bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Increase in Plasma Membrane Chloride Permeability during Wound Resealing in Starfish Oocytes
Authors: Fein Alan , Terasaki Mark
Published: July 2005

Plasma membrane wound repair is an important but poorly understood process. We used femtosecond pulses from a Ti-Sapphire laser to make multiphoton excitation–induced disruptions of the plasma membrane while monitoring the membrane potential and resistance. We observed two types of wounds that depolarized the plasma membrane. At threshold light levels, the membrane potential and resistance returned to prewound values within seconds; these wounds were not easily observed by light microscopy and resealed in the absence of extracellular Ca2+. Higher light intensities create wounds that are easily visible by light microscopy and require extracellular Ca2+ to reseal. Within a few seconds the membrane resistance is ∼100-fold lower, while the membrane potential has depolarized from −80 to −30 mV and is now sensitive to the Cl− concentration but not to that of Na+, K+, or H+. We suggest that the chloride sensitivity of the membrane potential, after wound resealing, is due to the fusion of chloride-permeable intracellular membranes with the plasma membrane.
Evidence for Sequential Ion-binding Loci along the Inner Pore of the IRK1 Inward-rectifier K+ Channel
Authors: Shin Hyeon-Gyu , Xu Yanping , Lu Zhe
Published: July 2005

Steep rectification in IRK1 (Kir2.1) inward-rectifier K+ channels reflects strong voltage dependence (valence of ∼5) of channel block by intracellular cationic blockers such as the polyamine spermine. The observed voltage dependence primarily results from displacement, by spermine, of up to five K+ ions across the narrow K+ selectivity filter, along which the transmembrane voltage drops steeply. Spermine first binds, with modest voltage dependence, at a shallow site where it encounters the innermost K+ ion and impedes conduction. From there, spermine can proceed to a deeper site, displacing several more K+ ions and thereby producing most of the observed voltage dependence. Since in the deeper blocked state the leading amine group of spermine reaches into the cavity region (internal to the selectivity filter) and interacts with residue D172, its trailing end is expected to be near M183. Here, we found that mutation M183A indeed affected the deeper blocked state, which supports the idea that spermine is located in the region lined by the M2 and not deep in the narrow K+ selectivity filter. As to the shallower site whose location has been unknown, we note that in the crystal structure of homologous GIRK1 (Kir3.1), four aromatic side chains of F255, one from each of the four subunits, constrict the intracellular end of the pore to ∼10 Å. For technical simplicity, we used tetraethylammonium (TEA) as an initial probe to test whether the corresponding residue in IRK1, F254, forms the shallower site. We found that replacing the aromatic side chain with an aliphatic one not only lowered TEA affinity of the shallower site ∼100-fold but also eliminated the associated voltage dependence and, furthermore, confirmed that similar effects occurred also for spermine. These results establish the evidence for physically separate, sequential ion-binding loci along the long inner pore of IRK1, and strongly suggest that the aromatic side chains of F254 underlie the likely innermost binding locus for both blocker and K+ ions in the cytoplasmic pore.
Resting Potential–dependent Regulation of the Voltage Sensitivity of Sodium Channel Gating in Rat Skeletal Muscle In Vivo
Authors: Filatov Gregory N. , Pinter Martin J. , Rich Mark M.
Published: July 2005

Normal muscle has a resting potential of −85 mV, but in a number of situations there is depolarization of the resting potential that alters excitability. To better understand the effect of resting potential on muscle excitability we attempted to accurately simulate excitability at both normal and depolarized resting potentials. To accurately simulate excitability we found that it was necessary to include a resting potential–dependent shift in the voltage dependence of sodium channel activation and fast inactivation. We recorded sodium currents from muscle fibers in vivo and found that prolonged changes in holding potential cause shifts in the voltage dependence of both activation and fast inactivation of sodium currents. We also found that altering the amplitude of the prepulse or test pulse produced differences in the voltage dependence of activation and inactivation respectively. Since only the Nav1.4 sodium channel isoform is present in significant quantity in adult skeletal muscle, this suggests that either there are multiple states of Nav1.4 that differ in their voltage dependence of gating or there is a distribution in the voltage dependence of gating of Nav1.4. Taken together, our data suggest that changes in resting potential toward more positive potentials favor states of Nav1.4 with depolarized voltage dependence of gating and thus shift voltage dependence of the sodium current. We propose that resting potential–induced shifts in the voltage dependence of sodium channel gating are essential to properly regulate muscle excitability in vivo.
Original Strategies of Screening, Evaluation, and Care of Adolescent Substance Abuse
Authors: Reynaud M , Karila L , Chinet L , Allen J P. , Streel E , Pelc I
Published: July 2005

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. The aim of this symposium was to discuss new and interesting strategies of screening, evaluation and care of adolescent substance abuse developed in various countries. Our speakers have had to explain these strategies and to detail and focus on the more original tools of diagnosis or way of care used in their country. This symposium described two ways for screening and assessment (one developed in France MR, LK and the other in Switzerland LC) and made the point about questionnaires and biomarkers for alcohol problems in adolescents (JPA). The symposium was concluded by the presentation of a cannabis clinic (ES, JP).
World Health Organization/International Society for Biomedical Research on Alcoholism Study on State and Trait Markers of Alcohol Use and Dependence: Back to the Future
Authors: Wurst Friedrich M. , Tabakoff Boris , Alling Christer , Aradottir Steina , Wiesbeck Gerhard A. , Müller‐Spahn Franz , Pragst Fritz , Johnson Bankole , Javors Marty , Ait‐Daoud Nassima , Skipper Gregory E. , Spies Claudia , Nachbar Yvonne , Lesch Otto , Ramskogler Katrin , Hartmann Susanne , Wolfersdorf Manfred , Dresen Sebastian , Weinmann Wolfgang , Hines Lisa , Kaiser Alan , Lu Ru‐Band , Ko Huei‐Chen , Huang San‐Yuan , Wang Tso‐Jen , Wu Yi‐Syuan , Whitfield John , Snell Larry D. , Wu Christine , Hoffman Paula L.
Published: July 2005

This article summarizes content proceedings of a symposium held at the 2004 International Society for Biomedical Research on Alcoholism Congress in Mannheim, Germany. The chairs were Boris Tabakoff and Friedrich M. Wurst. The presentations were (1) Genetic associations with alcoholism and affective disorders, by Paula Hoffman; (2) Proteomic analysis of blood constituents in alcoholism, by Boris Tabakoff; (3) Contrasts between the responses of GGT and CDT to high alcohol intake, and a test of their combined use, by John Whitfield; (4) Direct ethanol metabolites such as ethyl glucuronide, fatty acid ethyl esters, phosphatidylethanol and ethyl sulfate: a new line of sensitive and specific biomarkers, by Friedrich Martin Wurst; and (5) Genetic studies of alcoholism subtypes in a Han Taiwanese population, by Ru‐Band Lu.
Recent Advances in Alcohol‐Induced Adduct Formation
Authors: Freeman Thomas L. , Tuma Dean J. , Thiele Geoffrey M. , Klassen Lynell W. , Worrall Simon , Niemelä Onni , Parkkila Seppo , Emery Peter W. , Preedy Victor R.
Published: July 2005

This article presents the proceedings of a symposium presented at the ISBRA 12th World Congress on Biomedical Alcohol Research, held in Heidelberg/Mannheim, Germany, September 29 through October 2, 2004. The organizers of the symposium were Simon Worrall and Victor Preedy, and the symposium was chaired by Onni Niemelä and Geoffrey Thiele. The presentations scheduled for this symposium were (1) Adduct chemistry and mechanisms of adduct formation, by Thomas L. Freeman; (2) Malondialdehyde‐acetaldehyde adducts: the 2004 update, by Geoffrey Thiele; (3) Adduct formation in the liver, by Simon Worrall; (4) Protein adducts in alcoholic cardiomyopathy, by Onni Niemelä; and (5) Alcoholic skeletal muscle myopathy: a role for protein adducts, by Victor R. Preedy.
Health Economics of Addiction
Authors: Salize Hans Joachim , Mohler‐Kuo Meichun , Godfrey Christine , Holder Harold D.
Published: July 2005

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. The symposium covered some crucial of the manifold aspects in the field of health economic research of alcoholism, for example, results of cost of treatment studies, evolution of health economic research in past years, methodological problems of cost‐effectiveness studies, and the effects of tax or price policies for alcohol consumption and the increase of alcohol‐related problems. Studies from the United States, the United Kingdom, Switzerland, and Germany were presented, underlining that even in these highly industrialized countries, health economic research is far from providing the essential evidence needed for adequate service planning or effective cost containment strategies in the field of alcoholism or addiction in general.
Neuroactive Steroids and Ethanol
Authors: Purdy Robert H. , Valenzuela C Fernando , Janak Patricia H. , Finn Deborah A. , Biggio Giovanni , Bäckström Torbjörn
Published: July 2005

This article presents the proceedings of a symposium presented at the International Society for Biomedical Research on Alcoholism 12th World Congress on Biomedical Alcohol Research, held in Heidelberg/Mannheim, Germany, from September 29 to October 2, 2004. The organizer and chairperson was Robert H. Purdy. The presentations were (1) Fetal ethanol‐induced increase in brain levels of pregnenolone sulfate, by C. Fernando Valenzuela; (2) GABAergic neuroactive steroids after ethanol self‐administration and relapse, by Patricia H. Janak; (3) Neuroactive steroid modulation of ethanol intake patterns in C57BL/6J mice, by Deborah A. Finn; (4) Role of neurosteroids in ethanol dependence and GABAA receptor plasticity, by Giovanni Biggio; and (5) Alcohol and neuroactive steroid interactions in the menstrual cycle, by Torbjörn Bäckström.
Factors Mediating Alcohol Craving and Relapse: Stress, Compulsivity, and Genetics
Authors: Rodd Zachary A. , Anstrom Kristin K , Knapp Darin J. , Racz Ildiko , Zimmer Andreas , Serra Salvatore , Bell Richard L. , Woodward Donald J. , Breese George R. , Colombo Giancarlo
Published: July 2005

This article represents the proceedings of a symposium at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany. The symposium was organized by Zachary A. Rodd and Giancarlo Colombo. The presentations were (1) Pharmacological reversal of cycled withdrawal‐sensitized or stress‐sensitized withdrawal anxiety and enhanced ethanol drinking, by Darin J. Knapp and George R. Breese, (2) Alcohol craving and relapse in rats genetically selected for high alcohol preference, by Zachary A. Rodd and Richard L. Bell, (3) Exposure to stress increases dopaminergic burst firing in awake rats, by Kristin Anstrom and Donald J. Woodward, (4) Involvement of cannabinoid CB1 and GABAB receptors in the control of relapse‐like drinking in alcohol‐preferring Sardinian alcohol‐preferring rats by Giancarlo Colombo and Salvatore Serra, and (5) Stress‐induced ethanol drinking in CB1−/−, POMC, and PENK knockout mice, by Idiko Racz and Andreas Zimmer.
Health Risks of Chronic Moderate and Heavy Alcohol Consumption: How Much Is Too Much?
Authors: Meyerhoff Dieter J. , Bode Christiane , Nixon Sara Jo , de Bruin Eveline A. , Bode J Christian , Seitz Helmut K.
Published: July 2005

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. Most of what we know about the deleterious effects of alcohol in vivo has been gleaned from studies in sober alcoholics recruited from substance abuse treatment programs. Little is known about effects of chronic drinking in the moderate or heavy range encountered in a much larger fraction of modern society. Extrapolation of information on the adverse effects of chronic drinking on organ function from clinical samples to social drinkers in the general population has to be met with great skepticism, as it may lead to wrong conclusions about the chronic effects of alcohol in social drinkers. Several recent studies suggest that moderate alcohol consumption has certain beneficial health effects, whereas heavy social alcohol consumption has recently been associated with organ abnormalities and cognitive deficits. These social drinking effects have attracted great public interest; reports of benefits of moderate drinking have also inspired inappropriate publications by the media, including misleading advertisements by the alcohol producing and distributing industry. Although adverse effects of moderate to heavy drinking on heart, liver, and cancer development have attracted attention by clinicians and researchers for some time, its compromising effects on brain and cognition have only recently been studied. This symposium brought together researchers from different disciplines, who reviewed and presented new data on consequences of social drinking in the areas of clinical neuropsychology and behavior (Drs. Nixon and Meyerhoff), neurophysiology (Dr. Nixon, Ms. De Bruin), neuroimaging (Ms. de Bruin, Dr. Meyerhoff), hepatic disease (Dr. Bode), and cancer (Dr. Seitz). The symposium aimed to clarify both the potential health benefits of moderate alcohol consumption and risks of moderate and heavy drinking on proper organ function and to provide insights and new data to practicing physicians and public health authorities for education on problem drinking.
Revealing Alcohol Abuse: To Ask or to Test?
Authors: Alling C , Chick J D. , Anton R , Mayfield R D. , Salaspuro M , Helander A , Harris R A.
Published: July 2005

This article represents the proceedings of a symposium at the 2004 ISBRA Congress in Heidelberg/Mannheim, Germany. The chairs were C. Alling and R. A. Harris. The presentations were (1) Advantage and Disadvantage of Tests for Self‐Reported Intake in Different Settings, by J. D. Chick; (2) Update on the Use of Biological Markers to Monitor Outcome in Alcoholism Clinical Treatment Trials, by R. Anton; (3) Identification of Alcohol Biomarkers Using Genomic and Proteomic Approaches, by R. D. Mayfield; (4) Use of Biomarkers as Secondary or Primary Outcome Measures in Alcoholism Treatment Trials, by M. Salaspuro; and (5) Use of Tests for Drink‐Drive Offenders: A European Perspective, by A. Helander.
Mechanisms in Alcohol‐associated Carcinogenesis
Authors: Homann N , Seitz H K. , Wang X D. , Yokoyama A , Singletary K W. , Ishii H
Published: July 2005

This review represents an overview on some aspects of pathogenetic mechanisms in alcohol‐associated carcinogenesis and is based on presentations held on the symposium “Mechanisms in alcohol‐associated carcinogenesis” at the 2004 ISBRA Meeting in Heidelberg/Mannheim, Germany. The chairs were Nils Homann and Hiromasa Ishii. The presentations were (1) Genetic polymorphisms of alcohol and aldehyde dehydrogenases, mean corpuscular volume and cancer risk of the upper aerodigestive tract in Japanese by Akira Yokoyama; (2) Retinoids, alcohol and carcinogenesis by Xiang‐Dong Wang; (3) Bacterial ethanol metabolism and cancer by Nils Homann; (4) The role of ethanol metabolism in alcohol‐associated carcinogenesis by Helmut K. Seitz; (5) Alcohol and breast cancer: potential mechanisms by Keith W. Singletary.
Signal Transduction in Alcohol‐Related Diseases
Authors: Apte Minoti V. , Zima Tomá , Dooley Steven , Siegmund Sören V. , Pandol Stephen J. , Singer Manfred V.
Published: July 2005

This article summarizes the proceedings of a symposium presented at the 12th World Congress on Biomedical Alcohol Research, organized by the International Society for Biomedical Research on Alcoholism, held at the University of Heidelberg in Mannheim, Germany, in September and October 2004. The organizers and chairpersons were Manfred V. Singer and Stephen J. Pandol. The presentations were (1) Ethanol‐induced acinar cell injury, by Minoti V. Apte; (2) Oxidants and antioxidants: signal transduction and alcohol, by Thomá Zima; (3) Anti–TGF‐β strategies for the treatment of chronic liver disease, by Steven Dooley; (4) Immune mechanisms in alcohol‐induced liver disease, by Sören V. Siegmund; and (5) Alcoholic pancreatitis: insights from animal models, by Steven J. Pandol.
Alcoholic Liver Disease: From Pathophysiology to Therapy
Authors: Seitz Helmut K. , Lieber Charles S. , Stickel Felix , Salaspuro Mikko , Schlemmer Hans‐Peter , Horie Yoshimori
Published: July 2005

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. A salient feature of this symposium was to demonstrate how the striking advances made in our understanding of the pathophysiology of alcoholic liver disease are now raising prospects for better treatment as well. Genetic factors are now being elucidated, and F. Stickel (Germany) has summarized his own studies as well as those of others. M. Salaspuro (Finland) updated the possible role of gut bacteria in the pathogenesis of alcoholic liver disease, bringing us closer to antibacterial therapy as part of the treatment of alcoholic liver disease. Specifically, the gut bacterial flora may be important via the in situ production of acetaldehyde and the associated intestinal injury, which may favor the translocation of toxins from the gut lumen to the systemic circulation and the liver. The analytical progress in the assessment of alterations of phospholipid composition in liver membranes described by H. P. Schlemmer (Germany) may eventually give us an objective method to recognize patients in whom phospholipid therapy might be indicated. Other novel treatment modalities for severe alcoholic hepatitis were described by Y. Horie and H. Ishii (Japan), including plasma exchange. Finally, the pros and cons of nutraceutical therapy were analyzed by C. S. Lieber, with a demonstration that although some nutraceuticals may have toxicity exacerbated by alcohol and must be administered very carefully within a narrow therapeutic window, others are actually beneficial as demonstrated under controlled conditions.
Advances in Alcoholism Research in Germany
Authors: Schmidt L G. , Bleich S , Boening J , Buehringer G , Kornhuber J , Weijers H G. , Wiesbeck G A. , Wolfgramm J , Havemann‐Reinecke U
Published: July 2005

This article presents the proceedings of a symposium at the 2004 International Society for Biomedical Research on Alcoholism meeting in Heidelberg/Mannheim, Germany, put together by the German Society of Addiction Therapy and Research (DG‐Sucht e.V.). The aim was to give an overview on recent findings from animal to human studies that were conducted by several research groups engaged in the alcoholism field in Germany for longer periods. Results of his animal studies were presented by J. Wolfgramm; G. Buehringer reported on epidemiologic and psychotherapeutic research advances on alcohol‐related disorders in Germany. L. G. Schmidt summarized results of novel diagnostic and therapeutic approaches in alcohol dependence, and J. Boening focused on biopsychological personality traits as predictors for relapse in alcoholism. Data relating hyperhomocysteinemia and brain shrinkage in patients with alcoholism were presented by J. Kornhuber. Four addiction research networks federally funded represented their results in separate symposia and were therefore deliberately excluded from this symposium.
Effects of Systemic and Local CXC Chemokine Administration on the Ethanol‐Induced Suppression of Pulmonary Neutrophil Recruitment
Authors: Quinton Lee J. , Nelson Steve , Zhang Ping , Happel Kyle I. , Gamble Lisa , Bagby Gregory J.
Published: July 2005

Background:

Acute alcohol intoxication impairs the neutrophil response to intrapulmonary infection, resulting in impaired host defense and increased patient morbidity and mortality. We recently showed that intratracheal (IT) chemokine administration promotes pulmonary neutrophil migration in rats and that this process is enhanced by systemic administration of the Glu‐Leu‐Arg (ELR+) and CXC chemokine cytokine‐induced neutrophil chemoattractant (CINC). Here we hypothesized that exogenous chemokine administration would mitigate the suppressive effect of alcohol on neutrophil recruitment into the lung.

Methods:

Macrophage inflammatory protein‐2 (MIP‐2), a rat ELR+ CXC chemokine, or live Klebsiella pneumoniae (K. pneumoniae) was administered it to induce alveolar neutrophil migration in the absence or presence of acute ethanol intoxication. Depending on the experimental protocol, rats received either intravenous (IV) CINC or IT chemokines (CINC and MIP‐2) 20 min after it MIP‐2 or K. pneumoniae. Rats were euthanized 90 min or four hr after the first IT injection for sample collection.

Results:

Neutrophil counts were significantly elevated in bronchoalveolar lavage fluid (BALF) of rats receiving IT MIP‐2 compared with vehicle‐treated rats, and this response was significantly decreased in animals pretreated with ethanol. CINC IV enhanced the neutrophil response to IT MIP‐2 in both the absence and presence of acute ethanol intoxication. In rats challenged with K. pneumoniae, ethanol pretreatment significantly reduced BALF levels of CINC and MIP‐2, suppressed alveolar neutrophil recruitment, and decreased whole‐lung myeloperoxidase activity. CINC IV did not alter BALF neutrophil counts in the absence or presence of ethanol administration 4 hr after IT K. pneumoniae. Alternatively, IT chemokine instillation partially restored BALF neutrophil recruitment but not whole‐lung myeloperoxidase activity in ethanol‐treated rats.

Conclusions:

Ethanol significantly inhibits the pulmonary inflammatory responses to both MIP‐2 and K. pneumoniae. Exogenous chemokine administration may be a useful means to enhance host defenses in the ethanol‐intoxicated host, although the results of this study also indicate that ethanol intoxication can impair neutrophil recruitment, independent of its effects on local chemotactic gradients.
Influence of Age at Drinking Onset on Long‐Term Ethanol Self‐Administration With Deprivation and Stress Phases
Authors: Siegmund Sören , Vengeliene Valentina , Singer Manfred V. , Spanagel Rainer
Published: July 2005

Background:

Onset of alcohol use during adolescence has potentially long‐lasting consequences, e.g., prospective alcohol dependence. To obtain new insight into the effects of early chronic ethanol consumption, we compared the drinking behavior of two adult male Wistar rat groups: one that initiated alcohol consumption during adolescence (adolescent group) and the other that initiated their drinking during adulthood (adult group) in a model of long‐term alcohol self‐administration. We investigated the magnitude of the effects of deprivation and stress on alcohol intake and the influence of these events on the alcohol drinking behavior across time.

Methods:

Heterogeneous Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as 5% and 20% ethanol solutions during an observation period of 30 wk. A deprivation phase of 14 days was instituted after eight wk of access to alcohol. After 16 and 26 wk of alcohol access, all animals were subjected for three consecutive days to forced swimming and electric foot shocks, respectively.

Results:

At the onset of drinking, adolescent animals consumed less alcohol and showed lower preference than adults. The deprivation phase was followed by increased intake of highly concentrated ethanol solution without appreciable differences between age groups. Repeated swim stress produced a slight increase in ethanol consumption in both animal groups; however, alcohol intake was not significantly different between groups, whereas the foot shock stress‐induced increase in alcohol intake was significantly higher in the animal group that initiated alcohol consumption during adolescence. After swim stress, the drinking behavior of the adolescent group resembled that of the adult group. In particular, the adolescent group increased their preference for 20% ethanol solution for the remainder of the experiment.

Conclusions:

Age of voluntary alcohol drinking onset does not appear to be a strong predictor for prospective alcohol intake and relapse‐like drinking behavior under the present experimental conditions. However, male Wistar rats that initiated alcohol consumption during adolescence seem to be more susceptible to acute stressor‐specific effects in terms of alcohol consumption.
Antioxidant Pretreatment Does Not Ameliorate Alcohol‐Induced Purkinje Cell Loss in the Developing Rat Cerebellum
Authors: Grisel Jedidiah J. , Chen Wei‐Jung A.
Published: July 2005

Background:

Recent research has suggested that oxidative stress is a potential mechanism for alcohol‐induced injury and that supplementation with antioxidants can ameliorate alcohol‐induced damage. In this study, two known antioxidants, melatonin and U83836E, were assessed for their effectiveness in blocking the expected alcohol‐induced cerebellar Purkinje cell loss in neonatal rat pups.

Methods:

Sprague‐Dawley rat pups were artificially reared from postnatal days (PDs) 4–9 and were exposed to either alcohol or antioxidants (melatonin or U83836E) individually or in combination. A normal control group (raised by rat dams) was included in this study. On PD 9, the brain from each pup was removed and weighed, and the cerebellar vermis was processed for stereological cell counting.

Results:

Alcohol exposure during the brain growth spurt produced microencephaly, in addition to significant decreases in the number and density of Purkinje cells in lobule I and the volume of lobule I. The antioxidants did not reduce any of the adverse effects observed from alcohol exposure, and they did not decrease the Purkinje cell number when administered alone. Furthermore, antioxidants did not change the only blood alcohol concentration measured on PD 6.

Conclusions:

The results confirmed alcohol‐induced microencephaly and cerebellar Purkinje cell loss from neonatal alcohol exposure, and they showed that neither antioxidant could attenuate these adverse effects on the developing brain. The inability of antioxidants to reduce Purkinje cell loss from neonatal alcohol exposure suggests the existence of alternative mechanisms for developmental alcohol‐induced Purkinje cell loss.
A Temporal and Dose‐Response Association Between Alcohol Consumption and Medication Adherence Among Veterans in Care
Authors: Braithwaite R Scott , McGinnis Kathleen A. , Conigliaro Joseph , Maisto Stephen A. , Crystal Stephen , Day Nancy , Cook Robert L. , Gordon Adam , Bridges Michael W. , Seiler Jason F. S. , Justice Amy C.
Published: July 2005

Background:

Previous studies have shown that alcohol consumption is associated with decreased medication adherence, but this association may be confounded by characteristics common among those who drink heavily and those who fail to adhere (e.g., illicit drug use). Our objective was to determine whether there are temporal and dose‐response relationships between alcohol consumption and poor adherence.

Methods:

We administered telephone interview surveys to participants in the Veterans Aging Cohort Study, an eight‐site observational study of HIV& and matched HIV‐ veterans in care, to determine whether alcohol consumption on a particular day was associated with nonadherence to prescribed medications on that same day. We used the Time Line Follow Back to measure alcohol consumption and the Time Line Follow Back Modified for Adherence to measure adherence. Individuals were categorized as abstainers (no alcohol in past 30 days), nonbinge drinkers (alcohol in past 30 days but ≤four standard drinks on each day), or binge drinkers (≥five standard drinks on at least one day).

Results:

Among 2702 respondents, 1582 (56.6%) were abstainers, 931 (34.5%) were nonbinge drinkers, and 239 (8.9%) were binge drinkers. Abstainers missed medication doses on 2.4% of surveyed days. Nonbinge drinkers missed doses on 3.5% of drinking days, 3.1% of postdrinking days, and 2.1% of nondrinking days (p < 0.001 for trend), and this trend was more pronounced among HIV+ individuals than HIV‐ individuals. Binge drinkers missed doses on 11.0% of drinking days, 7.0% of postdrinking days, and 4.1% of nondrinking days (p < 0.001 for trend), and this trend was comparably strong for HIV+ and HIV‐ individuals.

Conclusions:

Among veterans in care, self‐reported alcohol consumption demonstrates a temporal and dose‐response relationship to poor adherence. HIV+ individuals may be particularly sensitive to alcohol consumption.
Alcohol Consumption, Lung Function, and Quality of Life in Pneumoconiosis
Authors: Tang Wai Kwong , Lum C M. , Ungvari Gabor S. , Chiu Helen F. K.
Published: July 2005

Background:

To our knowledge, there are no previous data on drinking problems in patients with pneumoconiosis. The aim of this study was to examine drinking patterns and the impact of drinking on lung function and health‐related quality of life (HRQOL) in Chinese patients with pneumoconiosis.

Methods:

Three hundred patients with pneumoconiosis were recruited from a community‐based case registry. The HRQOL was measured with the St. George's Respiratory Questionnaire (SGRQ). Pulmonary function, comorbidity, and psychosocial variables were also assessed. The alcohol use of the patients was evaluated with the Alcohol Use Disorders Identification questionnaire.

Results:

Of the 300 patients, 72.3% (217) reported that they had not consumed any alcohol during the past year, whereas 83 patients (27.7%) did report drinking alcohol. In the drinking group, 88.0% (73) consumed <7 standard drinks per week, and none of them exceeded the safety limit of 21 standard drinks per week. The drinking group (n= 83) was younger, had less concurrent medical diseases, and lower (i.e., better) unadjusted SGRQ symptom, activity, impact, and total scores than the nondrinking group (n= 217). The SGRQ scores, which were adjusted for age, duration of occupation, concurrent medical diseases, smoking status, and forced expiratory volume in 1 sec predicted tests (FEV1%), remained significantly lower for the drinking group. Although the drinking group had a higher unadjusted FEV1% predicted, the difference between the FEV1% of the two groups, after adjustment for covariates, was of borderline significance only.

Conclusions:

Most Chinese patients with pneumoconiosis in this study did not consume alcohol, and among those who did, the level of alcohol consumption was low. This low level of alcohol consumption was associated with a better HRQOL and possibly with better lung function.
Manipulations of Serotonin Function in the Nucleus Accumbens Core Produce Differential Effects on Ethanol and Sucrose Seeking and Intake
Authors: Czachowski Cristine L.
Published: July 2005

Objective:

Behaviorally relevant stimuli, including alcohol, are processed through the nucleus accumbens/ventral tegmental area (VTA)/prefrontal cortex circuit. It is hypothesized that serotonin affects ethanol‐directed behaviors by interacting with this system via projections from the dorsal raphe to the nucleus accumbens and VTA. The current studies utilized two different operant paradigms, one focusing on reinforcer seeking and one focusing on reinforcer self‐administration (both with an ethanol and a sucrose solution as the reinforcer) to elucidate serotonin‐specific regulation of these behaviors.

Methods:

The present experiments assessed the effects of microinjections of a serotonin1B agonist (CGS12066B) and a serotonin1A agonist (8‐OH‐DPAT) in the nucleus accumbens core on ethanol‐ and sucrose‐reinforced seeking and intake. In four separate experiments, male Long‐Evans rats were trained to complete a single response requirement that resulted in access to 10% ethanol or 2% sucrose for a 20‐min drinking period.

Results:

Before microinjections, ethanol‐reinforced subjects were consuming an average of 0.5‐0.95 g/kg ethanol and making 50‐100 responses during intermittent nonreinforced sham (no drug) sessions (sucrose groups had similar baseline response levels). In summary, findings from the four experiments showed the following: (1) manipulations of serotonin function that had effects on ethanol‐reinforced responding had either no effect or less pronounced effects on sucrose‐reinforced responding; (2) administration of the serotonin1B agonist decreased seeking behaviors to a greater degree than drinking behaviors; and (3) administration of the serotonin1A agonist decreased ethanol intake but not seeking with no impact at all on sucrose‐reinforced behaviors.

Conclusions:

Manipulations of serotonin activity in the nucleus accumbens core had little effect on sucrose‐reinforced behaviors and differential effects on ethanol seeking versus intake, suggesting that this area may play a complex but selective role in the stimulus processing of external and internal alcohol‐associated cues.
The −159C/T Polymorphism in the Promoter Region of the CD14 Gene Is Associated With Advanced Liver Disease and Higher Serum Levels of Acute‐Phase Proteins in Heavy Drinkers
Authors: Campos Joaquin , Gonzalez‐Quintela Arturo , Quinteiro Celsa , Gude Francisco , Perez Luis‐Fernando , Torre Jose‐Antonio , Vidal Carmen
Published: July 2005

Background:

Innate inflammatory responses to endotoxin (lipopolysaccharide) contribute to the development of alcoholic liver disease (ALD). A single‐nucleotide polymorphism (−159C/T) in the promoter region of the gene coding for CD14 (a lipopolysaccharide receptor) could be associated with the development of ALD. We sought too investigate the relationship between the CD14/−159C/T polymorphism and advanced ALD and acute‐phase protein levels in heavy drinkers.

Methods:

A total of 138 heavy drinkers consecutively admitted to an Internal Medicine department were genotyped for the CD14/−159C/T polymorphism. Serum samples were analyzed for lipopolysaccharide‐binding protein (LBP), soluble CD14 (sCD14), C‐reactive protein (CRP), and immunoglobulin (Ig) A, IgG, and IgM. Patients with ascites or liver encephalopathy (n= 35) were classified as having advanced ALD.

Results:

After adjusting for potential confounding variables, the CD14/‐159TT genotype was positively associated with advanced ALD (odds ratio, 2.99; 95% confidence interval, 1.09–8.24, p= 0.03) and serum LBP (p= 0.01) and sCD14 (p= 0.04) levels. The CD14/−159C/T polymorphism was not associated with serum levels of CRP, IgA, IgG, or IgM.

Conclusions:

Our results support the notion that CD14/−159TT homozygous heavy drinkers have higher levels of the LPS‐binding acute‐phase proteins (LBP and sCD14) than do carriers of the CD14/−159C allele. Also, the CD14/−159TT genotype may be a risk factor for advanced ALD.
Development of a Chinese Version of the Yale‐Brown Obsessive Compulsive Scale for Heavy Drinking
Authors: Gau Susan S. F. , Liu Chia‐Yih , Lee Chau‐Shoun , Chang Jung‐Chen , Chang Ching‐Jui , Li Chang‐Fang , Chen Chiao‐Chicy , Cheng Andrew T. A.
Published: July 2005

Background:

Measurement of craving is an important component in the investigation of the etiology and clinical pictures of alcoholism and dependence of other substances in different cultures. The aim of this study was to develop a Chinese version of the Yale‐Brown Obsessive Compulsive Scale for heavy drinking (YBOCS‐hd‐C), the instrument most frequently used in assessing the severity of alcohol craving in Taiwan.

Methods:

Four hundred twenty Han Chinese (220 with alcohol use disorders) and 218 Bunun aborigines (150 with alcohol use disorders) in Taiwan were interviewed by mental health professionals with the YBOCS‐hd‐C and a Chinese version of the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry to establish the psychiatric diagnosis. Validity and reliability of the YBOCS‐hd‐C were examined.

Results:

The YBOCS‐hd‐C was found to have acceptable interrater reliability (intraclass correlation, 0.89–0.96), internal consistency (Cronbach's α= 0.99), construct validity, concurrent validity, and cross‐cultural validity. The correlations between 10 items of the YBOCS‐hd‐C and 11 items of the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry adjusted for age, gender, and ethnicity ranged from 0.39 to 1.00. The YBOCS‐hd‐C also discriminated effectively among individuals with alcohol dependence, alcohol abusers, and normal drinkers.

Conclusions:

This study demonstrated that the YBOCS‐hd‐C is a reliable and valid instrument for assessing the extent of craving for alcohol in Taiwanese Han and Bunun individuals.
Hangover Susceptibility in Relation to Aldehyde Dehydrogenase‐2 Genotype, Alcohol Flushing, and Mean Corpuscular Volume in Japanese Workers
Authors: Yokoyama Masako , Yokoyama Akira , Yokoyama Tetsuji , Funazu Kazuo , Hamana Genichi , Kondo Shuji , Yamashita Takeshi , Nakamura Haruo
Published: July 2005

Background:

A study of Asian‐American students suggested a positive association between inactive ALDH2*2 and susceptibility to hangover. A biomarker for moderate‐to‐heavy drinking in persons with inactive aldehyde dehydrogenase‐2 (ALDH2) is increased mean corpuscular volume (MCV).

Methods:

Associations between hangover and ALDH2 genotype, alcohol flushing, and MCV were examined for 251 Japanese workers (139 men, 112 women).

Results:

Inactive ALDH2*1/2*2 heterozygotes drank less alcohol than active ALDH2*1/2*1 homozygotes (p < 0.0001), but the frequency of hangover did not significantly differ between the two groups for either gender. The amount of drinking reported to lead to hangover was significantly less for male and female ALDH2*1/2*2 heterozygotes than for their ALDH2*1/2*1 homozygous counterparts (p < 0.005). The proportion of men who had hangover three times or more during the past year increased significantly with increased daily alcohol consumption in men with the ALDH2*1/2*2 genotype (p= 0.0002) but not in those with the ALDH2*1/2*1 genotype. For men who usually consumed <44 g of ethanol/day, the median amount of drinking before hangover was significantly lower for ALDH2*1/2*2 men than for ALDH2*1/2*1 men reporting the same level of consumption. Hangover occurred with consistently high frequency among ALDH2*1/2*1 men, regardless of their daily consumption. Similar findings were observed in a comparison of men who never flushed and those who reported current or former flushing, a surrogate marker of inactive ALDH2. Assessment of hangover risk by quartiles of MCV showed that men with MCV of ≥96 had a significantly higher risk of hangover than did men with MCV of <91 (odds ratio = 5.56; 95% confidence interval = 1.69‐18.25).

Conclusions:

Inactive heterozygous ALDH2, alcohol flushing, and increased MCV were positively associated with hangover susceptibility in Japanese workers, suggesting that acetaldehyde is etiologically linked to the development of hangover.
Hormone Responses to Social Stress in Abstinent Alcohol‐Dependent Subjects and Social Drinkers with No History of Alcohol Dependence
Authors: Munro Cynthia A. , Oswald Lynn M. , Weerts Elise M. , McCaul Mary E. , Wand Gary S.
Published: July 2005

Background:

Previous studies have described blunted stress hormone responses after pharmacological activation of the hypothalamic‐pituitary‐adrenal (HPA) axis in sober alcoholics. The aim of the present study was to compare ACTH, cortisol, and prolactin responses to a psychological stressor in abstinent alcohol‐dependent subjects matched to healthy control subjects.

Methods:

Individuals who met DSM‐IV diagnostic criteria for a history of alcohol dependence but not for other axis I disorders were included in the study (n= 18; mean duration of abstinence ± SEM, 3.5 ± 5.7 years). Social drinkers (n= 23) served as control subjects. The sober alcohol‐dependent and control subjects were matched for demographic measures including levels of stress symptoms. All subjects underwent the Trier Social Stress Test (TSST), a laboratory‐based psychological stressor. Prestress and poststress plasma ACTH, cortisol, and prolactin levels, as well as a self‐report measure of anxiety (State‐Trait Anxiety Inventory), were obtained.

Results:

Nondepressed, abstinent alcoholics and control subjects did not differ with regard to age, racial composition, or baseline or poststress ratings of anxiety. Whereas ACTH and cortisol levels increased in response to the TSST, prolactin levels did not. Stress hormone response curves for the three hormones did not differ between the alcoholics and control subjects.

Conclusions:

When matched for levels of stress, a laboratory‐based psychological stress test did not induce differential hormone response curves for abstinent alcoholics and control subjects.
Ethanol Triggers Neural Crest Apoptosis through the Selective Activation of a Pertussis Toxin–Sensitive G Protein and a Phospholipase Cβ–Dependent Ca2+ Transient
Authors: Garic‐Stankovic Ana , Hernandez Marcos R. , Chiang Po Jen , Debelak‐Kragtorp Katherine A. , Flentke George R. , Armant D Randall , Smith Susan M.
Published: July 2005

Background:

Alcohol is a potent neurotoxin that triggers the selective apoptosis of neuronal populations in the developing fetus. For neural crest cells, clinically relevant ethanol levels (0.3%) rapidly elicit a phospholipase C (PLC)–dependent intracellular Ca2+ transient that is sufficient to activate apoptosis. We investigated the biochemical origins of this Ca2+ transient.

Methods:

Three somite chick embryos (stage 8‐) were pretreated with agonists and antagonists of PLC signaling pathways before ethanol challenge. The resulting intracellular Ca2+ release was quantified using Fluo‐3; apoptosis was assessed using vital dyes.

Results:

Pretreatment of embryos with PLC antagonists U73122 or ET‐18‐OCH3 confirmed that a phosphoinositide‐specific PLC was required for both the ethanol‐dependent Ca2+ transient and subsequent cell death. Ethanol rapidly elevated intracellular inositol‐1,4,5‐trisphosphate Ins(1,4,5)P3 levels in the rostral portion of the embryo that contains neural crest progenitors. The Ins(1,4,5)P3 receptor antagonist xestospongin C blocked the appearance of the ethanol‐dependent Ca2+ transient. Pretreatment with the pan‐Gα protein antagonist GDPβS, but not with the tyrosine kinase antagonist genistein, suppressed ethanol's ability to elicit the Ca2+ transient, suggesting that a rise in PLC activity and Ins(1,4,5)P3 concentration originates from stimulation of heterotrimeric G proteins. To probe the identity of this G protein, embryos were treated with G protein antagonists. Pertussis toxin and NF023 suppressed the ethanol‐induced Ca2+ transient and subsequent neural crest apoptosis, whereas suramin was weakly inhibitory. C3 exoenzyme was embryolethal over a wide concentration range, consistent with suggestions that Rho family GTPases participate in neural crest development. Gαi2 was identified by immunostaining in the neural crest cells.

Conclusion:

We propose a role for Gαi/o protein activation and subsequent interaction of Gβγ with PLCβ in mediating the proapoptotic effects of ethanol upon the developing neural crest.
Suppression of the HPA Axis Stress‐Response: Implications for Relapse
Authors: Adinoff Bryon , Junghanns Klaus , Kiefer Falk , Krishnan‐Sarin Suchitra
Published: July 2005

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic‐pituitary‐adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress‐responses of the HPA axis in abstinent alcohol‐dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol‐dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one‐month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol‐dependent or at‐risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the medication groups, but not the placebo group. Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan‐Sarin described her preliminary work, in which family‐history positive (FH+) and family history negative (FH‐) subjects were administered naltrexone, followed by an assessment of alcohol‐induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH‐, subjects. Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcohol‐dependent subjects, and disinhibition of the axis with medication may have therapeutic potential.
Theory of quantum space-time
Authors: Brody Dorje C , Hughston Lane P
Published: July 2005

A generalized equivalence principle is put forward according to which
space-time symmetries and internal quantum symmetries are indistinguishable before symmetry breaking
. Based on this principle, a higher-dimensional extension of Minkowski space is proposed and its properties examined. In this scheme the structure of space-time is intrinsically quantum mechanical. It is shown that the causal geometry of such a quantum space-time (QST) possesses a rich hierarchical structure. The natural extension of the Poincaré group to QST is investigated. In particular, we prove that the symmetry group of this space is generated in general by a system of irreducible Killing tensors. After the symmetries are broken, the points of the QST can be interpreted as
space-time valued operators
. The generic point of a QST in the broken symmetry phase then becomes a Minkowski space-time valued operator. Classical space-time emerges as a map from QST to Minkowski space. It is shown that the general such map satisfying appropriate causality-preserving conditions ensuring linearity and Poincaré invariance is necessarily a density matrix.