bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase synchronization in unidirectionally coupled chaotic ratchets
Authors: Vincent U. E. , Njah A. N. , Akinlade O. , Solarin A. R. T.
Published: October 2004

We study chaotic phase synchronization of unidirectionally coupled deterministic chaotic ratchets. The coupled ratchets were simulated in their chaotic states and perfect phase locking was observed as the coupling was gradually increased. We identified the region of phase synchronization for the ratchets and show that the transition to chaotic phase synchronization is via an interior crisis transition to strange attractor in the phase space.
The Form, Style, and Use of Cartographic Visualisations in European Spatial Planning: Examples from England and Germany
Authors: Dühr Stefanie
Published: October 2004

In most traditions of spatial planning in Europe, planning policy documents involve a symbolic representation of the territory in the form of icons, diagrams, and maps. There are, however, significant national and regional differences in the use of cartographic visualisations in strategic spatial planning in European countries, which can cause problems when several countries come together to discuss policy options for a transnational territory, as for the preparation of the European Spatial Development Perspective. In an attempt to understand better the differences in visualising spatial policy in different planning traditions, this paper reports on findings from an analysis of the form of cartographic visualisations in strategic spatial planning documents in England and Germany. In particular, differences in the written and visual representations of spatial policies, and the ‘scientific’ or ‘artistic’ representation on policy maps are considered. The findings show that, although the function of plans in the planning system ultimately determines the form and style of visualisations, traditional and ‘scientific’ representations seem to dominate planning at regional level in these countries, and experiences with an ‘artistic’ style of visualisation are limited. The paper concludes with a discussion of the relevance of these findings for transnational spatial policy processes, where a communication-oriented use of cartographic visualisations appears most appropriate.
Urban versus Rural Firms: Is there a Spatial Heterogeneity of Labour Demand?
Authors: Huiban Jean-Pierre , Détang-Dessendre Cécile , Aubert Francis
Published: October 2004

This paper analyses the spatial heterogeneity of labour demand. Our main assumption is that for each location there is a combination of factors which is the most efficient, given the endowment of the location in terms of technology access and the relative cost of factors. We estimate our model using a panel of more than 1000 industrial firms over a six-year period. The contribution of skilled labour is emphasised in the firms located in urban areas, unskilled labour in rural firms, and capital in periurban units. The functional distribution of jobs also plays a discriminating role: direct production and similar functions seem to be more concentrated in periurban and rural areas, whereas tertiary functions are clearly assigned to urban units. We then make conclusions as to the existence of different technical paths of growth, with high productivity growth and a dramatic decline of demand for unskilled labour in urban areas, and the maintenance of a labour-intensive method of production in rural areas.
New Agendas for Appraisal: Reflections on Theory, Practice, and Research
Authors: Owens Susan , Rayner Tim , Bina Olivia
Published: October 2004

Appraisal—defined here to include a variety of ex ante techniques and procedures that seek to predict and evaluate the consequences of certain human actions—has been afforded an increasingly important role in environmental policy. We argue in this paper, however, that both the nature of appraisal and its role in the political process have been inadequately conceptualised. Exploring a literature that has tended to polarise ‘technical’ and ‘deliberative’ models, we identify a need for sensitive selection and combination of approaches, taking account of both the object and the objective of appraisal in particular contexts. We suggest that an important role for appraisal (by design or by default) may be that of providing spaces for dialogue and learning in the making of policies and decisions. A better understanding of such processes requires further research, particularly well-designed longitudinal work involving retrospective and ‘real time’ studies of appraisal in practice.
Conservatives and Champions: River Managers and the River Restoration Discourse in the United Kingdom
Authors: Adams William M , Perrow Martin R , Carpenter Angus
Published: October 2004

We discuss two contrasting discourses of environmental management for the management of rivers and floodplain environments in the United Kingdom. Through the 1990s a long-established flood defence discourse gave way to a new discourse of river and floodplain restoration. We draw on qualitative interviews with river managers to set out these discourses, and consider the engagement between them. We consider particularly the way in which flood defence engineers have resisted and gradually been won over to aspects of the new restoration discourse, and the role of champions in that discourse transition.
‘Scale’ and the Instituted Construction of the Urban: Contrasting the Cases of Manchester and Lyon
Authors: Randles Sally , Dicken Peter
Published: October 2004

This paper combines recent advances which appreciate the ontological intricacies of scale; with the (re)turn of institutional perspectives on social and economic life and its governance. The authors use these perspectives to understand better questions of contingency, difference, and indeed convergence when comparing the historical process of scale construction and political governance (both institution building and image/narrative building) in two European cities. The paper thus reveals contrasting scalar strategies of interurban competition in two city case studies. The authors first outline the main theoretical and conceptual developments in the now burgeoning literature on scale, adding that in their opinion the perpetual construction and reconstruction of scale is not only an example of socially instituted process, but also one of constructed variety. The authors go on to propose a musical metaphor—a keyboard of scale—to capture the properties of simultaneity, elasticity, and multiplicity in scale construction, and use this metaphor to frame the discussion of the two cases. The authors conclude that when comparing cities—indeed all superficially commensurable territorial units—we must be sensitive to the specificity of scale construction in each and every instance. For example, the cases reported here demonstrate that a range of meanings shelter under the umbrella of the ‘urban’. Moreover, these meanings are reconstituted and reconfigured through history.
Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvβ1.1 A-type K
+
channels
Authors: Jow Flora , Zhang Zhi-Hao , Kopsco David C. , Carroll Karen C. , Wang KeWei
Published: October 2004

Voltage-gated Kv1.1/Kvβ1.1 A-type channels, as a natural complex, can switch from fast to slow inactivation under oxidation/reduction conditions. The mode-switching of inactivation, which is mediated by a cysteine residue in the inactivation ball domain of the Kvβ1.1 N terminus, can regulate membrane electrical excitability. In the present study, we identified a mechanism whereby inactivation in Kv1.1/Kvβ1.1 channels is regulated by calcium influx. The rise in intracellular calcium, due to either influx from extracellular space or release from intracellular stores, eliminates fast inactivation induced by Kvβ1.1, resulting in slower inactivation and increased steady-state current. This oxidation-independent calcium effect is mediated through the Kvβ1.1 N terminus, not the C terminus. We propose that a coupling between calcium influx and inactivation of voltage-gated A-type K
+
channels occurs as a result of membrane depolarization and may contribute to afterhyperpolarization as negative feedback to control neuronal excitability.
Microarray-based rapid cloning of an ion accumulation deletion mutant inArabidopsis thaliana
Authors: Gong Ji-Ming , Waner David A. , Horie Tomoaki , Li Shi Lun , Horie Rie , Abid Khush B. , Schroeder Julian I.
Published: October 2004

Here we describe the development of a microarray-based mapping strategy to rapidly isolate deletion mutant genes. The presented approach is particularly useful for mapping mutant genes that are difficult to phenotype. This strategy uses masking bulk segregant analysis to mask unrelated deletions, thus allowing identification of target deletions by microarray hybridization of pooled genomic DNA from both WT and mutant F2populations. Elemental profiling has proven to be a powerful tool for isolation of nutrient and toxic metal accumulation mutants inArabidopsis.Using microarray mapping, a sodium overaccumulation mutant FN1148 was identified as having a 523-bp genomic deletion within the second exon and intron of theAtHKT1gene. Further cosegregation, complementation, and comparative analyses among different salt-sensitive mutants confirmed that the deletion within theAtHKT1gene is responsible for the sodium overaccumulation in shoots and leaf sodium sensitivity of the FN1148 mutant. These results demonstrate that microarray-based cloning is an efficient and powerful tool to rapidly clone ion accumulation or other genetic deletion mutants that are otherwise difficult to phenotype for mapping, such as metabolic or cell signaling mutants.
The integrin α-subunit leg extends at a Ca2+-dependent epitope in the thigh/genu interface upon activation
Authors: Xie Can , Shimaoka Motomu , Xiao Tsan , Schwab Pascale , Klickstein Lloyd B. , Springer Timothy A.
Published: October 2004

Two activation-dependent Abs to the integrin αL-subunit were used to study conformational rearrangement of αLβ2on the cell surface. Activation lowered the concentration of Ca2+required for maximal expression of each epitope. Each Ab requires the Ca2+-binding loop in the integrin genu and nearby species-specific residues in the thigh domain. Key thigh residues are shielded from Ab in the bent integrin conformation by the α-subunit calf-1 domain and the nearby bent β leg, suggesting that extension at the genu is required for epitope exposure. Activating stimuli and α/β I-like small molecule antagonists demonstrate that exposure of epitopes in the integrin α- and β-subunit legs is coordinate during integrin activation. A coordinating residue donated by the calf-1 domain is as important as Ca2+for mAb binding. Together with inspection of the αVstructure, this result suggests that the genu/calf-1 interface is maintained in integrin activation, and that extension occurs by a rearrangement at the thigh/genu interface.
Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching
Authors: Li Ziqiang , Luo Zhonghui , Scharff Matthew D.
Published: October 2004

Class switch recombination (CSR) allows B cells to make effective protective antibodies. CSR involves the replacement of the μ constant region with one of the downstream constant regions by recombination between the donor and recipient switch (S) regions. Although histone H3 hyperacetylation in recipient S regions was recently reported to coincide with CSR, the relative histone H3 and H4 acetylation status of the donor and recipient S regions and the relationship between the generation of mutations and histone hyperacetylation in S regions have not been addressed. Here we report that histone H3 and H4 were constitutively hyperacetylated in the donor Sμ region before and after different mitogen and cytokine treatments. We observed an increased frequency of mutations in hyperacetylated Sγ DNA segments immunoprecipitated with anti-acetyl histone antibodies. Furthermore, time course experiments revealed that the pattern of association of RNA polymerase II with S regions was much like that of H3 hyperacetylation but not always like that of H4 hyperacetylation. Collectively, our data suggest that H3 and H4 histone hyperacetylation in different S regions is regulated differently, that RNA polymerase II distribution and H3 hyperacetylation reflect the transcriptional activity of a given S region, and that transcription, hyperacetylation, and mutation are not sufficient to guarantee CSR. These findings support the notion that there are additional modifications and/or factors involved in the complex process of CSR.
Metal ion-mediated polymer superquenching for highly sensitive detection of kinase and phosphatase activities
Authors: Rininsland Frauke , Xia Wensheng , Wittenburg Shannon , Shi Xiaobo , Stankewicz Casey , Achyuthan Komandoor , McBranch Duncan , Whitten David
Published: October 2004

An assay technology for high-throughput screening of kinase and phosphatase activities is introduced. The format is based upon superquenching of fluorescent-conjugated polymers by dye-labeled kinase/phosphatase peptide substrates. The sensor platform is composed of highly fluorescent-conjugated polyelectrolytes colocated with the phosphate coordinating metal ion gallium on microspheres. Phosphorylated peptide substrates containing a quencher bind specifically to the metal ions by means of phosphate groups, resulting in quench of polymer fluorescence. The modulation of fluorescence signal is proportional to kinase or phosphatase activity and is monitored as a turn-off or turn-on signal, respectively. The assay is homogeneous and simple and can be run either as an endpoint measurement or in a kinetic mode. The assay meets the sensitivity required for high-throughput screening of kinase or phosphatase inhibitors and is a valuable tool for drug discovery. A modified version of the assay allows for the detection of protein phosphorylation.
Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity
Authors: Harada Hisashi , Quearry Bonnie , Ruiz-Vela Antonio , Korsmeyer Stanley J.
Published: October 2004

The “BH3-only” proapoptotic BCL-2 family members initiate the intrinsic apoptotic pathway. A small interfering RNA knockdown of BIM confirms this BH3-only member is important for the cytokine-mediated homeostasis of hematopoietic cells. We show here that the phosphorylation status of BIM controls its proapoptotic activity. IL-3, a hematopoietic survival factor, induces extracellular signal-regulated kinase/mitogen-activated protein kinase-mediated phosphorylation of BIM on three serine sites (S55, S65, and S100). After IL-3 withdrawal, only nonphosphorylated BIM interacts with the multidomain proapoptotic effector BAX. Phosphorylation of BIM on exposure of cells to IL-3 dramatically reduces the BIM/BAX interaction. A nonphosphorylatable BIM molecule (S55A, S65A, and S100A) demonstrates enhanced interaction with BAX and enhanced proapoptotic activity. Thus, ERK/mitogen-activated protein kinase-dependent phosphorylation of BIM in response to survival factor regulates BIM/BAX interaction and the pro-death activity of BIM.
Spectral Doppler and resistive index: A promising tool in ultrasonographic evaluation of inflammation in rheumatoid arthritis
Authors: Terslev L. , Torp-Pedersen S. , Qvistgaard E. , Bliddal H.
Published: October 2004

Purpose: To evaluate the use of spectral Doppler in the longitudinal follow-up of inflammatory joint involvement in rheumatoid arthritis (RA) by comparing resistive index (RI) findings with color fraction and pain on a visual analog scale (VAS).

Material and Methods: Five patients on unchanged disease modifying anti-rheumatic drugs (DMARD) treatment were followed after an intra-articular corticosteroids injection and received no further injections in the observation period. They were followed clinically and by ultrasound using color Doppler pixels and the spectral Doppler RI as indicators of inflammation. At 1, 6 and 12 months the measurements were repeated on the same joint.

Results: At 1-month follow-up after the corticosteroids injection, a marked decrease in the color fraction was seen in 4 out of 5 patients, while the fifth patient had a moderate decrease (Wilcoxon p < 0.05). The changes in RI showed correspondingly a marked increase in 4 out of 5 patients indicating a diminished flow to the synovium (Wilcoxon p < 0.05). The effect of the corticosteroid injection could still be seen after 1 year in 4 out of 5 patients. In RI, pixel fraction and VAS there was improvement compared with the baseline values; however, only the pixel fraction was statistically significant (Wilcoxon p < 0.05).

Conclusion: RI seems to be an objective alternative to pixel estimation of the degree of inflammation and treatment response in RA.
Three-dimensional respiratory-gated coronary MR angiography with reference to X-ray coronary angiography
Authors: Ikonen A. E. J. , Manninen H. I. , Vainio P. , Hirvonen T. P. J. , Vanninen R. L. , Matsi P. J. , Soimakallio S. , Hartikainen J. E. K.
Published: October 2004

Purpose: To assess the clinical value of three-dimensional coronary MR angiography (CMRA) in the detection of significant coronary artery stenosis using conventional X-ray angiography as the standard reference.

Material and Methods: Sixty-nine patients underwent X-ray coronary angiography and CMRA because of suspected or previously diagnosed coronary artery disease. MRI was performed with a 1.5-T whole body imaging system using ECG-triggered 3D gradient echo sequence with retrospective navigator echo respiratory gating and fat suppression.

Results: A total of 276 coronary artery segments were analyzed. The X-ray coronary angiography was normal in 22 patients. Significant proximal stenoses (exceeding 50%) or occlusions were present in 102 coronary artery segments. In all, 120 stenoses or occlusions were identified in CMRA. Sixteen percent of the coronary artery segments had to be excluded because of poor image quality. The overall sensitivity and specificity for MRA for identification of significant stenosis were 75% and 62%, respectively. CMRA correctly detected 89% of patients with at least one vessel disease, but 6 patients with coronary artery disease would have been missed.

Conclusions: Because of the high data exclusion and false- negative case rate, CMRA with retrospective navigator echo triggering is at present not suitable as a clinical screening method in coronary artery disease.
Serial Analysis of Antimitochondrial Antibody in Patients with Primary Biliary Cirrhosis
Authors: Benson Gordon D. , Kikuchi Kentaro , Miyakawa Hiroshi , Tanaka Atsushi , Watnik Mitchell R. , Gershwin M. Eric
Published: October 2004

Antimitochondrial antibodies (AMAs) are the classic serologic
marker in primary biliary cirrhosis (PBC). However, there have been only
limited attempts to study changes in titer or isotype analysis of such AMAs in
patients followed for long periods of time

We took advantage of stored sera from well‐characterized patients with
PBC followed for a period of 7‐28 years (mean duration of 13.5 years). Immunoblot
and enzyme‐linked immunosorbant assays were performed against PDC‐E2,
BCOADC‐E2 and OGDC‐E2 as well as isotype analysis of antigen‐specific IgG,
IgA and IgM antibodies against each of these mitochondrial autoantigens. Sera
were analyzed for total IgG, IgA and IgM by radial immunodiffusion. The sera titer
of AMAs was significantly higher in younger patients with PBC. Indeed, age of onset
of clinical PBC was a significant predictor for the highest values of sera AMAs. In
contrast, the AMA titer did not significantly change over time in this prolonged
longitudinal study. The total sera levels of the individual immunoglobulins did not
show a time‐dependent change, when based on age of onset of the disease. Higher
titers of AMAs were noted in the younger patients. Furthermore, despite this long
follow‐up, there was no evidence for a significant change in AMA levels; also, levels
were not influenced by drug therapy used during the period of observation.
Inhibition of IL‐1β and TNF‐α Secretion from Resting and Activated Human Immunocytes by the Homeopathic Medication Traumeel® S
Authors: Porozov Svetlana , Cahalon Liora , Weiser Michael , Branski David , Lider Ofer , Oberbaum Menachem
Published: October 2004

Abstract
Traumeel® S (Traumeel), a mixture of highly diluted
(10-1‐10-9) extracts from
medicinal plants and minerals is widely used in humans to relieve trauma, inflammation
and degenerative processes. However, little is known about its possible effects on
the behavior of immune cells. The effects of Traumeel were examined in vitro on the ability
of resting and PHA‐, PMA‐ or TNF‐α‐activated human T cells, monocytes, and gut epithelial
cells to secrete the prototypic pro‐inflammatory
mediators IL‐1β, TNF‐α and IL‐8 over a period
of 24‐72 h. Traumeel inhibited the secretion of all three agents in resting, as well as
activated
immune cells. IL‐β secretion was reduced by up to 70% in both resting and activated cells;
TNF‐α secretion was reduced by up to 65 and 54%, respectively,
and IL‐8 secretion was
reduced by 50% in both resting and activated cells (P<0.01 for all cells). Interestingly,
the effect appeared to be inversely dose‐related; maximal inhibition (usually 30‐60%
inhibition; P<0.01) was seen with dilutions of
10-3‐10-6 of the Traumeel stock material. This
finding suggests that Traumeel does not inhibit immune cells functions by exerting a toxic
effect. Indeed, Traumeel did not affect T cell and monocyte proliferation. Although
additional studies are needed to clarify the mode of action of Traumeel and to demonstrate
causative relationship between the inhibition of cytokine/chemokine secretion in cell culture
and the reported clinical effects of the preparation, our in vitro results offer a mechanism for
the anti‐inflammatory effects of Traumeel observed in clinical use.
The Perfusion Paradox and Vascular Instability in Sickle Cell Disease
Authors: NATH KARL A. , KATUSIC ZVONIMIR S. , GLADWIN MARK T.
Published: October 2004

Sickle cell disease (SCD) exhibits a curious coexistence of contrasting perfusion profiles in the circulatory system: hypoperfusion is endemic in microcirculatory beds occluded by hemoglobin S‐containing erythrocytes while hyperperfusion characterizes the systemic (macro)circulation and a number of regional vascular circuits. This review highlights this perfusion paradox of SCD, focusing on forearm blood flow and the renal circulation, and exploring the extent to which alterations in vasoactive systems (such as nitric oxide and prostanoids) are involved. Also reviewed are the mechanisms and pathways that contribute to altered vascular reactivity and vascular instability observed in SCD. Finally, the possibility that the induction of heme oxygenase‐1, recently described in SCD, may confer a protective response in the vasculature and other tissues is discussed.
OCRE: a novel domain made of imperfect, aromatic-rich octamer repeats
Authors: Callebaut Isabelle , Mornon Jean-Paul
Published: October 2004

Summary: In this study, we describe a novel domain, OCRE, which is shared by the recently identified angiogenic factor VG5Q and a specific family of RNA-binding motif proteins.

The OCRE domain is characterized by a 5-fold, imperfectly repeated octameric sequence, which includes a triplet of often-conserved aromatic amino acids predicted to form a β-strand and in which the slightly modified fifth repeat might act as a repeat terminator.

Although the function of this domain remains to be elucidated, the domain architecture of OCRE containing proteins and experimental data suggest a role in RNA metabolism and/or in signalling pathways activated by the tumor necrosis factor superfamily of cytokines.

Contact:  Isabelle.Callebaut@lmcp.jussieu.fr
On the Integration of Alcohol‐Related Quantitative Trait Loci and Gene Expression Analyses
Authors: Hitzemann Robert , Reed Cheryl , Malmanger Barry , Lawler Maureen , Hitzemann Barbara , Cunningham Brendan , McWeeney Shannon , Belknap John , Harrington Christina , Buck Kari , Phillips Tamara , Crabbe John
Published: October 2004

Background: Quantitative trait loci (QTLs) have been detected for a wide variety of ethanol‐related phenotypes, including acute and chronic ethanol withdrawal, acute locomotor activation, and ethanol preference. This study was undertaken to determine whether the process of moving from QTL to quantitative trait gene (QTG) could be accelerated by the integration of functional genomics (gene expression) into the analysis strategy.

Methods: Six ethanol‐related QTLs, all detected in C57BL/6J and DBA/2J intercrosses were entered into the analysis. Each of the QTLs had been confirmed in independent genetic models at least once; the cumulative probabilities for QTL existence ranged from 10−6 to 10−15. Brain gene expression data for the C57BL/6 and DBA/2 strains (n= 6 per strain) and an F2 intercross sample (n= 56) derived from these strains were obtained by using the Affymetrix U74Av2 and 430A arrays; additional data with the U74Av2 array were available for the extended amygdala, dorsomedial striatum, and hippocampus. Low‐level analysis was performed by using multiple methods to determine the likelihood that a transcript was truly differentially expressed. For the 430A array data, the F2 sample was used to determine which of the differentially expressed transcripts within the QTL intervals were cis‐regulated and, thus, strong candidates for QTGs.

Results: Within the 6 QTL intervals, 39 transcripts (430A array) were identified as being highly likely to be differentially expressed between the C57BL/6 and DBA/2 strains at a false discovery rate of 0.01 or better. Twenty‐eight of these transcripts showed significant (logarithm of odds ≥3.6) to highly significant (logarithm of odds >7) cis‐regulation. The process correctly detected Mpdz (chromosome 4) as a candidate QTG for acute withdrawal.

Conclusions: Although improvements are needed in the expression databases, the integration of QTL and gene expression analyses seems to have potential as a high‐throughput strategy for moving from QTL to QTG.
Baclofen for Alcohol Dependence: A Preliminary Open‐Label Study
Authors: Flannery Barbara A. , Garbutt James C. , Cody Meghan W. , Renn William , Grace Kathy , Osborne Michael , Crosby Ken , Morreale Mary , Trivette Amy
Published: October 2004

Background: Recent preclinical and clinical studies have shown that the γ‐aminobutyric acid‐B agonist baclofen may be an effective treatment for reducing alcohol consumption. This preliminary open‐label investigation examined the tolerability and effect of a 30‐mg daily baclofen dose for reducing drinking, subclinical anxiety and depressive symptoms, and craving in alcohol‐dependent subjects.

Methods: Nine men and three women participated in a 12‐week trial during which they took baclofen on a 10 mg thrice‐daily regimen and received four sessions of motivational enhancement therapy. Each participant received a comprehensive physical and psychiatric screening before being enrolled. At each visit, side effects were monitored with a revised version of the Systematic Assessment of Treatment Emergent Events–General Inquiry, and drinking data were collected via the timeline follow‐back interview. Participants also completed the Beck Depression Inventory, the Beck Anxiety Inventory, and the Penn Alcohol Craving Scale at each visit.

Results: Baclofen was reasonably tolerated. Two participants discontinued because of side effects. No serious adverse events were noted. Six other individuals did not complete the trial. Overall, there were statistically significant reductions in the number of drinks per drinking day and the number of heavy‐drinking days, and there was an increase in the number of abstinent days. Significant decreases in anxiety and craving were also shown.

Conclusions: These findings suggest that baclofen is reasonably tolerated in an alcohol‐dependent population, although the high dropout rate in the study is of concern. Baclofen may be effective for the reduction of drinking, anxiety, and craving for some alcohol‐dependent individuals. A larger‐scale placebo‐controlled study is needed to further explore these effects and to determine the characteristics of those who respond to this medication.
Impairment on a Simulated Gambling Task in Long‐Term Abstinent Alcoholics
Authors: Fein G , Klein L , Finn P
Published: October 2004

Background: Recent research indicates that currently active or recently detoxified substance abusers make more disadvantageous decisions on a simulated gambling task (SGT). This study expands on the current literature by using the SGT to examine decision making in long‐term abstinent alcoholics (mean of 6.6 years’ abstinence) who do not have antisocial personality disorder or a history of conduct disorder.

Methods: A total of 102 subjects (58 controls and 44 abstinent alcoholics) were tested on the SGT, in which subjects choose cards from 4 different decks that vary in terms of the magnitude of the immediate win (large or small) and the magnitude of long‐term loss (large or small). The association of SGT performance with alcohol use variables, with the number of externalizing symptoms, and with personality measures of social deviance was examined.

Results: Compared with controls, long‐term abstinent alcohol‐dependent subjects had more externalizing symptoms, had personality profiles associated with a proneness to social deviance, and made more disadvantageous decisions on the SGT. The magnitude of disadvantageous decision making was associated with the duration of peak alcohol use but was associated with only one measure (low socialization) of socially deviant personality traits.

Conclusions: The results suggest that alcoholics can achieve long‐term abstinence despite persistent deficits in decision making and abnormal personality profiles. The decision‐making deficits either may be the result of long‐term alcoholism or may reflect a factor predisposing to alcoholism that persists with abstinence. The possibility is raised that alcoholics who cannot achieve long‐term abstinence are even more impaired on their decision making and have more abnormal personality profiles than the abstinent alcoholics studied here.
Rapid Intake of Alcohol (Binge Drinking) Inhibits Platelet Adhesion to Fibrinogen Under Flow
Authors: de Lange Dylan W. , Hijmering Michael L. , Lorsheyd Anouk , Scholman Wilco L.G. , Kraaijenhagen Rob J. , Akkerman Jan‐Willem N. , van de Wiel Albert
Published: October 2004

Background: Moderate alcohol consumption is associated with decreased mortality from cardiovascular disease. Drinking large amounts in a short period (binge drinking) is associated with increased cardiovascular morbidity. We tested whether rapid consumption of a large dose of alcohol affects platelet aggregation and adhesion.

Methods: Healthy volunteers (n= 20) were asked to drink three glasses of alcohol or red wine in a 45‐min period. Thereafter, another 45 min was allowed for absorption of alcohol. Ninety minutes after the start of the experiment, blood was collected. This entire cycle was repeated once, resulting in consumption of six alcohol‐containing drinks in 3 hr. Adenosine‐diphosphate (ADP)‐induced aggregation was measured and platelet adhesion to fibrinogen and collagen was measured in a perfusion chamber at shear rates of 300/sec and 1600/sec. Platelet coverage and aggregate size were measured.

Results: Acute alcohol intake significantly increased platelet aggregation in suspension when stimulated with low concentrations of ADP (0.1 and 0.5 μg/ml). This effect was not observed when consuming red wine. In contrast, adhesion to fibrinogen was significantly inhibited by alcohol but not red wine at high shear rate after six drinks (p= 0.025). The inhibition was accompanied by a reduction in aggregate size at 90 and 180 min after the start of the experiment. Adhesion to collagen was not altered by either alcohol or red wine.

Conclusions: Rapid intake of alcohol increases platelet aggregation, which might contribute to the increased mortality associated with binge drinking. Red wine does not show increased platelet aggregation, which might support the reduction of cardiovascular disease in red wine consumers. However, alcohol inhibits platelet adhesion to fibrinogen‐coated surface under flow. The diminished adhesion might contribute to the cardioprotective effects of alcohol.
Development of Alcoholic Fatty Liver and Fibrosis in Rhesus Monkeys Fed a Low n‐3 Fatty Acid Diet
Authors: Pawlosky Robert J. , Salem Norman
Published: October 2004

Background: The amount and type of dietary fat seem to be important factors that modulate the development of alcohol‐induced liver steatosis and fibrosis. Various alcohol‐feeding studies in animals have been used to model some of the symptoms that occur in liver disease in humans.

Methods: Rhesus monkeys (Macaca mulatta) were maintained on a diet that had a very low concentration of α‐linolenic acid and were given free access to an artificially sweetened 7% ethanol solution. Control and ethanol‐consuming animals were maintained on a diet in which the linoleate content was adequate (1.4% of energy); however, α‐linoleate represented only 0.08% of energy. Liver specimens were obtained, and the fatty acid composition of the liver phospholipids, cholesterol esters, and triglycerides of the two groups were compared at 5 years and histopathology of tissue samples were compared at 3 and 5 years.

Results: The mean consumption of ethanol for this group over a 5‐year period was 2.4 g · kg−1· day−1. As a consequence of the ethanol‐dietary treatment, there were significantly lower concentrations of several polyunsaturated fatty acids in the liver phospholipids of the alcohol‐treated group, including arachidonic acid and most of the n‐3 fatty acids and particularly docosahexaenoic acid, when compared with dietary controls. Liver specimens from animals in the ethanol group at 5 years showed a marked degree of steatosis, both focal and diffuse cellular necrosis, and an increase in the development of fibrosis compared with specimens obtained at 3 years and with those from dietary controls, in which there was no evidence of fibrotic lesions.

Conclusion: These findings suggest that the advancement of ethanol‐induced liver disease in rhesus monkeys may be modulated by the amount and type of dietary essential fatty acids and that a marginal intake of n‐3 fatty acids may be a permissive factor in the development of liver disease in primates.
Neuropeptide Y in the Paraventricular Nucleus of the Hypothalamus Increases Ethanol Intake in High‐ and Low‐Alcohol‐Drinking Rats
Authors: Gilpin N W. , Stewart R B. , Murphy J M. , Badia‐Elder N E.
Published: October 2004

Background: The behavioral effects of neuropeptide Y (NPY) attributed to its actions in the hypothalamus are complex and include effects on feeding, sedation, and the hypothalamic‐pituitary‐adrenal axis. NPY infused into the paraventricular nucleus (PVN) increases ethanol intake in unselected rats. High‐alcohol‐drinking (HAD1) and low‐alcohol‐drinking (LAD1) rats differ in basal NPY levels in the PVN, and HAD1, but not LAD1, rats exhibit decreases in ethanol intake after infusion of NPY into the ventricles. This study examined whether NPY infused into the PVN alters ethanol intake in HAD1 and LAD1 rats.

Methods: Female HAD1 (n= 14) and LAD1 (n= 18) rats were given 24‐hr free‐choice continuous access to 15% (v/v) ethanol and water for 6 weeks and then implanted bilaterally with cannulas aimed at the PVN. Two weeks later, rats received a series of microinfusions, each separated by 1 week, that included four doses of NPY (0.0, 0.25, 0.5, and 1.0 μg). Ethanol, water, and food were available ad libitum after infusions. All rats received a final microinfusion of 1.0 μg of NPY, after which ethanol and water, but no food, were made available for 2 hr.

Results: During the 2 hr after infusion, NPY yielded dose‐dependent increases in both water and food consumption. With food concurrently available, the 0.25‐ and 1.0‐μg doses of NPY did not alter baseline ethanol intake, whereas the 0.5‐μg dose increased ethanol intake. Infusion of 1.0 μg of NPY in the absence of food yielded a decrease in water intake and an increase in ethanol intake relative to the same dose in the presence of food. Twenty‐four hours after infusion, there were no effects of NPY on water and food intake, and increases in ethanol intake were no longer apparent.

Conclusions: Increases in ethanol intake after infusion of NPY into the PVN may depend on NPY dose and whether food is concurrently available.
Findings Across Subgroups Regarding the Level of Response to Alcohol as a Risk Factor for Alcohol Use Disorders: A College Population of Women and Latinos
Authors: Schuckit Marc A. , Smith Tom L. , Kalmijn Jelger
Published: October 2004

Background: The rates of alcohol dependence, a genetically influenced disorder, are increased among Latino men in the United States and are lower among women across ethnic groups. These analyses explored whether the differential rate of alcohol use disorders (AUDs) might reflect one genetically influenced phenotype related to alcoholism risk: the low level of response (LR) to alcohol.

Methods: A questionnaire was mailed to students at two universities to identify drinking but not alcohol‐dependent 18‐ to 29‐year‐old men and women who had a parent with alcohol dependence. Subjects were subsequently screened with a validated semistructured interview to corroborate the personal and family histories, and they participated in a challenge with alcohol 0.75 ml/kg for women and 0.90 ml/kg for men. LRs to alcohol were determined and compared between genders and between Latino versus Caucasian/Anglo subjects.

Results: The data revealed no consistent significant differences between genders regarding either subjective feelings of intoxication or alcohol‐induced changes in body sway. A similar lack of differential between groups was observed when Latino and Caucasian/Anglo subjects were compared. However, there was at least a statistical trend for interactions when gender, ethnicity, and time were considered together; there was some evidence for a higher LR in Latina women. Perhaps reflecting the different weights and doses of alcohol used, men demonstrated higher breath alcohol concentrations, but no differences in these values were noted between Latino and Anglo populations.

Conclusions: The results indicate that the LR to alcohol is not likely to explain differences in rates of AUDs between genders or these two ethnic groups overall. The possibility that a higher LR might be seen for the subgroup with the lowest AUD rate—Latina women—will require replication in larger samples of well matched groups before definitive conclusions can be drawn.
Prenatal Ethanol Exposure Reduces mGluR5 Receptor Number and Function in the Dentate Gyrus of Adult Offspring
Authors: Galindo Rafael , Frausto Shanti , Wolff Christina , Caldwell Kevin K. , Perrone‐Bizzozero Nora I. , Savage Daniel D.
Published: October 2004

Background: Previous studies in our laboratory indicated that metabotropic glutamate receptor (mGluR)‐stimulated phosphoinositide hydrolysis is markedly reduced in the hippocampal formation of adult rat offspring whose mothers drank moderate amounts of ethanol during pregnancy. In the present study, we extended these observations by measuring the impact of prenatal ethanol exposure on proteins associated with the mGluR5 receptor‐effector system along with two mGluR5 agonist‐mediated responses in dentate gyrus of adult offspring.

Methods: Sprague‐Dawley rat dams consumed one of three diets throughout gestation: (1) a BioServ liquid diet that contained 5% ethanol (v/v), (2) pair‐fed an isocalorically equivalent amount of 0% ethanol liquid diet, or (3) lab chow ad libitum. Microdissected slices of dentate gyrus were prepared from adult female offspring from each diet group and used for (1) Western blot analyses of mGluR5, the G‐proteins Gαq and Gα11, and phospholipase C‐β1; (2) 2‐chloro‐5‐hydroxyphenylglycine (CHPG)‐stimulated growth associated protein 43 (GAP‐43) phosphorylation; or (3) CHPG potentiation of electrically evoked [3H]‐d‐aspartate (D‐ASP) release from dentate gyrus slices.

Results: In tissue prepared from untreated control rats, CHPG produced a dose‐dependent increase in 32phosphate incorporation into GAP‐43, with maximal agonist stimulation occurring at 20 μM of CHPG. CHPG produced a quantitatively similar dose‐dependent increase in the potentiation of electrically evoked D‐ASP release from dentate gyrus slices from untreated controls. Fetal ethanol exposure reduced the amount of dentate gyrus mGluR5 receptor protein by 36% compared with the diet control groups. There were no significant differences between diet groups in the two G‐proteins or phospholipase C‐β1 protein. Fetal ethanol exposure reduced CHPG‐stimulated GAP‐43 phosphorylation to approximately one half the amount of CHPG stimulation observed in the control diet groups. Prenatal ethanol exposure also reduced CHPG potentiation of D‐ASP release to a similar degree compared with control.

Conclusions: These results indicate that prenatal exposure to moderate quantities of ethanol reduces mGluR5 expression in the dentate gyrus of adult offspring. Although the subcellular site(s) for reduced mGluR5 expression cannot be discerned from Western blot data, the quantitatively similar effects of prenatal ethanol exposure on mGluR5 agonist stimulation of presynaptically localized GAP‐43 phosphorylation and CHPG potentiation of evoked D‐ASP release suggest that the presynaptic nerve terminal is one site where prenatal ethanol exposure has reduced mGluR5 receptor number and function. Furthermore, these data implicate these neurochemical alterations as one factor contributing to the hippocampal synaptic plasticity and behavioral deficits that we have observed previously in prenatal ethanol‐exposed offspring.
Alcohol Dehydrogenase 2*3 Affects Alterations in Offspring Facial Morphology Associated With Maternal Ethanol Intake in Pregnancy
Authors: Das Utpala G. , Cronk Christine E. , Martier Susan S. , Simpson Pippa M. , McCarver D Gail
Published: October 2004

Background: Ethanol intake during pregnancy alters offspring facial morphology. However, significant variation that may be due to genetic diversity in ethanol metabolizing enzymes occurs. The alcohol dehydrogenase 1B*3 (ADH1B*3) allele is protective for offspring developmental outcome after maternal alcohol drinking in pregnancy and may explain the spectrum of facial morphology.

Methods: Faces of infants with known ADH1B genotype, whose mothers’ADH1B genotypes and ethanol intake were determined during pregnancy, were photographed using uniform procedures. Photographs were scanned and the inner canthal distance, palpebral fissure length, and distance from the bridge of the nose to the bottom of the upper lip were measured by an investigator who was blinded to genotype and ethanol exposure.

Results: Among 247 photographed infants, each facial measurement varied >2‐fold. Median absolute ethanol daily intake was 0.5 oz among mothers who reported drinking in the periconceptional period (N= 173) and 0.17 oz among mothers who reported drinking before the first prenatal visit (N= 62). Controlling for the amount of maternal ethanol intake just before the first prenatal visit and infant sex, the three‐way interaction among the absence of a maternal and offspring ADH1B*3 allele and the presence of ethanol consumption just before the first prenatal visit was associated with smaller facial measurements (p= 0.002, MANCOVA).

Conclusions: These are the first observations of a significant gene–environment interaction explaining variation in facial morphology associated with ethanol use in pregnancy. This positive effect of ADH1B*3 is consistent with its known positive effect on offspring birth weight and developmental outcome after in utero ethanol exposure.
Association of ALDH1 Promoter Polymorphisms With Alcohol‐Related Phenotypes in Southwest California Indians
Authors: Ehlers Cindy L. , Spence John P. , Wall Tamara L. , Gilder David A. , Carr Lucinda G.
Published: October 2004

Background: Cytosolic aldehyde dehydrogenase (ALDH1A1) is an important enzyme in the metabolism of acetaldehyde and the synthesis of retinoic acid. Two polymorphisms in the promoter region of ALDH1A1—ALDH1A1*2 and ALDH1A1*3—have recently been identified and described in small samples of Asian, Caucasian, and African individuals. The aim of this study was to determine the prevalence of these polymorphisms in a sample of Southwest California Indians and to test for associations with alcohol dependence and other substance‐related behaviors.

Methods: The participants in this study were 463 adult men and women recruited from 8 contiguous Indian reservations. A structured interview was used to gather information on demographics, psychiatric diagnoses, and personal drinking and drug use history. A blood sample was obtained from each participant, and leukocyte DNA was extracted and used to genotype for the presence of the ALDH1A1 promoter polymorphisms.

Results: Twenty‐seven participants (6%) possessed ALDH1A1*2 (frequency, 0.03), two participants possessed ALDH1A1*3, and one participant displayed both of these alleles. Individuals with an ALDH1A1*2 allele had lower rates of alcohol dependence and regular tobacco use than those without this allele. Individuals with ALDH1A1*2 also reported a significantly lower maximum number of drinks ever consumed in a 24‐hr period, reported drinking fewer drinks per occasion when they first started drinking regularly, and reported lower expectations of alcohol's effects compared with individuals without this allele.

Conclusions: Results from this study suggest that ALDH1A1*2 may be associated with protection from the development of alcohol and other substance use disorders.
Association of Sleep Disturbance with Chronicity and Remission of Alcohol Dependence: Data from a Population‐Based Prospective Study
Authors: Crum Rosa M. , Ford Daniel E. , Storr Carla L. , Chan Ya‐Fen
Published: October 2004

Objective:We assessed the association of three types of self‐reported sleep disturbances (insomnia, hypersomnia, and sleep disturbance caused by worry) among individuals with chronic and remitted alcohol dependence, using prospectively gathered data from a population‐based sample.

Methods:Probability samples of area residents were selected by census tracks and households in Baltimore, MD, in 1981, as part of the Epidemiologic Catchment Area program (n= 3481). Between 1993 and 1996, the original cohort was traced, and 73% of the survivors were re‐interviewed (n= 1920). Three groups for alcohol dependence status were identified: (1) chronic, (2) remitted, and (3) no lifetime or current history of dependence. Logistic regression models were used to assess the association between alcohol dependence status for each type of sleep disturbance.

Results:Of the 248 individuals with alcohol dependence, most had achieved remission of dependence by the time of the median 13‐year follow‐up interview (n= 211). A total of 37 met criteria for chronic dependence. After holding constant potential confounders (age, sex, race, educational level, marital status, psychiatric and illicit drug disorder history, health services use, and age of onset of first alcohol‐related problem), we found that chronic dependence was associated with insomnia (odds ratio = 2.60; 95% confidence interval = 1.11–6.08;p= 0.03), relative to those without a history of dependence. Remitted dependence was not associated with sleep disturbance in the models adjusted for covariates. In supplemental analyses, we assessed the association of drinking status with alcohol dependence remission.

Conclusions:Individuals with persistent alcohol dependence have greater odds of insomnia than those whose alcohol dependence remits. The need for prospectively gathered data from community‐based samples to assess further the temporal relationships of sleep disturbance, alcohol dependence, and alcohol consumption level is discussed.