bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors
Authors: Pata Janice D. , Stirtan William G. , Goldstein Steven W. , Steitz Thomas A.
Published: July 2004

We have determined the crystal structure of the HIV type 1 reverse transcriptase complexed with CP-94,707, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), to 2.8-Å resolution. In addition to inhibiting the wild-type enzyme, this compound inhibits mutant enzymes that are resistant to inhibition by nevirapine, efavirenz, and delaviridine. In contrast to other NNRTI complexes where tyrosines 181 and 188 are pointing toward the enzyme active site, the binding pocket in this complex has the tyrosines pointing the opposite direction, as in the unliganded protein structure, to accommodate CP-94,707. This conformation of the pocket has not been observed previously in NNRTI complexes and substantially alters the shape and surface features that are available for interactions with the inhibitor. One ring of CP-94,707 makes extensive stacking interactions with tryptophan 229, one of the few residues in the NNRTI-binding pocket that cannot readily mutate to give rise to drug resistance. In this conformation of the pocket, mutations of tyrosines 181 and 188 are less likely to disrupt inhibitor binding. Modeling the asparagine mutation of lysine 103 shows that a hydrogen bond between it and tyrosine 188 could form as readily in the CP-94,707 complex as it does in the apoenzyme structure, providing an explanation for the activity of this inhibitor against this clinically important mutant.
A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast
Authors: Mitra Prasenjit , Zhang Yingjie , Rameh Lucia E. , Ivshina Maria P. , McCollum Dannel , Nunnari John J. , Hendricks Gregory M. , Kerr Monica L. , Field Seth J. , Cantley Lewis C. , Ross Alonzo H.
Published: July 2004

The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases.
Vav GEFs are required for β2 integrin-dependent functions of neutrophils
Authors: Gakidis M. Angelica Martinez , Cullere Xavier , Olson Timothy , Wilsbacher Julie L. , Zhang Bin , Moores Sheri L. , Ley Klaus , Swat Wojciech , Mayadas Tanya , Brugge Joan S.
Published: July 2004

Integrin regulation of neutrophils is essential for appropriate adhesion and transmigration into tissues. Vav proteins are Rho family guanine nucleotide exchange factors that become tyrosine phosphorylated in response to adhesion. Using Vav1/Vav3-deficient neutrophils (Vav1/3ko), we show that Vav proteins are required for multiple β2 integrin-dependent functions, including sustained adhesion, spreading, and complement-mediated phagocytosis. These defects are not attributable to a lack of initial β2 activation as Vav1/3ko neutrophils undergo chemoattractant-induced arrest on intercellular adhesion molecule-1 under flow. Accordingly, in vivo, Vav1/3ko leukocytes arrest on venular endothelium yet are unable to sustain adherence. Thus, Vav proteins are specifically required for stable adhesion. β2-induced activation of Cdc42, Rac1, and RhoA is defective in Vav1/3ko neutrophils, and phosphorylation of Pyk2, paxillin, and Akt is also significantly reduced. In contrast, Vav proteins are largely dispensable for G protein-coupled receptor–induced signaling events and chemotaxis. Thus, Vav proteins play an essential role coupling β2 to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis.
GITR Activation Induces an Opposite Effect on Alloreactive CD4+ and CD8+ T Cells in Graft-Versus-Host Disease
Authors: Muriglan Stephanie J. , Ramirez-Montagut Teresa , Alpdogan Onder , van Huystee Thomas W. , Eng Jeffrey M. , Hubbard Vanessa M. , Kochman Adam A. , Tjoe Kartono H. , Riccardi Carlo , Pandolfi Pier Paolo , Sakaguchi Shimon , Houghton Alan N. , van den Brink Marcel R.M.
Published: July 2004

Glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) is a member of the tumor necrosis factor receptor (TNFR) family that is expressed at low levels on unstimulated T cells, B cells, and macrophages. Upon activation, CD4+ and CD8+ T cells up-regulate GITR expression, whereas immunoregulatory T cells constitutively express high levels of GITR. Here, we show that GITR may regulate alloreactive responses during graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Using a BMT model with major histocompatibility complex class I and class II disparity, we demonstrate that GITR stimulation in vitro and in vivo enhances alloreactive CD8+CD25− T cell proliferation, whereas it decreases alloreactive CD4+CD25− proliferation. Allo-stimulated CD4+CD25− cells show increased apoptosis upon GITR stimulation that is dependent on the Fas–FasL pathway. Recipients of an allograft containing CD8+CD25− donor T cells had increased GVHD morbidity and mortality in the presence of GITR-activating antibody (Ab). Conversely, recipients of an allograft with CD4+CD25− T cells showed a significant decrease in GVHD when treated with a GITR-activating Ab. Our findings indicate that GITR has opposite effects on the regulation of alloreactive CD4+ and CD8+ T cells.
Rapid Turnover of Effector–Memory CD4+ T Cells in Healthy Humans
Authors: Macallan Derek C. , Wallace Diana , Zhang Yan , de Lara Catherine , Worth Andrew T. , Ghattas Hala , Griffin George E. , Beverley Peter C.L. , Tough David F.
Published: July 2004

Memory T cells can be divided into central–memory (TCM) and effector–memory (TEM) cells, which differ in their functional properties. Although both subpopulations can persist long term, it is not known whether they are maintained by similar mechanisms. We used in vivo labeling with deuterated glucose to measure the turnover of CD4+ T cells in healthy humans. The CD45R0+CCR7− TEM subpopulation was shown to have a rapid proliferation rate of 4.7% per day compared with 1.5% per day for CD45R0+CCR7+ TCM cells; these values are equivalent to average intermitotic (doubling) times of 15 and 48 d, respectively. In contrast, the CD45RA+CCR7+ naive CD4+ T cell population was found to be much longer lived, being labeled at a rate of only 0.2% per day (corresponding to an intermitotic time of approximately 1 yr). These data indicate that human CD4+ TEM cells constitute a short-lived cell population that requires continuous replenishment in vivo.
Naltrexone Depot for Treatment of Alcohol Dependence: A Multicenter, Randomized, Placebo‐Controlled Clinical Trial
Authors: Kranzler Henry R. , Wesson Donald R. , Billot Laurent ,   DrugAbuse Sciences Naltrexone Depot Study Group
Published: July 2004

Background: Studies of the efficacy of naltrexone for alcohol dependence have yielded variable findings, which may be due, in part, to variation in compliance with oral naltrexone. Efforts to improve naltrexone compliance have included the development of injectable, long‐acting depot formulations.

Methods: We conducted a multicenter trial in 315 subjects who were randomly assigned to receive an intramuscular injection of a depot formulation containing naltrexone (n= 158) or a placebo formulation (n= 157) monthly for 3 months. All patients received five sessions of manual‐guided motivational enhancement therapy during the 12 weeks of the study. The outcomes of interest were based on self‐reported alcohol use and γ‐glutamyl transpeptidase level. Missing data or data from subjects who discontinued the study were conservatively treated as heavy‐drinking days.

Results: Groups were comparable on pretreatment demographic and clinical measures. The medication was well tolerated; 73.7% of subjects received all injections. The time to the first heavy‐drinking day, the percentage of subjects with no heavy drinking throughout the study, and γ‐glutamyl transpeptidase levels favored the naltrexone depot, although the effects did not reach statistical significance. There was a significant advantage for naltrexone depot treatment on the time to the first drinking day. Naltrexone depot subjects also had significantly fewer drinking days during treatment and a significantly greater abstinence rate than the placebo group (18% vs. 10%).

Conclusions: This is the first multicenter study of a depot formulation of naltrexone for the treatment of alcohol dependence. Using a conservative intent‐to‐treat analysis, the study showed an advantage for the active medication. Further research with this formulation is warranted.
Desensitization of PKA‐Stimulated Ciliary Beat Frequency in an Ethanol‐Fed Rat Model of Cigarette Smoke Exposure
Authors: Wyatt Todd A. , Gentry‐Nielsen Martha J. , Pavlik Jacqueline A. , Sisson Joseph H.
Published: July 2004

Background: Our previous studies have shown that the ciliary beat frequency (CBF) of cultured ciliated airway epithelial cells exposed to chronic ethanol fails to increase in response to β‐agonist stimulation. This loss of the ciliary “flight response” correlates with an ethanol‐mediated desensitization of adenosine 3′:5′‐cyclic monophosphate‐dependent protein kinase (PKA), a known regulatory component of CBF stimulation. We hypothesized that a similar ethanol‐mediated desensitization of CBF would occur in vivo.

Methods: Sprague Dawley® rats were fed a liquid diet containing various concentrations of ethanol for 1 or 5 weeks. Half were exposed to cigarette smoke for 12 weeks and half were sham exposed. Animals were killed and tracheal epithelial cells analyzed for CBF and PKA activity.

Results: Baseline CBF (∼6Hz) was unchanged in tracheal epithelial cells of rats consuming diets containing 0–36% ethanol for 5 weeks. Isoproterenol stimulated CBF to 12 to 13 Hz in the tracheal epithelial cells of control rats not administered ethanol. However, isoproterenol stimulation of CBF was blunted to 7.5 Hz in rats eating a 26% ethanol diet, and there was no stimulation of CBF in rats fed a diet containing 36% ethanol. Similarly, isoproterenol stimulated a 2‐ to 3‐fold increase in PKA activity in control rats, but this PKA response to isoproterenol was blunted in rats fed increasing concentrations of ethanol. No isoproterenol‐stimulated PKA response was observed in rats fed 36% ethanol. No ethanol‐induced changes in cyclic guanosine monophosphate‐dependent protein kinase or protein kinase C were observed in the rats’ tracheal epithelial cells. Cigarette smoke exposure slightly elevated baseline CBF and lowered the ethanol consumption level for isoproterenol‐desensitization of CBF and PKA activation to 16%. No isoproterenol desensitization was observed after 1 week of alcohol feeding. Furthermore, 36% ethanol‐feeding for 1 week stimulated rat tracheal CBF and PKA.

Conclusion: These data demonstrate that in vivo administration of ethanol to rats results in decreased ciliary beating and the desensitization of PKA. This suggests a mechanism for mucociliary clearance dysfunction in alcoholics.
Using Daily Interactive Voice Response Technology to Measure Drinking and Related Behaviors in a Pharmacotherapy Study
Authors: Kranzler Henry R. , Abu‐Hasaballah Khamis , Tennen Howard , Feinn Richard , Young Kevin
Published: July 2004

Background: Interactive voice response technology (IVR) allows investigators to collect daily measures of drinking, medication adherence, mood, and other treatment‐relevant variables that may change day to day during a clinical trial. Despite these advantages, no published studies have used IVR in alcohol pharmacotherapy trials.

Methods: Subjects provided daily data via IVR during the 12‐week treatment period. Seven subjects completed the trial.

Results: We found a high level of participant adherence to the IVR protocol, higher levels of drinking reported by IVR than by a commonly used recall method, and distinct within‐day associations between daily mood and alcohol consumption: these could not be obtained through traditional assessment methods.

Conclusions: IVR seems to be feasible for the collection of daily indicators of treatment outcomes and processes in pharmacotherapy studies among problem drinkers.
Adipogenic Effect of Alcohol on Human Bone Marrow‐Derived Mesenchymal Stem Cells
Authors: Wezeman Frederick H. , Gong Zhaodi
Published: July 2004

Background: In addition to a decrease in bone mass in alcoholics their osteopenic skeletons show an increase in bone marrow adiposity. Human bone marrow mesenchymal stem cells (hMSC) in vivo differentiate into several phenotypes including osteogenic and adipogenic cells, both of which remain as resident populations of bone marrow. In vitro, the lineage commitment and differentiation of hMSC toward the adipogenic pathway can be promoted by alcohol.

Methods: Human male and female mesenchymal stem cells from joint replacement surgery were cultured. Cells were grouped as: 1) Control (no additions to the culture medium), 2) EtOH (50 mm alcohol added to the culture medium), 3) OS (osteogenic inducers added to the culture medium), and 4) OS + EtOH (osteogenic inducers and 50 mm alcohol added to the culture medium). Cultures stained with Nile Red confirmed the development of differentiated adipocytes. Population analysis was performed using fluorescence‐activated cell sorting. Gene expression of early, middle, late, and terminal differentiation stage markers (PPAR)γ2, lipoprotein lipase, adipsin, leptin, and adipocyte P2 (aP2)] was studied by Northern hybridization, and protein synthesis of aP2 was determined by Western analysis.

Results: Nile red staining confirmed increased adipocyte development 10 days after the onset of treatment with 50 mm alcohol and osteogenic induction. By day 21 the number of adipocytes increased to 13.6% of the total population. Alcohol up‐regulated the gene expression of PPARγ2 whereas no up‐regulation was observed for the other genes. Protein production of aP2 was significantly increased in hMSC cells by culture in the presence of alcohol.

Conclusions: The data suggest that alcohol's adipogenic effect on cultured hMSC is through up‐regulation of PPARγ2 at the point of lineage commitment as well as through enhancement of lipid transport and storage through increased aP2 synthesis. The alcohol‐induced expression and synthesis changes account for the increased Nile red staining of cultured hMSC.
Dose‐Dependent Activation of Ca2+‐Activated K+ Channels by Ethanol Contributes to Improved Endothelial Cell Functions
Authors: Kuhlmann Christoph R. W. , Li Fang , Lüdders Dörte W. , Schaefer Christian A. , Most Astrid K. , Backenköhler Ulrich , Neumann Thomas , Tillmanns Harald , Waldecker Bernd , Erdogan Ali , Wiecha Johannes
Published: July 2004

Background: Regular moderate alcohol (EtOH) intake seems to protect against both coronary artery disease and ischemic stroke, whereas the risk increases with heavy EtOH consumption. Effects of EtOH on endothelial cell function may be relevant to these disparate effects. Potassium channels play an important role in the regulation of endothelial cell functions. Therefore, we investigated whether Ca2+‐activated K+ channels (BKCa) are modulated by EtOH. Furthermore, we examined whether EtOH‐induced changes of endothelial nitric oxide (NO) formation and cell proliferation are due to BKCa activation.

Methods: The patch‐clamp technique was used to investigate BKCa activity in cultured human umbilical vein endothelial cells (HUVEC). NO formation was analyzed by using the fluorescence dye 4,5‐diaminofluorescein. Endothelial proliferation was examined by using cell counts and measuring [3H]thymidine incorporation.

Results: EtOH dose‐dependently (10–150 mmol/liter) modulated BKCa‐activity, with the highest increase of open‐state probability at a concentration of 50 mmol/liter (n= 13; p < 0.05). Inside‐out recordings revealed that this effect was due to direct BKCa activation, whereas open‐state probability was not changed in cell‐attached recordings after pertussis toxin preincubation. EtOH (10 and 50 mmol/liter) caused a significant increase of NO levels, which was blocked by the highly selective BKCa inhibitor iberiotoxin (100 nmol/l; n= 30; p < 0.05). Higher concentrations of EtOH (100 and 150 mmol/liter) significantly reduced NO synthesis (n= 30; p < 0.05). Both methods revealed a significant increase of HUVEC proliferation, which was inhibited by iberiotoxin (n= 30; p < 0.05). At a concentration of 150 mmol/liter, EtOH caused a significant reduction of endothelial proliferation.

Conclusions: EtOH directly activates BKCa in HUVEC, leading to an increase of endothelial proliferation and production of NO. These results indicate a possible beneficial effect of low‐dose EtOH on endothelial function, whereas higher concentrations must be considered as harmful.
Early Experience and Sex Interact to Influence Limbic‐Hypothalamic‐Pituitary‐Adrenal‐Axis Function After Acute Alcohol Administration in Rhesus Macaques (Macaca mulatta)
Authors: Barr C S. , Newman T K. , Lindell S , Becker M L. , Shannon C , Champoux M , Suomi S J. , Higley J D.
Published: July 2004

Background: Studies in rodents demonstrate sex differences in neuroendocrine stress axis activity after treatment with alcohol. In abstinent alcoholics, atypical depressives, and individuals with posttraumatic stress disorder, limbic‐hypothalamic‐pituitary‐adrenal (LHPA)‐axis activity is often blunted; among females in these patient populations, however, resistance to glucocorticoid feedback and increased pituitary reactivity is observed. Early parental loss is a major life stressor and is a risk factor for both affective disturbances and LHPA‐axis abnormalities later in life. We wanted to determine whether sex and early life parental absence would interact to influence alcohol‐induced alterations in LHPA‐axis activity after exposure to ethanol in macaques.

Methods: Animals were reared with their mothers in social groups (MR, n= 94) or without adults in peer‐only groups (PR, n= 79). At 5 years of age, they received an intravenous infusion of alcohol (2–2.2 g/kg), and the effects of alcohol, sex, and rearing condition on ACTH and cortisol levels were analyzed by ANOVA.

Results: Peer‐reared females had higher ACTH levels than did PR males, MR females, and MR males after alcohol infusion. Alcohol‐induced cortisol levels were not affected by sex and rearing condition.

Conclusions: These findings suggest that there are sex differences in glucocorticoid negative feedback, pituitary responsivity, or release of ACTH secretagogues among individuals exposed to early life stress and emphasize the importance of considering sex effects when studying LHPA‐axis dysregulation in alcoholism and other stress‐related neuropsychiatric disorders.
Nursing From an Ethanol‐Intoxicated Dam Induces Short‐ and Long‐Term Disruptions in Motor Performance and Enhances Later Self‐Administration of the Drug
Authors: Ponce Luciano F. , Pautassi Ricardo M. , Spear Norman E. , Molina Juan C.
Published: July 2004

Rationale: During interactions with an ethanol‐intoxicated dam, preweanling rats encode ethanol‐related chemosensory information. These experiences have been observed to enhance subsequent recognition of ethanol's chemosensory properties and to modulate learning about ethanol.

Objective: The present study tested the effects of ethanol‐related nursing experiences on motor function in later infancy and adolescence and on ethanol intake during adolescence.

Methods: Wistar‐derived rats were reared by dams intragastrically administered with ethanol (2.5 g/kg) or with water during postnatal days (PDs) 3, 5, 7, 9, 11, and 13. Later in infancy or in adolescence, these rats were tested on a motor coordination task (Accelerod) while either sober or acutely intoxicated with ethanol (1 g/kg). During adolescence, animals had simultaneous access to varying ethanol concentrations (3, 4, 5, or 6% v/v) and water.

Results: Both infants and adolescents that had been reared by ethanol‐intoxicated dams exhibited dramatic behavioral impairments in the Accelerod task when compared with the offspring of water control dams. Ethanol intoxication disrupted motor performance in both age groups, but this effect was independent of prior maternal treatment. When tested for voluntary ethanol intake as adolescents, those with prior nursing experiences with an intoxicated dam ingested more ethanol than adolescents reared by sober dams.

Conclusions: Early experiences with alcohol comprising interactions with an alcohol‐intoxicated dam result in motor impairment and enhanced ethanol intake later in life.
Anxiety‐Like Behavior in Mice in Two Apparatuses During Withdrawal From Chronic Ethanol Vapor Inhalation
Authors: Kliethermes C L. , Cronise K , Crabbe J C.
Published: July 2004

Background: Anxiety during ethanol withdrawal may be a factor in relapse to alcohol abuse and dependence. Animal models of ethanol withdrawal have typically used forced consumption of an ethanol‐containing liquid diet to induce dependence. Ethanol vapor inhalation offers an advantage over liquid diet consumption in that the onset of withdrawal can be temporally controlled more precisely, allowing studies of the development of withdrawal symptoms.

Methods: The purpose of the current study was to induce ethanol dependence in mice using an inhalation procedure and to assess withdrawal anxiety symptoms behaviorally in the elevated zero maze and in the light/dark box. Male and female mice were exposed to 3 days of ethanol vapors. Anxiety‐like behavior was measured on the elevated zero maze and light/dark box at multiple time points during withdrawal.

Results: Mice experiencing ethanol withdrawal demonstrated increased anxiety‐like behaviors relative to control animals in both apparatuses. However, this finding was specific to the procedure used with the elevated zero maze and was strongly influenced by sex in the light/dark box.

Conclusions: Ethanol vapor inhalation appears to be a valid tool for the study of withdrawal‐induced anxiety.
Alcohol Reduces GM1 Ganglioside Content in the Serum of Inbred Mouse Strains
Authors: Saito Mitsuo , Saito Mariko , Cooper Thomas B. , Vadasz Csaba
Published: July 2004

Background: Endogenous and exogenous gangliosides in the plasma affect physiologic and pathologic processes such as angiogenesis and atherogenesis. However, the genetic and environmental factors that regulate the expression of plasma gangliosides are not well known. As shown in the liver and the brain, profiles of gangliosides in the plasma may be strain‐specific and can be altered by intake of alcohol. Therefore, we analyzed serum gangliosides derived from inbred mouse strains with and without alcohol treatment.

Methods: C57BL/6ByJ (B6By) and BALB/cJ mice (60–70 days old) were injected with 20% alcohol (1–6 g/kg) or saline intraperitoneally, and the ganglioside content of the serum, liver, and cerebellum was measured 4 hr after the injection. Also, the effect of oral alcohol self‐administration for 18 days with escalating (3–12%) concentrations of alcohol on the serum GM1 content was studied in B6By mice. The quantification of GM1 was performed with a thin‐layer chromatography‐staining procedure using a cholera toxin B subunit, and the content of other gangliosides was measured after staining with resorcinol reagent.

Results: We found that basal GM1 (containing N‐glycolylneuraminic acid) content in the serum of BALB/cJ mice (4.8 ± 0.26 ng/μl) was 25 times higher than that of B6By mice (0.19 ± 0.01 ng/μl); the major ganglioside in both strains was GM2. The ganglioside profile in the liver was similar to that of the serum, and the GM1 content in BALB/cJ was nine times higher than that of B6By. Both injection and oral self‐administration of alcohol lowered GM1 levels in the serum.

Conclusions: Endogenous ganglioside profiles in the serum are under genetic control among inbred mouse strains, and they can be altered by acute and chronic alcohol administration. These genetic and alcohol‐induced differences in the plasma gangliosides, which appear to reflect ganglioside metabolism in the liver, may affect alcohol‐related behaviors and pathologic processes.
Differential Increase in Taurine Levels by Low‐Dose Ethanol in the Dorsal and Ventral Striatum Revealed by Microdialysis With On‐Line Capillary Electrophoresis
Authors: Smith A , Watson C J. , Frantz K J. , Eppler B , Kennedy R T. , Peris J
Published: July 2004

Ethanol increases taurine efflux in the nucleus accumbens or ventral striatum (VS), a dopaminergic terminal region involved in positive reinforcement. However, this has been found only at ethanol doses above 1 g/kg intraperitoneally, which is higher than what most rats will self‐administer. We used a sensitive on‐line assay of microdialysate content to test whether lower doses of ethanol selectively increase taurine efflux in VS as opposed to other dopaminergic regions not involved in reinforcement (e.g., dorsal striatum; DS). Adult male rats with microdialysis probes in VS or DS were injected with ethanol (0, 0.5, 1, and 2 g/kg intraperitoneally), and the amino acid content of the dialysate was measured every 11 sec using capillary electrophoresis and laser‐induced fluorescence detection. In VS, 0.5 g/kg ethanol significantly increased taurine levels by 20% for 10 min. A similar increase was seen after 1 g/kg ethanol, which lasted for about 20 min after injection. A two‐phased taurine efflux was observed with the 2.0 g/kg dose, where taurine was increased by 2‐fold after 5 min but it remained elevated by 30% for at least 60 min. In contrast, DS exhibited much smaller dose‐related increases in taurine. Glycine, glutamate, serine, and γ‐aminobutyric acid were not systematically affected by lower doses of ethanol; however, 2 g/kg slowly decreased these amino acids in both brain regions during the hour after injection. These data implicate a possible role of taurine in the mechanism of action of ethanol in the VS. The high sensitivity and time resolution afforded by capillary electrophoresis and laser‐induced fluorescence detection will be useful for detecting subtle changes of neuronally active amino acids levels due to low doses of ethanol.
Recent Advances in Cyclic‐Adenosine Monophosphate/Protein Kinase A Signaling in Ethanol‐Induced Synaptic and Behavioral Alterations
Authors: Chandler L Judson , Bonci Antonello , Wand Gary S. , Morrisett Richard A.
Published: July 2004

This article represents the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, California, organized and co‐chaired by L. Judson Chandler and Richard A. Morrisett. The presentations were (1) PKA regulates chronic ethanol‐induced synaptic targeting of NMDA receptors, by L. Judson Chandler; (2) Long‐lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure, by Antonello Bonci; (3) The DARPP‐32 cascade and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens, by Richard A. Morrisett; (4) and The cAMP/PKA signal transduction pathway modulates ethanol consumption and sedative effects of ethanol, by Gary S. Wand.
Observations of synaptic structures: origins of the neuron doctrine and its current status
Authors: Guillery R.W
Published: July 2004

The neuron doctrine represents nerve cells as polarized structures that contact each other at specialized (synaptic) junctions and form the developmental, functional, structural and trophic units of nervous systems. The doctrine provided a powerful analytical tool in the past, but is now seldom used in educating neuroscientists. Early observations of, and speculations about, sites of neuronal communication, which were made in the early 1860s, almost 30 years before the neuron doctrine was developed, are presented in relation to later accounts, particularly those made in support of, or opposition to, the neuron doctrine. These markedly differing accounts are considered in relation to limitations imposed by preparative and microscopical methods, and are discussed briefly as representing a post-Darwinian, reductionist view, on the one hand, opposed to a holistic view of mankind as a special part of creation, on the other. The widely misunderstood relationship of the neuron doctrine to the cell theory is discussed, as is the degree to which the neuron doctrine is still strictly applicable to an analysis of nervous systems. Current research represents a ‘post-neuronist’ era. The neuron doctrine provided a strong analytical approach in the past, but can no longer be seen as central to contemporary advances in neuroscience.
What can we learn by studying enzymes in non–aqueous media?
Authors: Halling Peter J.
Published: July 2004

What is the role of water in enzyme structure and function? One approach to answers should come from studies in which the amount of water present is a variable. In the absence of bulk liquid water, effective monitoring of enzyme action requires an alternative fluid medium through which substrates and products may be transported. The past 20 years have seen quite extensive study of enzyme behaviour when reactants are transferred via a bulk phase that is an organic liquid, a supercritical fluid or a gas. Some lipases, at least, remain highly active with only a few, if any, residual water molecules. Many enzymes seem to require larger amounts of water, but still not a liquid water phase. There are hysteresis effects on both the amount of bound water and the observed catalytic activity. Increasing hydration promotes mobility of the enzyme molecule, as revealed by various techniques, and there are correlations with catalytic activity. There are other plausible roles for hydration, such as opening up proton conduction pathways.
Enhancing Strategy Evaluation in Scenario Planning: a Role for Decision Analysis
Authors: Goodwin Paul , Wright George
Published: July 2004

Scenario planning can be a useful and attractive tool in strategic management. In a rapidly changing environment it can avoid the pitfalls of more traditional methods. Moreover, it provides a means of addressing uncertainty without recourse to the use of subjective probabilities, which can suffer from serious cognitive biases. However, one underdeveloped element of scenario planning is the evaluation of alternative strategies across the range of scenarios. If this is carried out informally then inferior strategies may be selected, while those formal evaluation procedures that have been suggested in relation to scenario planning are unlikely to be practical in most contexts. This paper demonstrates how decision analysis can be used to structure the strategy evaluation process in a way which avoids the problems associated with earlier proposals. The method is flexible, versatile and transparent and leads to a clear and documented rationale for the selection of a particular strategy.
Market Orientation and Performance: Objective and Subjective Empirical Evidence from UK Companies
Authors: Harris Lloyd C.
Published: July 2004

The link between market orientation and performance has been claimed largely on the basis of the analysis of subjective measures of performance. Consequently, the aim of this study is to examine the links between market orientation and objectively measured financial performance. The paper begins with a brief examination of the definition and components of market orientation. Thereafter, extant research into the consequences of developing market orientation is reviewed critically, leading to the development of a number of research hypotheses. After detailing the research design and methodology adopted in this study, the findings of a survey of UK industry are presented. Briefly, the results indicate that when subjective measures of performance are adopted, market orientation is associated with company performance in certain environmental conditions. However, when objective measures of performance are adopted, we see a narrower range of environmental conditions where market orientation is positively associated with performance. The paper concludes with a series of implications for both theorists and practitioners.
The Dynamics of the Adoption of Product and Process Innovations in Organizations
Authors: Damanpour Fariborz , Gopalakrishnan Shanthi
Published: July 2004

While many researchers have fruitfully explored the patterns of adoption of product and process innovations across industries, few have studied these same patterns within individual firms. In this study we address this issue, examining the dynamics that govern the adoption of product and process innovations at the firm level over time. We examine questions such as: Which type of innovation is more readily adopted? Does the adoption of one type of innovation lead or lag the adoption of the other type? And, would the pattern of adoption of innovation types have an effect on organizational performance? Using data on the innovations introduced between 1982 and 1993 by a sample of 101 commercial banks in the United States, we find that: (1) product innovations are adopted at a greater rate and speed than process innovations; (2) a product–process pattern of adoption is more likely than a process–product pattern; (3) the adoption of product innovations is positively associated with the adoption of process innovations; and (4) high‐performance banks adopt product and process innovations more evenly than low‐performance banks.
A Belief‐focused Process Model of Organizational Learning*
Authors: Williams Allan P. O.
Published: July 2004

Applying the property of learning to organizations has caused confusion. The paper develops a proposed model or framework for capturing the essential process of organizational learning, and adopts a definition of learning which is applicable to both individual and organizational learning. A discussion of emergent and planned learning enables a case to be made for the importance of understanding organizational learning in a competitive and changing environment, and for the key role of senior managers in managing this process. The theoretical orientation is the social rather than the information processing perspective in that organizational learning is reflected in the construction, modification and maintenance of beliefs; particularly the beliefs towards those stakeholders who are instrumental in achieving an organization's mission and strategic goals. Theories and concepts are explored which account for these belief systems, and for the interaction between individual and organizational learning. They include: reinforcement, modelling, mental models and sensemaking, tacit and explicit knowledge, memory and culture. The paper concludes by examining a number of concerns in the literature in the light of the assumptions and suggestions incorporated in the model. The hope is that these will provoke discussion (and initiate learning) among practitioners and academics.
On durable goods markets with entry and adverse selection
Authors: Janssen Maarten , Roy Santanu
Published: July 2004

Abstract.  We investigate the nature of trading and sorting induced by the dynamic price mechanism in a competitive durable good market with adverse selection and exogenous entry of traders over time. The model is a dynamic version of Akerlof (1970). Identical cohorts of durable goods, whose quality is known only to potential sellers, enter the market over time. We show that there exists a cyclical equilibrium where all goods are traded within a finite number of periods after entry. Market failure is reflected in the length of waiting time before trade. The model also provides an explanation of market fluctuations. JEL classification: D82

A propos des marchés de biens durables quand il y a entrée de nouveaux commerçants et sélection adverse.  Les auteurs analysent la nature du commerce et du triage engendrés par le mécanisme dynamique des prix dans un marché concurrentiel de biens durables quand il y a sélection adverse et entrée exogène de nouveaux commerçants dans le temps. Ce modèle est une version dynamique du modèle d’Akerlof (1970). Des cohortes identiques de biens durables, dont la qualité est connue seulement des vendeurs potentiels, arrivent sur le marché dans le temps. Il semble qu’il y ait plus de commerce actif que ce qui est prévu par un modèle statique. En particulier, on montre qu’il existe un équilibre cyclique où tous les biens sont transigés à l’intérieur d’un nombre fini de périodes après leur arrivage et que, à chaque phase du cycle, l’éventail de qualité des biens transigés s’accroît. Les commerçants qui transigent des produits de plus haute qualité attendent plus longtemps et l’imperfection du marché se traduit par la longueur de temps d’attente avant la transaction. Le modèle fournit aussi une explication des fluctuations du marché.
Tax‐deferred savings plans and interest deductibility
Authors: Burbidge John B.
Published: July 2004

Abstract.  Programs that defer taxes on savings (e.g., RRSPs or 401(k)s) are supposed to move income tax systems closer to the more efficient consumption tax. Whether or not RRSPs move income tax systems away from or closer to a consumption tax depends on whether or not interest on debts incurred to make RRSP contributions is deductible for income tax purposes. If people optimize as assumed in simple life‐cycle models, then it may be that governments can convert a non‐linear income tax system to a proportional consumption tax system. I argue this is plausible for some Canadian households. JEL classification: H21, H24
Real exchange rates, preferences, and incomplete markets: evidence, 1961–2001
Authors: Head Allen C. , Mattina Todd D. , Smith Gregor W.
Published: July 2004

Abstract.  Many international macroeconomic models link the real exchange rate to a ratio of marginal utilities. We examine this link empirically, allowing the marginal utility of consumption to depend on government expenditure, real money balances, or external habit. We also consider two environments with incomplete asset markets; one with exogenously missing markets but an endogenous discount rate that anchors the distribution of wealth and one with endogenous market segmentation. Although none of these satisfies theoretical and over‐identifying restrictions for every country, utility with external habit persistence provides the best match with real exchange rates for OECD countries between 1961 and 2001. JEL classification: F41
HYPERTENSION IN HEMODIALYSIS PATIENTS: Blood Pressure Measurement in Hemodialysis Patients
Authors: Lazar Andrew E. , Smith Michael C. , Rahman Mahboob
Published: July 2004

Measurement of blood pressure (BP) poses some unique challenges in hemodialysis patients. Timing of BP measurement in relation to dialysis, changes in interdialytic weight gain, and inconsistent BP measurement technique in dialysis units contribute to the variability of BP readings in this population. This may contribute to the equivocal relationship between hypertension and cardiovascular outcomes documented in several epidemiologic studies in this population. Home BP readings are promising, but need to be validated as a measure of the burden of hypertension in this population. It is important to standardize BP measurement in all hemodialysis units according to published guidelines to improve the management of hypertension. Future research studies should carefully validate the technique used to measure BP.
HYPERTENSION IN HEMODIALYSIS PATIENTS: Ambulatory Blood Pressure Monitoring in Hemodialysis Patients: A Critique and Literature Review
Authors: Covic Adrian , Haydar Ali A. , Goldsmith David
Published: July 2004

Ambulatory blood pressure (ABP) monitoring has been in use for nearly four decades. In that time, the advantages of using a more reproducible and accurate method to assess the true contribution of blood pressure to the cardiovascular risk profile of patients have steadily become more clearly established, balanced by the additional expense and expertise involved. In nephrology, and in particular in dialysis patients, there are significant difficulties in accurately registering truly representative blood pressure values and understanding the relationship between blood pressure, end‐organ damage, and patient mortality. This arises because of the way in which hemodialysis acutely changes blood pressure values as well as the widespread abnormality of diurnal blood pressure rhythm seen in dialysis patients. Use of ABP monitoring can go some way to overcoming these obstacles. In this review we critically examine the use of ABP monitoring in the understanding of blood pressure control in dialysis patients.
HYPERTENSION IN HEMODIALYSIS PATIENTS: Role of Sodium and Volume in the Pathogenesis of Hypertension in Hemodialysis
Authors: Wilson Jimmy , Shah Tariq , Nissenson Allen R.
Published: July 2004

Hypertension is a common finding in chronic hemodialysis (HD) patients. Cardiovascular (CV) disease is the leading cause of death in this population, and hypertension is a significant risk factor for CV events. Understanding the etiology of hypertension in chronic HD patients is critical in order to optimize treatment and reduce the morbidity and mortality associated with hypertension. Although the pathogenesis of hypertension in HD patients is multifactorial, two of the major risk factors are increased extracellular volume and sodium intake. Control of extracellular volume has been shown to normalize blood pressure (BP), but this normalization lags behind the extracellular volume contraction (“lag phenomenon”). A sodium load leads to an increase in BP by causing an increase in extracellular volume, resulting in a transient increase in cardiac output and an increase in total peripheral resistance. Sodium may be implicated in the hypertension of end‐stage renal disease (ESRD) patients through hypervolemia‐independent mechanisms. Aggressive control of extracellular volume and dietary sodium intake can normalize BP in chronic HD patients and reduce the morbidity associated with hypertension‐related CV disease.
HYPERTENSION IN HEMODIALYSIS PATIENTS: Hypertension and Survival in Hemodialysis Patients
Authors: Lynn Kelvin L.
Published: July 2004

Hypertension is clearly an independent risk factor for cardiovascular (CV) events and death in the general population, but the relationship between blood pressure (BP) and survival in dialysis patients is less clear. In dialysis populations at lower risk of CV events, BP is directly related to survival, while in those with high risk, it has been difficult to show such an effect. The effects of cardiac disease complicate the relationship between BP and outcome. Retrospective studies of large cohorts, with high prevalence of CV disease, have shown a U‐shaped relationship between both systolic and diastolic BP and outcome. These findings probably reflect a high prevalence of cardiac failure and thus high mortality associated with low BP (i.e., a so‐called reverse causation). Pulse pressure (high systolic BP and low diastolic BP) predicts outcome in hypertensive dialysis patients. Whether this reflects advanced vessel wall disease or is an independent etiologically significant risk factor is unclear. However, the current uncertainties as to the exact relationship between BP and outcome in dialysis patients do not warrant complacency regarding the prevention and treatment of hypertension.
HYPERTENSION IN HEMODIALYSIS PATIENTS: Cardiac Disease in Chronic Uremia: Can it Explain the Reverse Epidemiology of Hypertension and Survival in Dialysis Patients?
Authors: Foley Robert N.
Published: July 2004

Definitive randomized trials are rare in the dialysis literature. Treatment decisions are often based on extrapolation from trials in other populations and observational studies in dialysis patients. “Reverse epidemiology” is a term increasingly applied to classic cardiovascular risk factors in studies of dialysis patients. The term is used when outcome associations are the opposite of those seen in general population studies. Hypertension is an archetypal example, with several studies showing inverse associations with mortality. As a term, “reverse epidemiology” is intellectually unsatisfactory because validation of the real direction of an association is only possible with experimental designs. In contrast, blood pressure (BP) is associated with typical association patterns for outcomes other than death, including left ventricular hypertrophy and cardiac failure, which are dominant entities in dialysis populations. There is a strong suspicion that current analytical approaches may partly explain the paradox. For example, it is possible that unmeasured comorbidities are associated with lower BP levels. In addition, few studies use BP as a time‐integrated parameter, which is problematic given the variability of this parameter. Several recent studies suggest that using pulse pressure as a BP parameter may normalize associations with mortality. BP, extracellular blood volume, residual renal function, and vasoactive medications are interlinked. Time‐integrated analysis that examines all these parameters concurrently makes sense, but has rarely been attempted. A large burden of cardiac disease and insensitive analytical approaches may go a long way toward explaining the reverse epidemiology of hypertension and survival in dialysis patients.
HYPERTENSION IN HEMODIALYSIS PATIENTS: Cardiac Consequences of Hypertension in Hemodialysis Patients
Authors: Zoccali Carmine , Benedetto Francesco Antonio , Tripepi Giovanni , Mallamaci Francesca
Published: July 2004

Hypertension in end‐stage renal disease (ESRD) is an important risk factor for left ventricular hypertrophy (LVH), cardiac failure, coronary artery disease (CAD), and arrhythmia. LVH is generally considered an integrator of the long‐term effects of hypertension and other cardiovascular (CV) risk factors and represents the strongest predictor of adverse CV outcomes in ESRD patients. The risk of heart failure is higher in patients with a history of hypertensive renal disease than in those with other diagnoses. Both coronary heart disease (CHD) and LVH predict congestive heart failure, which is often the ultimate cause of death in patients with cardiac ischemia or LVH. A history of long‐standing hypertension is associated with ischemic heart disease both in cross‐sectional and prospective studies in ESRD. Atrial fibrillation and ventricular arrhythmias are highly prevalent in dialysis patients and are implicated in mortality and sudden death in this population. Despite the lack of evidence from randomized controlled trials, it appears reasonable that interventions aimed at curbing the high CV mortality of ESRD should be targeted to both hypertension and LVH.