bluuebunny/crossref_metadata_2025 huggingface dataset:
High-dose Remifentanil Does Not Impair Cerebrovascular Carbon Dioxide Reactivity in Healthy Male Volunteers
Authors: Klimscha Walter , Ullrich Roman , Nasel Christian , Dietrich Wolfgang , Illievich Udo M. , Wildling Eckart , Tschernko Edda , Weidekamm Claudia , Adler Leopold , Heikenwälder Georg , Horvath Gyongyi , Sladen Robert N.
Published: November 2003

Background

Cerebrovascular carbon dioxide reactivity during high-dose remifentanil infusion was investigated in volunteers by measurement of regional cerebral blood flow (rCBF) and mean CBF velocity (CBFv).

Methods

Ten healthy male volunteers with a laryngeal mask for artificial ventilation received remifentanil at an infusion rate of 2 and 4 microg x kg-1 x min-1 under normocapnia, hypocapnia, and hypercapnia. Stable xenon-enhanced computed tomography and transcranial Doppler ultrasonography of the left middle cerebral artery were used to assess rCBF and mean CBFv, respectively. If required, blood pressure was maintained within baseline values with intravenous phenylephrine to avoid confounding effects of altered hemodynamics.

Results

Hemodynamic parameters were maintained constant over time. Remifentanil infusion at 2 and 4 microg x kg-1 x min-1 significantly decreased rCBF and mean CBFv. Both rCBF and mean CBFv increased as the arterial carbon dioxide tension increased from hypocapnia to hypercapnia, indicating that cerebrovascular reactivity remained intact. The average slopes of rCBF reactivity were 0.56 +/- 0.27 and 0.49 +/- 0.28 ml. 100 g-1 x min-1 x mmHg-1 for 2 and 4 microg x kg-1 x min-1 remifentanil, respectively (relative change in percent/mmHg: 1.9 +/- 0.8 and 1.6 +/- 0.5, respectively). The average slopes for mean CBFv reactivity were 1.61 +/- 0.95 and 1.54 +/- 0.83 cm x s-1 x mmHg-1 for 2 and 4 microg x kg-1 x min-1 remifentanil, respectively (relative change in percent/mmHg: 1.86 +/- 0.59 and 1.79 +/- 0.59, respectively). Preanesthesia and postanesthesia values of rCBF and mean CBFv did not differ.

Conclusion

High-dose remifentanil decreases rCBF and mean CBFv without impairing cerebrovascular carbon dioxide reactivity. This, together with its known short duration of action, makes remifentanil a useful agent in the intensive care unit when sedation that can be titrated rapidly is required.
The Neuroprotective Effect of Xenon Administration during Transient Middle Cerebral Artery Occlusion in Mice
Authors: Homi H. Mayumi , Yokoo Noriko , Ma Daqing , Warner David S. , Franks Nicholas P. , Maze Mervyn , Grocott Hilary P.
Published: November 2003

Background

Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion.

Methods

C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated.

Results

The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2 versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2 versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3 versus 59 +/- 11 mm3, respectively; P = 0.0009).

Conclusions

In this model of transient focal cerebral ischemia, xenon administration improved both functional and histologic outcome.
Isoflurane Pretreatment Has Immediate and Delayed Protective Effects against Cytokine-induced Injury in Endothelial and Vascular Smooth Muscle Cells
Authors: de Klaver Manuela J. M. , Buckingham Mary-Gordon , Rich George F.
Published: November 2003

Background

Volatile anesthetics have protective effects against cytokine-induced injury in endothelial and vascular smooth muscle cells. The authors hypothesized that isoflurane pretreatment may trigger immediate and delayed protection that is modulated by adenosine triphosphate-sensitive potassium channels.

Methods

Human and bovine endothelial cells and rat vascular smooth muscle cells were pretreated with isoflurane (1.5% for 30 min) and then exposed to cytokines (tumor necrosis factor-alpha, interferon-gamma, and interleukin-beta) for 72 h. Cytokine exposure was initiated immediately after isoflurane pretreatment or after a delay of 1-48 h. Cell survival and viability were evaluated by trypan blue exclusion and lactate dehydrogenase release. The role of mitochondrial and cell membrane adenosine triphosphate-sensitive potassium channels, or both, were evaluated with the antagonists 5-hydroxydecanoate, HMR-1098, or glybenclamide.

Results

Immediate isoflurane pretreatment was approximately 70% effective in increasing cell survival and prevented lactate dehydrogenase release in all cell lines. However, cellular protection was completely lost if the time between isoflurane and cytokine exposure was extended to 2-12 h, depending on the cell type. Delayed protection was equal to immediate protection when the interval was extended to 12-24 h, with protection being sustained at 48 h in human endothelial and rat vascular smooth muscle cells. The immediate and delayed protection was inhibited by glybenclamide and 5-hydroxydecanoate but not by HMR-1098, whereas diazoxide, a mitochondrial adenosine triphosphate-sensitive potassium channels agonist, mimicked the time course of isoflurane-induced immediate and delayed protection in all cell lines.

Conclusion

Isoflurane pretreatment has immediate and delayed protective effects against cytokine-induced injury in endothelial and vascular smooth muscle cells that seem to be modulated by mitochondrial adenosine triphosphate-sensitive potassium channels. The time course of immediate and delayed protection is similar but not identical for each cell type.
Immunoneutralization of c-Fos Using Intrathecal Antibody Electroporation Attenuates Chronic Constrictive Injury-induced Hyperalgesia and Regulates Preprodynorphin Expression in Rats
Authors: Lan Chen-Yu , Tan Ping-Heng , Cheng Jiin-Tsuey , Lu Hsiao-Feng , Lin Ming-Wei , Hsiao Po-Ni , Lin Chung-Ren
Published: November 2003

Background

In vivo electroporation has been successfully used for the introduction of DNA, RNA, oligonucleotides, and proteins into cells for experimental and therapeutic purposes. The authors evaluated the efficacy of electroporation-mediated c-Fos antibody therapy for neuropathic pain in vitro and in vivo.

Methods

First, the authors studied the inhibitory effects of intrathecal c-Fos antibody electroporation on the activating protein (AP-1) promoter activity in cultured spinal neuronal cells transfected with p-AP-Luc plasmid and activated with 100 microm glutamate. The inhibitory effect of c-Fos antibody electroporation in the regulation of AP-1 promoter activity was assessed according to the relative luciferase activity. Second, rats with chronic constrictive injury underwent electroporation treatment for neuropathic pain using c-Fos antibody. Thermal nociceptive thresholds were measured before chronic constrictive injury and then on even-numbered days, up to and including day 14, to assess and compare the therapeutic effects of intrathecal electroporation. The time course was assessed by Western blot analysis and by immunohistochemical analysis. Pronociceptive gene expression was measured by assessing prodynorphin mRNA and dynorphin peptides on days 2 and 10 after intrathecal c-Fos electroporation.

Results

Cotransfection of c-Fos antibody significantly decreased glutamate-induced AP-1 activity. Intrathecal electrotransfer of c-Fos antibody attenuated spinal dynorphin levels, as manifested by significantly elevated pain thresholds in the chronic constrictive injury-affected limbs.

Conclusion

This study shows that transfer of antibody into rat spinal cords by intrathecal electroporation is a useful method to study the function of endogenous factors of spinal-related disorders.
Women Have the Same Desflurane Minimum Alveolar Concentration as Men
Authors: Wadhwa Anupama , Durrani Jaleel , Sengupta Papiya , Doufas Anthony G. , Sessler Daniel I.
Published: November 2003

Background

Women generally report greater sensitivity to pain than do men, and healthy young women require 20% more anesthetic than healthy age-matched men to prevent movement in response to noxious electrical stimulation. In contrast, minimum alveolar concentration (MAC) for xenon is 26% less in elderly Japanese women than in elderly Japanese men. Whether anesthetic requirement is similar in men and women thus remains in dispute. The authors therefore tested the hypothesis that the desflurane concentration required to prevent movement in response to skin incision (MAC) differs between men and women.

Methods

Using the Dixon "up and down" method, the authors determined MAC for desflurane in 15 female and 15 male patients (18-40 yr old) undergoing surgery.

Results

MAC was 6.2 +/- 0.4% desflurane for women versus 6.0 +/- 0.3% for men (P = 0.31), a difference of only 3%. These data provide 90% power to detect a 9% difference between the groups.

Conclusions

The MAC of desflurane did not differ between young men and women undergoing surgery with a true surgical incision. Although pain sensitivity may differ in women versus men, MAC of desflurane does not.
Using Front-end Kinetics to Optimize Target-controlled Drug Infusions
Authors: Avram Michael J. , Krejcie Tom C.
Published: November 2003

Background

The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target.

Methods

Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 mug/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated.

Results

Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters.

Conclusions

Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.
The Critical Role of Concentration for Lidocaine Block of Peripheral Nerve In Vivo
Authors: Nakamura Tadashi , Popitz-Bergez Frederique , Birknes John , Strichartz Gary R.
Published: November 2003

Background

The adjustment of local anesthetic dosage for peripheral nerve block must meet two basic requirements: a drug concentration sufficient to inhibit Na+ channels to the point of impulse failure and a volume of drug sufficient to expose a length of nerve longer than the "critical length" for propagation failure. This study examines the lidocaine dosage requirement, in milligrams, for functionally assayed sciatic nerve block in the rat using a fourfold range of volume corresponding to concentrations from 2 to 7 mg/ml and compares these blocks with the intraneural lidocaine content after injection of equipotent doses.

Methods

Lidocaine was injected percutaneously at the sciatic nerve in volumes of 0.05 ml, 0.1 ml, and 0.2 ml (all at pH 6.8), and quantitative neurobehavioral assays were conducted on male Sprague-Dawley rats weighing from 200 to 250 g. The dose requirements for 50% maximum possible effect (ED50) and for just achieving complete block (i.e., minimal blocking dose for 90% effect), the fraction of completely blocked animals, and the duration of complete block at all doses were assessed for the inhibition of three different functions: proprioception, motor, and nocifensive activities. Radiolabeled (14C) lidocaine was injected in separate experiments, and the total drug content and its longitudinal distribution were determined in nerves dissected from animals (sevoflurane anesthetized) at 10 min, the time of peak block, after injection of the E50 and minimal blocking dose for 100% effect for the three different volumes.

Results

For all functions, the smaller the volume, the lower was the E50, resulting in a nearly constant concentration to achieve an equivalent degree of block. Durations of block were longer, and the dose to full block was lower for the smaller injected volumes. Intraneural lidocaine, at the equipotent doses for analgesia, was not related to concentration but rather increased with increasing volume, being almost proportional to the given dose. The longitudinal spread of lidocaine was also greater with increasing volume of lidocaine solution.

Conclusion

Blocks of greater depth and longer duration result from injection of smaller volumes and, correspondingly, higher lidocaine concentrations containing the same dose. The corollary is that lower lidocaine doses are required to achieve the same effect when smaller volumes are injected. Curiously, when the equivalent E50 is injected, total drug taken into the nerve is less from the smaller volumes than from the larger volumes, even though the peak functional effects are equal. Total intraneural local anesthetic may not represent the effective drug in the compartment that contains nerve axons, the actual location of neural blockade.
Chemosensory Factors Influencing Alcohol Perception, Preferences, and Consumption
Authors: Bachmanov Alexander A. , Kiefer Stephen W. , Molina Juan Carlos , Tordoff Michael G. , Duffy Valerie B. , Bartoshuk Linda M. , Mennella Julie A.
Published: November 2003

This article presents the proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, California, co‐organized by Julie A. Mennella and Alexander A. Bachmanov of the Monell Chemical Senses Center. The goal of this symposium was to review the role that chemosensory factors (taste, smell, and chemical irritation) play in the perception, preference, and consumption of alcohol. The presented research focused on both humans and laboratory animals and used a variety of approaches including genetic, developmental, pharmacological, behavioral, and psychophysical studies. The presentations were as follows: (1) Introduction and overview of the chemical senses (Julie A. Mennella and Alexander A. Bachmanov); (2) Taste reactivity as a measure of alcohol palatability and its relation to alcohol consumption in rats (Stephen W. Kiefer); (3) Early learning about the sensory properties of alcohol in laboratory animals (Juan Carlos Molina); (4) Early learning about the sensory properties of alcohol in humans (Julie A. Mennella); (5) Genetic dissection of the ethanol‐sweet taste relationship in mice (Alexander A. Bachmanov and Michael Tordoff); and (6) Human genetic variation in taste: connections with alcohol sensation and intake (Valerie B. Duffy and Linda M. Bartoshuk). The symposium concluded with a general discussion.
Herbal Remedies for Alcoholism: Promises and Possible Pitfalls
Authors: Overstreet David H. , Keung Wing‐Ming , Rezvani Amir H. , Massi Maurizio , Lee David Y. W.
Published: November 2003

This review summarizes the findings of the effects on alcohol intake in alcohol‐preferring rats of extracts or purified compounds from two of the most promising herbs: kudzu (Pueraria lobata) and St. John's Wort (Hypericum perforatum). It is a summary of a symposium presented at the 2002 RSA meeting in San Francisco. The meeting organizers/co‐chairs were David Overstreet and Wing‐Ming Keung. The presentations were (1) Introduction to the symposium, by David Y. W. Lee and David H. Overstreet; (2) Effects of daidzin on alcohol intake—search for mechanisms of action, by Wing‐Ming Keung; (3) Long‐term suppressive effects of puerarin on alcohol drinking in rats, by David Overstreet and David Y. W. Lee; (4) St. John's Wort extract reduces alcohol intake in FH and P rats, by Amir Rezvani and David Overstreet; and (5) Hypericum perforatum extracts reduce alcohol intake in Marchigian Sardinian alcohol‐preferring rats, by Maurizio Massi.
Disruption of Frontocerebellar Circuitry and Function in Alcoholism
Authors: Sullivan Edith V. , Harding Antony J. , Pentney Roberta , Dlugos Cynthia , Martin Peter R. , Parks Mitchell H. , Desmond John E. , Chen S. H. Annabel , Pryor Michelle R. , De Rosa Eve , Pfefferbaum Adolf
Published: November 2003

This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol‐related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical‐cerebellar circuits through neuroimaging study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and Functional reorganization of the brain in alcoholism: neuroimaging evidence, by John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf Pfefferbaum, and Edith V. Sullivan.
How Important Are Brain Banks for Alcohol Research?
Authors: Harper Clive , Garrick Therese , Matsumoto Izuru , Pfefferbaum Adolf , Adalsteinsson Elfar , Sullivan Edith , Dodd Peter , Lewohl Joanne , Butterworth Roger
Published: November 2003

This article contains the proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, organized and chaired by Clive Harper and co‐chaired by Izuru Matsumoto. The presentations were (1) Introduction, by Clive Harper; (2) The quality of tissue—a critical issue, by Therese Garrick; (3) The first systematic brain tissue donor program in Japan, by Izuru Matsumoto; (4) Brain scans after death—really! by Adolf Pfefferbaum, Elfar Adalsteinsson, and Edith Sullivan; (5) Capture that (genial) expression, by Joanne Lewohl and Peter Dodd; and (6) Neurochemical/pharmacological studies: experimental design and limitations, by Roger Butterworth.
Course of Alcohol Problems in Treated Adolescents
Authors: Chung Tammy , Martin Christopher S. , Grella Christine E. , Winters Ken C. , Abrantes Ana M. , Brown Sandra A.
Published: November 2003

Knowledge of the clinical course in treated adolescents is fundamental to determining the influence of treatment on long‐term functioning and the factors associated with change in the severity of alcohol problems over time. This symposium, held at the 2002 annual Research Society on Alcoholism meeting and organized by Tammy Chung and Christopher S. Martin, presented research on the course of alcohol‐related problems in treated adolescents who were followed prospectively for 1 to 8 years. Presentations included (1) Alcohol use outcomes at 1 year among adolescents in the drug abuse treatment outcomes studies (DATOS‐A), by Christine E. Grella; (2) Pathways and predictors of the course of adolescent alcohol problems across 1‐ and 3‐year follow‐ups, by Tammy Chung; (3) Young adult outcomes of an adolescent clinical sample at 5‐year follow‐up, by Ken C. Winters; and (4) Trajectories of alcohol involvement following addiction treatment through 8‐year follow‐up in adolescents, by Ana M. Abrantes, Denis M. McCarthy, Gregory A. Aarons, and Sandra A. Brown. Sandra A. Brown, discussant, commented on the presentations. Results from these studies indicate multiple pathways of change, distinguished by fluctuations in the chronicity and severity of alcohol problems. Across studies, most adolescents showed reductions in alcohol use and problems after treatment, with concurrent improvements in psychosocial functioning. Findings highlight the influence of other drug use on posttreatment patterns of alcohol involvement and the need to consider the effect of normative developmental transitions on the course of adolescent‐onset substance use disorders.
Strain‐Specific Brain Metallothionein II (MT‐II) Gene Expression, Its Ethanol Responsiveness, and Association With Ethanol Preference in Mice
Authors: Loney Kimberly D. , Uddin K. Raihan , Singh Shiva M.
Published: November 2003

Background: Metallothioneins (MTs) are ubiquitously expressed intracellular proteins that bind heavy metals such as zinc, copper, and cadmium. Although their specific function has yet to be discovered, they are known to regulate the metabolism of these metals as well as respond to cellular stress agents, particularly oxidants.

Methods: Brain RNA from experimental (8 g/kg 25% ethanol injection) and control (saline injection) mice from four strains (A/J, BALB/cJ, C57BL/6J, DBA/2J) that are known to differ with respect to ethanol preference was used in differential displays. This report includes molecular results on one gene (MT‐II) identified.

Results: Our results on differential displays suggest that a proportion of genes are differentially expressed across pair‐wise strain comparisons. We identified MT‐II as a strain‐specific and ethanol‐responsive gene. The level of MT‐II messenger RNA (mRNA) in control mice of A/J, BALB/cJ, C57BL/6J, and DBA/2J strains was variable (0.50, 0.51, 0.90, and 0.14 times G3PDH expression, respectively). The degree of up‐regulation in experimental mice was also somewhat variable among strains, ranging from 2.5 to 3.2 times expression over the matched controls. Experiments indicate that the promoter and genomic organization of the MT‐II gene is identical in sequence for all four strains, and methylation studies revealed that the MT‐II promoter region is unmethylated in the brains of these mice. Interestingly, MT‐II expression in control mice demonstrated a positive correlation with the ethanol preference phenotype.

Conclusion: An increase in MT‐II mRNA levels after injection of ethanol is attributed to the antioxidant properties of MT‐II. The differential mRNA levels of this gene among four strains are not accounted for by the genomic organization, DNA sequence, or methylation status of this gene. Furthermore, the observed correlation between MT‐II mRNA levels and ethanol preference raises an interesting hypothesis about the possible role of MT‐II in ethanol effects and preference in mice.
The Decreased Phosphorylation of Cyclic Adenosine Monophosphate (cAMP) Response Element Binding (CREB) Protein in the Central Amygdala Acts as a Molecular Substrate for Anxiety Related to Ethanol Withdrawal in Rats
Authors: Pandey Subhash C. , Roy Adip , Zhang Huaibo
Published: November 2003

Background: Several lines of evidence indicate a high comorbidity between anxiety and alcohol abuse. This study investigated the molecular mechanisms in the amygdaloid neurocircuitry governing anxiety related to ethanol withdrawal and also the phenomenon of alcohol preference.

Methods: Male Sprague Dawley® rats were treated with ethanol or control diet for 15 days, and ethanol‐fed rats were withdrawn for 0 and 24 hr. Ethanol‐withdrawn or control diet‐fed rats were bilaterally infused into central or basolateral amygdala with artificial cerebrospinal fluid or protein kinase A (PKA) activator or inhibitor. These rats were used to measure anxiety levels by the elevated plus‐maze test. Protein levels of various signaling molecules related to cyclic adenosine monophosphate (cAMP)‐response element binding (CREB) protein signaling in amygdaloid structures were determined by gold immunolabeling procedure. The messenger RNA levels of neuropeptide Y were determined by in situ polymerase chain reaction procedure.

Results: Ethanol withdrawal (24 hr) after chronic exposure (15 days) produced anxiety in rats as measured by elevated plus‐maze test. Ethanol withdrawal but not treatment significantly decreased the phosphorylation of CREB protein and protein levels of Ca2+/calmodulin‐dependent protein kinase IV without modulating the protein levels of total CREB and α‐catalytic subunit of protein kinase A (PKA‐Cα) in the central and medial amygdala. However, these changes were not observed in the basolateral amygdala. We also investigated the effects of manipulation of the phosphorylation status of CREB in the central amygdala by infusion of the PKA activator (Sp‐cAMPS) or inhibitor (Rp‐cAMPS) on anxiety levels in rats during ethanol withdrawal. When Sp‐cAMPS is specifically infused into the central amygdala, it dose‐dependently normalizes the decrease in CREB phosphorylation and prevents the development of anxiety in rats during ethanol withdrawal. On the other hand, Rp‐cAMPS infusions into the central or basolateral amygdala decrease CREB phosphorylation, but only infusion into the central amygdala provokes anxiety and increases alcohol preference in normal rats. We also found that alcohol preference provoked by decreased CREB phosphorylation is related to decreased expression of the neuropeptide Y gene in the central amygdala.

Conclusions: These novel results suggest the possibility that decreased CREB phosphorylation in the central amygdala acts as a common molecular correlate for anxiety and alcohol‐drinking behaviors and also is correlated with anxiety related to ethanol withdrawal.
Further Evidence of an Inverse Genetic Relationship Between Innate Differences in Alcohol Preference and Alcohol Withdrawal Magnitude in Multiple Selectively Bred Rat Lines
Authors: Chester Julia A. , Blose Annette M. , Froehlich Janice C.
Published: November 2003

Background: We have previously shown that a genetic association exists between low alcohol drinking and high alcohol withdrawal magnitude after acute alcohol exposure in alcohol‐naïve rats. However, the behavioral rating scale used in this prior study was not optimal for assessing the magnitude of mild alcohol withdrawal. The present study examined whether a genetic relationship is again found between alcohol preference and alcohol withdrawal magnitude when a sensitive measure is used to index mild alcohol withdrawal in rats.

Methods: Alcohol‐naïve, male rats selectively bred for alcohol preference (P, HAD1, HAD2) or nonpreference (NP, LAD1, LAD2) received a single intragastric infusion of alcohol (4.0 g/20.3 ml/kg body weight; 25% v/v) or water followed by acoustic startle testing.

Results: Startle probability and magnitude was greater in water‐treated P than in water‐treated NP rats. During alcohol withdrawal, startle probability and magnitude was suppressed in P rats and elevated in NP rats relative to water‐treated controls. Startle probability and magnitude was greater in water‐treated LAD1 rats than in water‐treated HAD1 rats. During alcohol withdrawal, startle probability and magnitude was suppressed in HAD1 and elevated in LAD1 rats relative to water‐treated controls at 20 hr after acute alcohol exposure. Startle probability and magnitude did not differ between water‐treated HAD2 and water‐treated LAD2 rats. During alcohol withdrawal, there was a trend toward decreased startle probability and magnitude in HAD2 rats compared with water‐treated controls.

Conclusions: The acoustic startle response to a tone stimulus is a sensitive measure of mild alcohol withdrawal in rats. Rats selectively bred for low alcohol intake showed greater alcohol withdrawal magnitude than did rats selectively bred for high alcohol intake. These results provide further evidence that an inverse genetic association exists between alcohol withdrawal magnitude and propensity toward alcohol drinking in rats.
Identification and Brief Treatment of Alcohol Problems with Medical Patients: An International Perspective
Authors: Barnett Nancy P. , Monti Peter M. , Cherpitel Cheryl , Bendtsen Preben , Borges Guilherme , Colby Suzanne M. , Nordqvist Cecilia , Johansson Kjell
Published: November 2003

This article summarizes the proceedings of a symposium at the 2002 RSA meeting in San Francisco, California. The chair was Peter Monti and co‐chair was Nancy Barnett. The aim of the symposium was to bring together researchers from the United States, Sweden, and Mexico to present current findings on the development and implementation of screening and intervention research in Emergency Departments (ED). Cheryl Cherpitel presented findings on the performance of the Rapid Alcohol Problems Screen (RAPS4), a 4‐item instrument used for screening for alcohol dependence and harmful drinking in the ED. Dr. Cherpitel also presented for her collaborator, Guilherme Borges, their research on the performance of a number of screening measures including the RAPS among Mexicans and Mexican‐Americans with alcohol‐related disorders in the ED. Preben Bendtsen described the implementation of an alcohol screening and intervention procedure delivered by ordinary ED staff in Sweden. Nancy Barnett presented data on characteristics related to readiness to change alcohol use in a sample of young adults who were treated in an ED for injury or intoxication.
Participation in Alcoholics Anonymous: Intended and Unintended Change Mechanisms
Authors: Owen Patricia L. , Slaymaker Valerie , Tonigan J. Scott , McCrady Barbara S. , Epstein Elizabeth E. , Kaskutas Lee Ann , Humphreys Keith , Miller William R.
Published: November 2003

This article is a compilation of the information presented at a symposium at the 2001 RSA Meeting in Montreal, Canada. The presentations were: (1) Maintaining change after conjoint behavioral alcohol treatment for men: the role of involvement with Alcoholics Anonymous, by Barbara S. McCrady and Elizabeth E. Epstein; (2) Changing AA practices and outcomes: Project MATCH 3‐year follow‐up, by J. Scott Tonigan; (3) Life events and patterns of recovery of AA‐exposed adults and adolescents, by Patricia L. Owen and Valerie Slaymaker; (4) Social networks and AA involvement as mediators of change, by Lee Ann Kaskutas and Keith Humphreys; and (5) What do we know about Alcoholics Anonymous? by William R. Miller, discussant.
G × E: A NIAAA Workshop on Gene‐Environment Interactions
Authors: Gunzerath Lorraine , Goldman David
Published: November 2003

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a May 2002 workshop on gene‐environment interaction (G × E) research to identify potential roadblocks to further research and to propose solutions to those roadblocks, to optimize investigative opportunities and multidisciplinary or multi‐institution collaborations, and to explore ways that NIAAA can facilitate G × E studies. Sessions included panels on animal models; phenotypes; genetic findings in humans; study designs and analytical methods; and assessment of environmental risk. Key among the identified challenges to progress in G × E research were issues of study design and sampling strategies; logistic and methodological costs and constraints; availability and understanding of data analysis techniques; potential stigmatization of study populations; and organizational/bureaucratic structures that are inadequate to address the unique needs of large‐scale, multicenter, longitudinal projects. Participants proposed a series of recommendations to address these issues.

Session coordinators included: Gayle Boyd, Kendall Bryant, Page Chiapella, Vivian Faden, David Goldman, and Antonio Noronha. Session participants included: Laura Almasy, Henri Begleiter, Raul Caetano, Bruce Dudek, Mary Dufour, Cindy Ehlers, Mary‐Anne Enoch, Joel Gelernter, David Goldman, Bridget Grant, Lorraine Gunzerath, Deborah Hasin, Andrew Heath, Victor Hesselbrock, J. Dee Higley, Shirley Hill, Kerry Jang, Raynard S. Kington, Rick Kittles, George Koob, Kenneth Leonard, Ting‐Kai Li, Jeffrey Long, William McBride, Matthew McGue, Kathleen Merikangas, Tamara Phillips, Bernice Porjesz, Carol Prescott, Theodore Reich, John Rice, Richard Rose, Charmaine Royal, Arnold Sameroff, Marc Schuckit, Kenneth Sher, Renee Sieving, Robert Taylor, Michael Windle, and Robert Zucker.
The Validity of DSM‐IV Alcohol Dependence: What Do We Know and What Do We Need to Know?
Authors: Hasin Deborah S. , Schuckit Marc A. , Martin Christopher S. , Grant Bridget F. , Bucholz Kathleen K. , Helzer John E.
Published: November 2003

This article presents the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, California. Deborah S. Hasin organized the symposium and co‐chaired it with Marc Schuckit. The purpose of the symposium was to provide an overview of what is known about the validity of DSM‐IV and ICD‐10 alcohol dependence and abuse, with a focus on work done since 1994. Presentations included: (1) Validity of DSM‐III‐R alcohol dependence in adolescents, by Christopher S. Martin; (2) Reliability and validity of DSM and ICD formulations of alcohol use disorders: findings from epidemiology, by Bridget F. Grant; (3) Validity and reliability of the alcohol‐dependence phenotype in the context of genetic studies, by Kathleen K. Bucholz; and (4) DSM‐IV and beyond: uniting the clinical utility of categories with the precision of dimensions, by John E. Helzer. The findings supported the validity of DSM‐IV alcohol dependence across numerous study designs and samples, suggested some value in a dimensional dependence measure, and raised questions about the validity of the diagnosis of alcohol abuse as currently defined. Marc Schuckit, as discussant for the symposium, placed the issues in perspective for the upcoming DSM‐V.
Ego Depletion and Self‐Regulation Failure: A Resource Model of Self‐Control
Authors: Baumeister Roy F.
Published: November 2003

Effective self‐regulation is an important key to successful functioning in many spheres, and failed self‐regulation may be centrally conducive to substance abuse and addiction. The program of research summarized here indicates that self‐regulation operates as a limited resource, akin to strength or energy, especially insofar as it becomes depleted after use‐leaving the depleted self subsequently vulnerable to impulsive and undercontrolled behaviors (including increased consumption of alcohol). The self's resources, which are also used for decision‐making and active responding, can be replenished by rest and positive emotions.
Persistent Alterations of Vasopressin and N‐Terminal Proatrial Natriuretic Peptide Plasma Levels in Long‐Term Abstinent Alcoholics
Authors: Döring Wolf K. H. , Herzenstiel Marie‐Nœlle , Krampe Henning , Jahn Henriette , Pralle Lars , Sieg Sonja , Wegerle Elisabeth , Poser Wolfgang , Ehrenreich Hannelore
Published: November 2003

Background: During alcohol withdrawal and early abstinence, severe alterations of electrolyte and water homeostasis and their regulating hormones are well recognized. Almost nothing is known about regeneration of these functions with long‐term abstinence. This cohort study was designed to monitor determinants of electrolyte and water balance over 280 days of abstinence in alcohol‐dependent men compared with healthy controls.

Methods: Vasopressin (AVP), N‐terminal proatrial natriuretic peptide, aldosterone, angiotensin II, and electrolytes, together with major parameters of kidney and liver function, were monitored in 35 male alcoholics aged 44 ± 8 years. Of these, 21 could be followed up to 280 days of strictly controlled abstinence due to their participation in the Outpatient Long‐Term Intensive Therapy for Alcoholics. The control group comprised 20 healthy male volunteers aged 39 ± 7 years.

Results: Basal AVP levels were found to be suppressed over the whole study period. In contrast, N‐terminal proatrial natriuretic peptide remained increased over all 280 days. No persistent alterations were found for aldosterone or angiotensin II. Sodium and potassium in plasma and urine returned to normal within a few weeks. Creatinine clearance, urea nitrogen in plasma and urine, urinary osmolality, hematocrit, and hemoglobin remained low as compared with controls over the entire study.

Conclusions: Chronic alcohol abuse causes severe and persistent alterations in the hormonal regulatory systems of electrolyte and water balance. The suppressed basal secretion of AVP may reflect a dysregulation in the brain that influences the hypothalamic‐pituitary‐adrenal axis function, mood, memory, addiction behavior, and craving during alcohol abstinence. These findings may provide a ground for future therapeutic approaches to stable abstinence.
Alcohol Consumption and HIV Disease Progression: Are They Related?
Authors: Samet Jeffrey H. , Horton Nicholas J. , Traphagen Elizabeth T. , Lyon Sarah M. , Freedberg Kenneth A.
Published: November 2003

Background: The relationship between alcohol consumption and HIV disease progression has received limited attention in the era of highly active antiretroviral therapy (HAART).

Methods: We assessed CD4 cell count, HIV RNA levels, and alcohol consumption in the past month, defined as none, moderate, and at risk, in 349 HIV‐infected people with a history of alcohol problems. We investigated the relationship between alcohol consumption and HIV disease markers CD4 cell count and HIV RNA level, stratified by HAART use, using multivariable regression.

Results: No significant differences in CD4 cell count or HIV RNA level were found across the categories of alcohol consumption for patients who were not receiving HAART. However, among patients who were receiving HAART, log HIV RNA levels were significantly higher in those with moderate (2.17 copies/ml) and at‐risk (2.73 copies/ml) alcohol use compared with none (1.73 copies/ml;p= 0.006). CD4 cell counts in those with moderate (368 cells/μl) and at‐risk (360 cells/μl) alcohol use were lower than for subjects who reported none (426 cells/μl;p= 0.07).

Conclusion: Among patients who have a history of alcohol problems and are receiving antiretroviral treatment, alcohol consumption was associated with higher HIV RNA levels and lower CD4 counts. No comparable association was found for similar patients who were not receiving HAART. Addressing alcohol use in HIV‐infected patients, especially those who are receiving HAART, may have a substantial impact on HIV disease progression.
Age‐Dependent Changes in Electroencephalographic Responses to Alcohol Consumption in Subjects with Aldehyde Dehydrogenase‐2 Genetic Variations
Authors: Nishimura Fusae T. , Fukunaga Tatsushige , Yokomukai Yoshiko , Kajiura Hideaki , Ono Taketoshi , Nishijo Hisao
Published: November 2003

Background: We have recently reported that alcohol consumption resulted in a significant increase in α power of the EEGs in aldehyde dehydrogenase‐2 (ALDH2)‐normal (NN) subjects but not in ALDH2‐deficient heterozygote (ND) subjects. The purpose of the present study was to investigate interactive effects of individual factors such as age and ALDH2 genotype on alcohol‐induced EEG changes.

Methods: We examined EEG power spectral changes induced by 0.4 ml/kg of alcohol ingestion in 53 NN and 21 ND subjects of two different age groups: younger and older groups. Blood ethanol and acetaldehyde levels were also determined in 17 NN and 13 ND subjects in separate studies.

Results: Alcohol consumption markedly increased EEG power in the NN subjects of the older group, especially in θ and slow α power, whereas only slight increases were noted in fast α and β power in the NN subjects of the younger group. However, no such differences between the two age groups were observed in the ND subjects. It should be noted that there were no differences in blood ethanol and acetaldehyde level at 30 min after alcohol ingestion between the different age groups in both genotypes. However, there was a significant increase in frequency of alcohol intake in the older group of both genotype groups. The multiple regression analysis indicated that both alcohol use habits and genotype, as well as aging, significantly modulated EEG changes after alcohol ingestion.

Conclusions: The results suggest that both ALDH2 genotype and age as well as alcohol use habits modify alcohol sensitivity in the central nervous system, resulting in greater increases in EEG energy in response to alcohol intake in the older group of the NN subjects.
Alcohol Choice and Amphetamine Effects in Light and Moderate Drinkers
Authors: Stoops William W. , Fillmore Mark T. , Poonacha Melania S. , Kingery Joe E. , Rush Craig R.
Published: November 2003

Background: The results of previously published reports suggest that light and moderate drinkers respond differently to the effects of commonly abused sedatives (e.g., diazepam or ethanol). The purpose of this experiment was to determine whether light and moderate drinkers respond differentially to the effects of ethanol and d‐amphetamine.

Methods: In the first phase of this experiment, volunteers (eight light drinkers and eight moderate drinkers) randomly sampled 0.5 g/kg of ethanol and placebo across two separate sessions. In the second phase, volunteers completed three sessions in which they chose either ethanol or placebo. In the third phase, volunteers received 0, 5, 10, and 15 mg of d‐amphetamine. Each dose was tested twice. After drug administration in each phase, volunteers completed a battery of subject‐rated, performance, and physiologic measures periodically for 5 hr.

Results: Ethanol produced prototypical subject‐rated effects (e.g., increased ratings on the Alcohol Sensation Scale), but it was chosen over placebo infrequently. Light and moderate drinkers did not differ in terms of the self‐reported or reinforcing effects of ethanol. d‐Amphetamine produced prototypical subject‐rated stimulant‐like effects (e.g., dose‐dependent increases in ratings of High and Rush). Moderate drinkers reported significantly greater drug effects than light drinkers. Responses to ethanol reliably predicted subsequent responses to d‐amphetamine on several measures.

Conclusions: The results of this experiment suggest that even moderate ethanol use may increase an individual's vulnerability to abuse drugs. Future studies should determine whether light and moderate drinkers respond differentially to other commonly abused drugs (e.g., opioids) and whether behavioral responses to ethanol also predict responses to these compounds.
Correlation Between Adenosine Triphosphate Content and Apoptosis in Liver of Rats Treated With Alcohol
Authors: Fukumura Atsushi , Tsutsumi Mikihiro , Tsuchishima Mutsumi , Takase Shujiro
Published: November 2003

Background: Chronic alcohol consumption depresses adenosine triphosphate (ATP) synthesis and induces mitochondrial DNA (Mt‐DNA) deletion. ATP content in cells may play a critical role in inducing cell death, apoptosis, or necrosis. However, it is unknown which type of cell death occurs in alcoholic liver disease. In this study, the deletions of hepatic Mt‐DNA, hepatic ATP content, and the number of single‐stranded DNA (ss‐DNA) of hepatocytes in rats treated with ethanol were determined to elucidate the relationship among Mt‐DNA deletion, ATP synthesis, and/or hepatic apoptosis.

Methods: Sixteen male Wistar rats were fed with a liquid diet containing 36% ethanol (E group) or liquid diet without ethanol (C group) for 5 weeks. Hepatic ATP content was measured and the deletions of Mt‐DNA encoding complexes I, IV, and V were determined in fresh liver tissue, and ss‐DNA was stained in paraffin sections.

Results: Fatty change was observed in the E group, but not in the C group. Hepatic ATP content in the E group was 0.44 μmol/g of liver, which was significantly lower than that in the C group (0.84 μmole/g of liver). However, no deletion of Mt‐DNA encoding complexes I, IV, and V was detected in either the E or the C group. ss‐DNA staining was clearly observed in the nuclei of hepatocytes in both groups. The number of ss‐DNA‐positive hepatocytes in the E group was 5.6 ± 1.8/10,000 hepatocytes, which was significantly less than that in the C group: 20.6 ± 4.8/10,000 hepatocytes. There was a positive correlation between hepatic ATP contents and the number of ss‐DNA‐positive cells.

Conclusions: The results suggest that mitochondrial function, at least in part ATP synthesis, was depressed before the damage of Mt‐DNA by chronic ethanol consumption. Chronic ethanol consumption may not be responsible for the apoptosis of hepatocytes.
The Production of Tumor Necrosis Factor‐α by Macrophages in Rats With Acute Alcohol Loading
Authors: Kitazawa Toshiyuki , Nakatani Yoshihiro , Fujimoto Masao , Tamura Nobuhiro , Uemura Masahito , Fukui Hiroshi
Published: November 2003

Background:It is suggested that endotoxin, proinflammatory cytokines, and lipopolysaccharide‐binding protein (LBP) play an important role in the development of alcoholic liver disease. Our previous study showed that splenic macrophages were important for endotoxin uptake and excessive production of tumor necrosis factor (TNF) in rats given large amounts of alcohol. To study the pathophysiological roles of macrophages in alcoholic liver diseases, we examined the production of TNF‐α by rat Kupffer cells, splenic macrophages, and alveolar macrophages with acute alcohol loading in the presence or absence of LBP.

Methods:Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from male Wistar rats given 5 mg/g body weight of ethanol intraperitoneally after an hour. The production of TNF‐α by these cells incubated with endotoxin 100 ng/ml in the presence or absence of LBP (1% rat serum) was determined.

Results:Acute alcohol loading did not affect the production of TNF‐α by Kupffer cells. With acute alcohol loading, splenic macrophages tended to produce more TNF‐α. Alveolar macrophages produced more TNF‐α than Kupffer cells, and although the production of TNF‐α by alveolar macrophages tended to be suppressed by acute alcohol loading, the production of TNF‐α by alveolar macrophages still remained high in the presence of rat serum.

Conclusions:Splenic macrophages and alveolar macrophages may be related to excessive production of TNF‐α in acute alcoholics with endotoxemia.