bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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.
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.