC. This seems to occur in a sufficient number of cases to warrant regular screening for this complication.
Hypervascular Liver Nodules in Heavy Drinkers of Alcohol
Authors: Kim Soo Ryang , Maekawa Yoko , Imoto Susumu , Sugano Masahiko , Kudo Masatoshi
Published: April 2006

Background: Three cases of hypervascular nodules in the liver, without hepatitis B or C virus infection and with a history of alcohol abuse (120 ml/day for 15 to 30 years), are presented.

Results: Ultrasound examination revealed hypoechoic nodules in segment 6 (2 cm in diameter, case 1), in the right and left lobes (1–2 cm multiple type, case 2), and in segment 4 (4 cm, case 3). Hepatic angiography and computed tomography during arteriography revealed hypervascular nodules in the three cases. First, hepatocellular carcinoma, focal nodular hyperplasia, hemangioma, hemangioendothelioma, inflammatory pseudotumor, and pseudolymphoma were diagnostically differentiated. Histologically, there was no evidence of hepatocellular carcinoma or of any of the pathologies considered in the differential diagnosis by imaging studies. In case 1, the lesion was composed of an irregular, thin, trabecular‐patterned hepatic acinus with slighter hypercellularity than in the nonnodular area. In cases 2 and 3, the lesions were composed mainly of fibrosis without hyperplasia, showing stellate scar–like fibrosis septa dividing the nodule. Marked pericellular fibrosis, neutrophilic infiltration, and Mallory bodies in the cytoplasm were also observed. In cases 1 and 2, small unpaired arteries explaining the hypervascularity of the nodules were observed.

Conclusion: These hypervascular nodules were classified as regenerative, not neoplastic, nodules according to the classification of the International Working Party.
Role of Hepatitis B Virus in Hepatocarcinogenesis in Alcoholics
Authors: Yotsuyanagi Hiroshi , Hashidume Kiyoe , Suzuki Michihiro , Maeyama Shiro , Takayama Tadatoshi , Uchikoshi Toshiyuki
Published: April 2006

Background: The pathogenesis of hepatocellular carcinoma (HCC) in alcoholics is not understood well. Occult hepatitis B virus (HBV) infection may have some roles.

Methods: We compared the clinical features of HCC in patients with and without a history of excessive alcohol consumption. For hepatitis B surface antigen (HBsAg)‐negative, anti–hepatitis C virus (HCV)‐negative (NBNC) patients, HBV DNA in the tumor was detected by polymerase chain reaction (PCR)‐Southern blotting. Integrated and episomal forms of HBV DNA were detected using agarose gel electrophoresis after nested PCR and were quantified by real‐time PCR.

Results: For patients who were anti–HCV positive in serum, the age at diagnosis of HCC was lower for alcoholics than nonalcoholics. For serum HBsAg‐positive patients and those who were NBNC, the age at diagnosis of HCC was the same for alcoholics and nonalcoholics. The numbers of tumors and of patients with vascular invasion did not differ between alcoholics and nonalcoholics in any subset. In three NBNC‐HCC patients with a history of alcohol abuse, HBV DNA was detected in the tumor. Integrated HBV DNA was detected in one patient, and the episomal form of HBV DNA was detected in two patients.

Conclusion: HBV may be found in episomal and integrated forms in the chromosomal DNA of the livers of habitual drinkers who are negative for HBsAg and anti‐HCV and may have a direct role in hepatocarcinogenesis.
Clinicopathological Study of Hepatic Nodular Lesions in Patients With Alcoholic Liver Cirrhosis
Authors: Sobue Satoshi , Nomura Tomoyuki , Nakao Haruhisa , Mizuno Yaichi , Nojiri Syunsuke , Kanematsu Takayoshi , Senda Katsuhiro , Murasaki Gengo , Itoh Makoto
Published: April 2006

Background: There have been few reports concerning the occurrence of hepatocellular carcinoma (HCC) in heavy drinkers not sensitized by hepatitis B virus (HBV) or hepatitis C virus. With current advances in diagnostic methods, hypervascular tumors are often discovered on imaging findings in alcoholics, and it is important to differentiate them from HCCs.

Methods: The subjects were 16 alcoholics who had hepatic nodules and were hepatitis B surface antigen negative and hepatitis C virus antibody negative and were classified into two groups: (1) the HBV group with hepatitis B surface antibody and/or hepatitis B core antibody and (2) the alcoholic group without these antibodies. Computed tomography (CT), magnetic resonance imaging, and tumor biopsy were conducted for all subjects, and digital subtraction angiography or CT during arterial portography and CT during arteriography were performed for all but one case.

Results: In the alcoholic group, there were no significant differences in the clinical features between the presence and absence of HCC. All nodules in the HBV group were HCCs, whereas in the alcoholic group, 6 of 16 lesions were HCCs and the others were hyperplastic nodules. Limited to the hypervascular tumors in the alcoholic group, on magnetic resonance imaging T1‐weighted images, hyperplastic nodules showed hyperintensity, whereas HCCs were iso‐ or hypointense.

Conclusion: HCCs can occur at a high rate in alcoholics, especially in those with HBV‐associated antibodies. The patients with alcoholic liver cirrhosis sometimes have hypervascular tumors that are not cancer but hyperplastic nodules, and care must be taken in their treatment.
The Effect of Information Quality on Optimal Portfolio Choice
Authors: Lundtofte Frederik
Published: April 2006

Three types of agents acting on different information sets are considered: fully informed agents, insiders, and outsiders. Differences in information quality are shown to affect the properties of their optimal portfolios. For an outsider, the share of wealth invested in the stock is decreasing in the variance of the stock. However, for an insider, the effect of an increasing stock variance on the optimal portfolio weight is ambiguous. In a calibration to U.S. data, the confidence intervals of the insider's demand for the stock converge, whereas the outsider's confidence intervals become wider.
The Original Maturity of Corporate Bonds: The Influence of Credit Rating, Asset Maturity, Security, and Macroeconomic Conditions
Authors: Bali Geetanjali , Skinner Frank S.
Published: April 2006

We examine the determinants of the new issue maturity of corporate bonds. As credit rating decreases, new bond issues have longer maturities, but substantial variation in maturity within each rating class remains. We seek to explain the variation of new issue maturity within credit classes. We find that asset maturity, security covenants, and macroeconomic conditions influence the new issue maturity of bonds within rating categories.
Block Trade Price Asymmetry and Changes in Depth: Evidence from the Australian Stock Exchange
Authors: Anderson Hamish D. , Cooper Sapphire , Prevost Andrew K.
Published: April 2006

This paper examines the price response to large block transactions on the Australian Stock Exchange during the 1999 sample period. We find asymmetry in the price reaction between buyer‐ and seller‐initiated trades with respect to size and resiliency following the trade. We extend previous research by examining order book changes surrounding block trades and relating price effects to changes in book depth. Purchases are associated with persistent order book imbalance, while the sales imbalance is insignificant. Cross‐sectional analysis demonstrates that price resiliency following a trade is related to the speed at which limit orders arrive to replenish book depth.
The Asymmetric Impact of Monetary Policy on Currency Markets
Authors: Lobo Bento J. , Darrat Ali F. , Ramchander Sanjay
Published: April 2006

This study examines whether tightening and easing actions of the Federal Reserve symmetrically influence currency markets. Using daily data on four exchange rates from 1989 to 2001, we find that changes in the Fed's interest rate target are positively related to changes in the value of the dollar. Surprises associated with monetary tightening have a larger announcement effect as compared to monetary easing for the British pound, German mark, and Canadian dollar, whereas the opposite is true for the Japanese yen. The results appear to be driven by the reactions of foreign central banks to Fed actions, the Fed's credibility as a policymaker, and by the change in the Fed's disclosure policy beginning in 1994.