bluuebunny/crossref_metadata_2025 huggingface dataset:
Isoflurane Reduction of Carbachol-evoked Cytoplasmic Calcium Transients Is Dependent on Caffeine-sensitive Calcium Stores
Authors: Corrales Alexandra , Xu Fang , Garavito-Aguilar Zayra , Blanck Thomas J. J. , Recio-Pinto Esperanza
Published: November 2003

Background

Many muscarinic functions are relevant to anesthesia, and alterations in muscarinic activity affect the anesthetic/analgesic potency of various drugs. Volatile anesthetics have been shown to depress muscarinic receptor function, and inhibition of the muscarinic signaling pathway alters the minimal alveolar anesthetic concentration of inhaled anesthetics. The purpose of this investigation was to determine in a neuronal cell which source of Ca2+ underlying the carbachol-evoked transient increase in cytoplasmic Ca2+ was reduced by isoflurane.

Methods

Experiments were performed at 37 degrees C on continuously perfused monolayers of human neuroblastoma SH-SY5Y cells using Fura-2 as the cytoplasmic Ca2+ indicator. Carbachol (1 mm) was applied to evoke a transient increase in cytoplasmic Ca2+.

Results

Isoflurane (1 mm) reduces the carbachol-evoked transient increase in cytoplasmic Ca2+, and this isoflurane action is eliminated when the cells are continuously stimulated with 200 mm KCl or pretreated with 10 mm caffeine or 200 microm ryanodine.

Conclusions

Isoflurane reduction of the carbachol-evoked transient increase in cytoplasmic Ca2+ requires full caffeine-sensitive Ca2+ stores and Ca2+ release from the caffeine-sensitive stores through the ryanodine-sensitive Ca2+ release channels. The results indicate that isoflurane interferes with a muscarinic Ca2+ signaling through a mechanism downstream from the muscarinic receptors.
Acetazolamide Reduces Referred Postoperative Pain after Laparoscopic Surgery with Carbon Dioxide Insufflation
Authors: Woehlck Harvey J. , Otterson Mary , Yun Hyun , Connolly Lois A. , Eastwood Daniel , Colpaert Krista
Published: November 2003

Background

Carbon dioxide is the preferred insufflating gas for laparoscopy because of greater safety in the event of intravenous embolism, but it causes abdominal and referred pain. Acidification of the peritoneum by carbonic acid may be the major cause of pain from carbon dioxide insufflation. Carbonic anhydrase is an enzyme that increases the rate of carbonic acid formation from carbon dioxide. Because acetazolamide inhibits carbonic anhydrase, the authors hypothesized that the pain caused by carbon dioxide insufflation may be decreased by the administration of acetazolamide.

Methods

A prospective, randomized, double-blind study of 38 patients undergoing laparoscopic surgery during general anesthesia was performed. Acetazolamide (5 mg/kg) or a saline placebo was administered intravenously during surgery. Pain was rated on a visual analog scale (0-10) at four times: when first awake, at discharge from the recovery room, when discharged from the hospital, and on the day after surgery. The site and quality of pain were recorded, as were medications and side effects.

Results

Initial referred pain scores were lower after acetazolamide (1.00 +/- 1.98; n = 18) than after placebo (3.40 +/- 3.48; n = 20; P = 0.014), and 78% of patients in the acetazolamide group had no referred pain; however, only 45% patients in the placebo group had no referred pain. Incisional pain scores were not statistically different, and referred pain scores were similar at later times.

Conclusions

Acetazolamide reduces referred but not incisional pain after laparoscopic surgical procedures. The duration of pain reduction is limited to the immediate postsurgical period.
Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2Cannabinoid Receptors
Authors: Quartilho Aline , Mata Heriberto P. , Ibrahim Mohab M. , Vanderah Todd W. , Porreca Frank , Makriyannis Alexandros , Malan T. Philip
Published: November 2003

Background

Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia.

Methods

Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251.

Results

AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection.

Conclusions

Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.
Comparative Neurotoxicity of Intrathecal and Epidural Lidocaine in Rats
Authors: Kirihara Yumiko , Saito Yoji , Sakura Shinichi , Hashimoto Keishi , Kishimoto Tomomune , Yasui Yukihiko
Published: November 2003

Background

Although there is a considerable difference in the number of clinical reports of neurologic injury between spinal anesthesia and other regional techniques, there are no animal data concerning a difference in the local anesthetic neurotoxicity between intrathecal and epidural administration. In the current study, the functional and morphologic effects of lidocaine administered intrathecally and epidurally were compared in rats.

Methods

Male rats were implanted with an intrathecal or epidural catheter through L4-L5 vertebra in the caudal direction. In experiment 1, to determine relative anesthetic potency, 16 rats received repetitive injections of 2.5% lidocaine into intrathecal or epidural space in different volumes and were examined for tail flick test for 90 min. In experiment 2, to ascertain whether the relative potency obtained in experiment 1 would apply to other concentrations of lidocaine, additional rats received saline, 1%, 2.5%, or 5% lidocaine in a volume of 20 or 100 microl through the intrathecal or epidural catheter, respectively. In experiment 3, additional rats that received saline, 2.5% lidocaine, or 10% lidocaine in a volume of 20 or 100 microl through the intrathecal or epidural catheter, respectively, were examined for persistent functional impairment and morphologic damage.

Results

In experiment 1, the two techniques produced parallel dose-effect curves that significantly differed from each other. The potency ratio calculated was approximately 4.72 (3.65-6.07):1 for intrathecal:epidural lidocaine. In experiment 2, every lidocaine solution produced a similar increase in tail flick latency for the two techniques. In experiment 3, five of eight rats given 10% intrathecal lidocaine incurred functional impairment 4 days after injection, whereas no rats in the other groups did. Significantly more morphologic damage was observed in rats given 10% intrathecal lidocaine than in those given 10% epidural lidocaine.

Conclusions

Persistent functional impairment occurred only after intrathecal lidocaine. Histologic damage in the nerve roots and the spinal cord was less severe after epidural lidocaine than after intrathecal lidocaine. The current results substantiate the clinical impression that neurologic complications are less frequent after epidural anesthesia than after spinal anesthesia.
Comparison of the LMA-Classic ™ with the New Disposable Soft Seal Laryngeal Mask in Spontaneously Breathing Adult Patients
Authors: van Zundert André A. J. , Fonck Kristine , Al-Shaikh Baha , Mortier Eric
Published: November 2003

Background

The laryngeal mask airway LMA-Classic has been used widely in clinical practice. A new disposable supraglottic airway device, the Soft Seal LM, has been introduced recently. In a randomized study, the authors compared the LMA-Classic and the disposable Soft Seal LM in terms of their clinical performance, cuff pressures during nitrous oxide anesthesia, position of the laryngeal mask in situ by fiberoptic evaluation, and morbidity in a wide range of routine general surgery procedures.

Methods

A total of 200 adult patients were randomly assigned to a size 4 laryngeal mask in two equal-sized groups for airway management during surgery: (1) LMA-Classic (Intavent Orthofix Ltd., Maidenhead, Berkshire, United Kingdom); or (2) Soft Seal LM (Portex Ltd., Hythe, Kent, United Kingdom). Anesthesia was administered with fentanyl, propofol, nitrous oxide, oxygen, and sevoflurane. The variables studied were ease of insertion, fiberoptic view, time in situ, incidence of blood on the laryngeal mask at the time of removal, and the incidence of postoperative sore throat at 2 and 24 h. The laryngeal mask cuff pressures were measured continuously. Intracuff pressure limitation was not attempted.

Results

The LMA-Classic and the Soft Seal LM showed similar clinical performances, as shown by their insertion time (successful insertion at first attempt was achieved within 20 s in 97% with LMA-Classic trade mark vs. 95% with Soft Seal LM), fiberoptic evaluation of the anatomic position of the laryngeal mask, and satisfactory anesthesia conditions. Laryngeal mask cuff pressures increased from 45 to 100.3 mmHg in the LMA-Classic and from 45 to 46.8 mmHg in the Soft Seal LM (P < 0.001). Macroscopic blood was seen on only four occasions in the LMA-Classic group. The incidence of sore throat was significantly increased at 2 h postoperatively when using the LMA-Classic, although there was no difference at 24 h after surgery.

Conclusions

In spontaneously breathing adult patients requiring a size 4 laryngeal mask airway, the new disposable Soft Seal LM device is an acceptable alternative to the reusable LMA-Classic trade mark, resulting in a good laryngeal seal and offering similar clinical performance. Cuff pressures increase substantially when the LMA-Classic is used but not when using the Soft Seal LM. There was less trauma to patients using the Soft Seal LM, as assessed by the incidence of sore throat in the early postoperative period.
Evaluation of Rapid Ischemic Preconditioning in a Rabbit Model of Spinal Cord Ischemia
Authors: Kakimoto Meiko , Kawaguchi Masahiko , Sakamoto Takanori , Inoue Satoki , Furuya Hitoshi , Nakamura Mitsutoshi , Konishi Noboru
Published: November 2003

Background

Rapid ischemic preconditioning (IPC) has been shown to reduce cellular injury after subsequent cardiac and cerebral ischemia. However, the data on rapid IPC of the spinal cord is limited. The authors investigated whether pretreatment with sublethal ischemia of spinal cord can attenuate neuronal injury after spinal cord ischemia in rabbits.

Methods

Forty-seven male New Zealand white rabbits were randomly assigned to one of three groups (n = 15 or 16 each). In the IPC(-) group, the infrarenal aorta was occluded for 17 min to produce spinal cord ischemia. In the IPC(+) group, 5 min of aortic occlusion was performed 30 min before 17 min of spinal cord ischemia. In the sham group, the aorta was not occluded. Hind limb motor function was assessed at 3 h, 24 h, 4 days, and 7 days after reperfusion using Tarlov scoring (0 = paraplegia; 4 = normal). Animals were killed for histopathologic evaluation at 24 h or 7 days after reperfusion. The number of normal neurons in the anterior spinal cord (L4-L6) was counted.

Results

Neurologic scores were significantly higher in the IPC(+) group than the IPC(-) group at 3 and 24 h after reperfusion (P < 0.05). However, neurologic scores in the IPC(+) group gradually decreased and became similar to those in the IPC(-) group at 4 and 7 days after reperfusion. At 24 h after reperfusion, the numbers of normal neurons were significantly higher in the IPC (+) group than in the IPC(-) group (P < 0.05) and were similar between the IPC(+) and sham groups. At 7 days after reperfusion, there was no difference in the number of normal neurons between the IPC(+) and IPC(-) groups.

Conclusion

The results indicate that rapid IPC protects the spinal cord against neuronal damage 24 h but not 7 days after reperfusion in a rabbit model of spinal cord ischemia, suggesting that the efficacy of rapid IPC may be transient.
Selective Blockade of AT1 Receptor Attenuates Impairment of Hypotensive Autoregulation and Improves Cerebral Blood Flow after Brain Injury in the Newborn Pig
Authors: Baranov Dimitry , Armstead William M.
Published: November 2003

Background

Fluid percussion injury (FPI) in piglets produces vasoconstriction of pial arteries (PAs), decreases in cerebral blood flow (CBF), and impairment of hypotensive autoregulation. Two types of angiotensin II receptors, AT1 and AT2, have been identified in the brain. This study characterized the effect of pretreatment with AT1- and AT2-selective antagonists on CBF and hypotensive autoregulation after FPI.

Methods

Fluid percussion injury was induced in chloralose-anesthetized newborn pigs equipped with closed cranial windows. CBF was determined by the radiolabeled microsphere technique.

Results

Moderate and severe hypotension (71 +/- 3, 53 +/- 2, and 40 +/- 1 mmHg for normotension, moderate hypotension, and severe hypotension, respectively) elicited PA dilation without changes in CBF in sham control piglets. The AT1 antagonist ZD 7155 partially restored impaired hypotension-induced PA dilation after FPI (19 +/- 1 and 34 +/- 1 vs. 5 +/- 1 and 7 +/- 1 vs. 12 +/- 1 and 20 +/- 3% for PA dilation during moderate and severe hypotension in sham control, FPI, and FPI + ZD 7155 animals, respectively). ZD 7155 also blunted the reductions in CBF during normotension and hypotension observed in untreated animals (43 +/- 4, 38 +/- 5, and 55 +/- 3 vs. 32 +/- 4, 19 +/- 2, and 27 +/- 5% CBF reductions during normotension, moderate hypotension, and severe hypotension in untreated and pretreated animals, respectively). The AT2 selective antagonist PD 123,319 did not restore hypotension-induced PA dilation and did not prevent decreases in CBF observed during normotension and moderate and severe hypotension after FPI.

Conclusion

These data indicate that blockade of the AT1 and not the AT2 receptor diminished the reduction in hypotensive PA dilation after FPI. AT1 blockade also blunted the decrease in CBF during normotension as well as the further decrease in CBF observed during hypotension after FPI. These data suggest that AT1 receptor activation by angiotensin II contributes to cerebrovascular dysregulation during hypotension after FPI.
Severe Hypotension Is Not Essential for Isoflurane Neuroprotection against Forebrain Ischemia in Mice
Authors: Homi H. Mayumi , Mixco Javier M. , Sheng Huaxin , Grocott Hilary P. , Pearlstein Robert D. , Warner David S.
Published: November 2003

Background

Volatile anesthetics provide protection in experimental models of global cerebral ischemia. To date, all models evaluated have included profound systemic arterial hypotension as a component of the ischemic insult. This study was designed to determine if isoflurane protection persists in a global insult devoid of hypotension.

Methods

C57BL/6J mice having a high incidence of posterior communicating artery atresia were anesthetized with isoflurane (1.2%) or fentanyl/N2O and subjected to bilateral carotid artery occlusion for 15 min or 20 min with normotension (80-110 mmHg mean arterial pressure) or for 10 min with hypotension (35 mmHg mean arterial pressure). Three days later, neurologic function and histologic damage were assessed. Other mice underwent measurement of intraischemic cerebral blood flow (4-iodo-N-methyl-[14C]antipyrine autoradiography) or plasma norepinephrine.

Results

Isoflurane reduced the percentage of hippocampal CA1 dead neurons (e.g., 10 min bilateral carotid occlusion + hypotension: 43 +/- 18 (isoflurane) vs. 67 +/- 20 (fentanyl/N2O), P = 0.003; 20 min bilateral carotid occlusion + normotension: 49 +/- 27 (isoflurane) vs. 71 +/- 22 (fentanyl/N2O), P = 0.003). Isoflurane also reduced CA3 damage and improved neurologic function under all conditions. Intraischemic forebrain blood flow was similar during bilateral carotid occlusion plus normotension for the two anesthetic states. Plasma norepinephrine values were greater when hypotension was added to the ischemic insult.

Conclusions

Isoflurane resulted in improved neurologic function and reduced histologic damage regardless of the presence or absence of systemic hypotension during the ischemic insult. This indicates that beneficial effects of isoflurane are most likely attributable to direct effects at the neuronal level as opposed to indirect effects resulting from interactions with profound hypotension.
Arthroscopic Knee Surgery Does Not Modify Hyperalgesic Responses to Heat Injury
Authors: Werner Mads U. , Duun Preben , Kraemer Otto , Lassen Birgit , Kehlet Henrik
Published: November 2003

Background

Experimental studies suggest that surgical injury may up- or down-regulate nociceptive function. Therefore, the aim of this clinical study was to evaluate the effect of elective arthroscopically assisted knee surgery on nociceptive responses to a heat injury.

Methods

Seventeen patients scheduled to undergo repair of the anterior cruciate ligament and 16 healthy controls were studied. The first burn injury was induced 6 days before surgery, and the second burn was induced 1 day after surgery with a contact thermode (12.5 cm2, 47 degrees C for 7 min) placed on the medial aspect of the calf contralateral to the surgical side. Ibuprofen and acetaminophen were given for 2 days before the first burn injury and again from the time of surgery. In the controls, the two burn injuries were separated by 7 days. Sensory variables included cumulated pain score during induction of the burn (visual analog scale), secondary hyperalgesia area, and mechanical and thermal pain perception and pain thresholds assessed before and 1 h after the burn injury.

Results

The heat injuries induced significant increases in pain perception (P < 0.001) and decreases in pain thresholds (P < 0.02). Baseline heat pain thresholds were higher during the second burn injury in patients (P < 0.001) and controls (P < 0.01). However, there were no significant differences in pain to heat injury (P > 0.8), secondary hyperalgesia areas (P > 0.1), mechanical and thermal pain perception (P > 0.1), or mechanical and thermal pain thresholds (P > 0.08) in the burn area before surgery compared to after surgery.

Conclusion

Arthroscopic knee surgery did not modify nociceptive responses to a contralaterally applied experimental burn injury.
Efficacy, Safety, and Pharmacokinetics of Levobupivacaine with and without Fentanyl after Continuous Epidural Infusion in Children
Authors: Lerman Jerrold , Nolan Judith , Eyres Rob , Schily Mark , Stoddart Peter , Bolton Christopher M. , Mazzeo Frank , Wolf Andrew R.
Published: November 2003

Background

Levobupivacaine, the levo-enantiomer of bupivacaine, is as potent as bupivacaine but less toxic. Therefore, the authors investigated the efficacy, safety, and pharmacokinetics of perioperative epidural levobupivacaine with and without fentanyl in children.

Methods

After Research Ethics Board approval and informed written consent, 120 healthy children aged 6 months to 12 yr who were scheduled to undergo urologic or abdominal surgery were randomized in a double-blinded and concealed manner to receive one of four epidural solutions as a continuous infusion for 24 h: 0.125% levobupivacaine; 0.0625% levobupivacaine; 1 mug/ml fentanyl; or the combination, 0.0625 levobupivacaine and 1 mug/ml fentanyl. After induction of anesthesia and tracheal intubation, a lumbar epidural catheter was sited, a loading dose was administered (0.75 ml/kg levobupivacaine, 0.175%), and the epidural infusion was commenced. The primary endpoint was the need for rescue analgesia (morphine) in the first 10 h after surgery. Pain, motor strength, and side effects were recorded for 24 h. Venous blood was collected from 18 children to determine the plasma concentrations of levobupivacaine and/or fentanyl before and 2, 4, 8, 16, 24, and 26 or 30 h after the start of the epidural infusion.

Results

Of the 114 children who were analyzed for intention to treat, a similar number of children in each group reached the 10-h mark. The time to the first dose of morphine in the first 10 h was less in the plain fentanyl group (P < 0.044). All other effects were similar among the four groups. The plasma concentration of levobupivacaine increased during the infusion period, reaching a maximum of 0.76 +/- 0.11 mug/ml in the 0.125% group and 0.48 +/- 0.12 mug/ml in the 0.0625% group by 24 h. The plasma concentration of fentanyl also increased steadily, reaching a maximum concentration of 0.37 +/- 0.11 ng/ml by 24 h.

Conclusion

We conclude that 0.0625% levobupivacaine without fentanyl is an effective perioperative epidural solution in children when infused at a rate of 0.3 ml. kg-1. h-1. The plasma concentrations of 0.125% and 0.0625% levobupivacaine and fentanyl (1 mug/ml) at the end of a 24-h infusion are low.
Reporting of Ethical Approval and Informed Consent in Clinical Research Published in Leading Anesthesia Journals
Authors: Myles Paul S. , Tan Nicole
Published: November 2003

Background

Ethical conduct in human research in anesthesia includes approval by an institutional review board (IRB) or ethics committee and informed consent. Evidence of these is sometimes lacking in journal publications.

Methods

The authors reviewed all publications involving human subjects in six leading anesthesia journals for the year 2001 (n = 1189). Rates of IRB approval and informed consent were examined and compared with potential predictors that included journal, type of publication, and patient demographics (age, sex, elective or emergency status). Rates were compared by use of chi-square and logistic regression.

Results

The authors found that IRB approval was documented in 71% of publications and consent was obtained in 66% of publications. Significant variation in IRB approval and consent was found among journals (P < 0.0005) and according to type of publication (P < 0.0005). Because publication type affected rates of IRB approval and consent (trials > mechanistic studies > observational studies > case reports), an analysis restricted to prospective studies also found a significant difference in IRB approval and consent among journals (P < 0.0005).

Conclusions

This study suggests that rates of IRB approval and informed consent vary among publications in anesthesia journals. Clearer guidelines (and author adherence) for all types of publication are needed, both as a protection for research subjects and to maintain public trust in the process.
New Neuronal Networks Involved in Ethanol Reinforcement
Authors: Kiianmaa Kalervo , Hyytiä Petri , Samson Herman H. , Engel Jörgen A. , Svensson Lennart , Söderpalm Bo , Larsson Anna , Colombo Giancarlo , Vacca Giovanni , Finn Deborah A. , Bachtell Ryan K. , Ryabinin Andrey E.
Published: November 2003

This article represents the proceedings of a symposium at the 2002 ISBRA/RSA meeting in San Francisco. The organizers were Kalervo Kiianmaa and Andrey E. Ryabinin. The chairs were Kalervo Kiianmaa and Jörgen A. Engel. The presentations were (1) The role of opioidergic and dopaminergic networks in ethanol‐seeking behavior, by Kalervo Kiianmaa and Petri Hyytiä; (2) Interaction between the dopamine systems in the prefrontal cortex and nucleus accumbens during ethanol self‐administration, by Herman H. Samson; (3) Neurochemical and behavioral studies on ethanol and nicotine interactions, by Jörgen A. Engel, Lennart Svensson, Bo Söderpalm, and Anna Larsson; (4) Involvement of the GABAB receptor in alcohol reinforcement in sP rats, by Giancarlo Colombo and Giovanni Vacca; (5) Neuroactive steroids and ethanol reinforcement, by Deborah A. Finn, and (6) Potential contribution of the urocortin system to regulation of alcohol self‐administration, by Andrey E. Ryabinin and Ryan K. Bachtell.
Changing Expectancies: Cognitive Mechanisms and Context Effects
Authors: Wiers Reinout W. , Wood Mark D. , Darkes Jack , Corbin William R. , Jones Barry T. , Sher Kenneth J.
Published: November 2003

This article presents the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, organized by Reinout W. Wiers and Mark D. Wood. The symposium combined two topics of recent interest in studies of alcohol expectancies: cognitive mechanisms in expectancy challenge studies, and context‐related changes of expectancies. With increasing recognition of the substantial role played by alcohol expectancies in drinking, investigators have begun to develop and evaluate expectancy challenge procedures as a potentially promising new prevention strategy. The two major issues addressed in the symposium were whether expectancy challenges result in changes in expectancies that mediate intervention (outcome relations), and the influence of simulated bar environments (“bar labs,” in which challenges are usually done) on expectancies. The presentations were (1) An introduction, by Jack Darkes; (2) Investigating the utility of alcohol expectancy challenge with heavy drinking college students, by Mark D. Wood; (3) Effects of an expectancy challenge on implicit and explicit expectancies and drinking, by Reinout W. Wiers; (4) Effects of graphic feedback and simulated bar assessments on alcohol expectancies and consumption, by William R. Corbin; (5) Implicit alcohol associations and context, by Barry T Jones; and (6) A discussion by Kenneth J. Sher, who pointed out that it is important not only to study changes of expectancies in the paradigm of an expectancy challenge but also to consider the role of changing expectancies in natural development and in treatments not explicitly aimed at changing expectancies.
Neurobehavioral Consequences of Prenatal Alcohol Exposure: An International Perspective
Authors: Riley Edward P. , Mattson Sarah N. , Li Ting‐Kai , Jacobson Sandra W. , Coles Claire D. , Kodituwakku P. W. , Adnams Colleen M. , Korkman Marit I.
Published: November 2003

This article represents the proceedings of a symposium at the 2002 Research Society on Alcoholism/International Society for Biomedical Research on Alcoholism meeting in San Francisco, CA. The organizers were Edward P. Riley and Sarah N. Mattson, and the chairperson was Edward P. Riley. The presentations were (1) Neurobehavioral deficits in alcohol‐exposed South African infants: preliminary findings, by Sandra W. Jacobson, Christopher D. Molteno, Denis Viljoen, and Joseph L. Jacobson; (2) A pilot study of classroom intervention for learners with fetal alcohol syndrome in South Africa, by Colleen Adnams, M. W. Rossouw, M. D. Perold, P. W. Kodituwakku, and W. Kalberg; (3) Differential effects of prenatal alcohol exposure on fluid versus crystallized intelligence, by P. W. Kodituwakku, W. Kalberg, L. Robinson, and P. A. May; (4) Neurobehavioral outcomes of prenatal alcohol exposure: early identification of alcohol effects, by Claire D. Coles; (5) Fetal alcohol syndrome in Moscow, Russia: neuropsychology test performance, by Sarah N. Mattson, E. P. Riley, A. Matveeva, and G. Marintcheva; and (6) Long‐term follow‐up of Finnish children exposed to alcohol in utero in various durations, by Marit I. Korkman and I. Autti‐Rämö. The discussant was Ting‐Kai Li.
Neuropeptide Y and Alcoholism: Genetic, Molecular, and Pharmacological Evidence
Authors: Pandey Subhash C. , Carr Lucinda G. , Heilig Markus , Ilveskoski Erkki , Thiele Todd E.
Published: November 2003

This article presents the proceedings of a symposium presented at the combined meeting of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism, held in San Francisco, CA, in June 2002. The organizers and chairpersons were Subhash C. Pandey and Todd E. Thiele. The presentations were (1) Altered ethanol‐induced sedation and ethanol drinking in mutant mice lacking specific NPY receptor, by Todd E. Thiele; (2) NPY in P and NP rats: polymorphism and mRNA expression, by Lucinda G. Carr; (3) The cAMP‐dependent PKA in the central amygdala regulates alcohol intake through NPY gene, by Subhash C. Pandey; (4) Involvement of NPY in alcohol dependence: from animal models to human genetics, by Markus Heilig; and (5) Association of neuropeptide Y polymorphism with the occurrence of type 1 and type 2 alcoholism, by Erkki Ilveskoski.
IGF‐I Induced Phosphorylation of S6K1 and 4E‐BP1 in Heart is Impaired by Acute Alcohol Intoxication
Authors: Lang Charles H. , Kumar Vinayshree , Liu Xiaoli , Frost Robert A. , Vary Thomas C.
Published: November 2003

Background: The purpose of the present study was to determine whether acute alcohol (EtOH) intoxication impairs the signal transduction pathway used to coordinate insulin‐like growth factor (IGF)‐I stimulation of myocardial protein synthesis.

Methods: Rats were injected intraperitoneally with EtOH or saline. After 2.5 h, IGF‐I or saline was injected intravenously and the heart was excised at 2 min or 20 min. Additional rats were pretreated with RU486 or tumor necrosis factor (TNF) binding protein (BP) to assess the importance of elevations in glucocorticoids or TNF, respectively, as endogenous modulators of IGF‐I signal transduction.

Results: EtOH did not alter the total amount or tyrosine phosphorylation of the IGF‐I receptor, IRS‐1 or PKB under basal or IGF‐stimulated conditions. However, EtOH attenuated the ability of IGF‐I to phosphorylate ribosomal S6 kinase (S6K)‐1 on residues T389 (∼62%) and T421/S424 (∼40%), and also reduced ribosomal protein S6 phosphorylation. Under basal conditions, EtOH altered the distribution of eukaryotic initiation factor (eIF) 4E, as evidenced by a decreased amount of the active eIF4E·eIF4G complex (53%), an increased amount of inactive eIF4E·4E‐BP1 complex (∼3‐fold), and decreased phosphorylation of 4E‐BP1 (56%). EtOH also impaired the ability of IGF‐I to reverse the above‐mentioned changes in the eIF4E system. Pretreatment of rats with RU486 or TNFBP was unable to attenuate the EtOH‐induced changes in either eIF4E distribution or the phosphorylation state of 4E‐BP1, S6K1 or S6.

Conclusions: These data indicate that acute EtOH intoxication alters selected aspects of translational control in the heart under basal conditions. Furthermore, despite appropriate stimulation of IGF‐I receptor, IRS‐1 and PKB, EtOH impairs IGF‐I signaling via S6K1 and 4E‐BP1 pathways, and this defect is regulated in a glucocorticoid‐ and TNF‐independent manner. This IGF‐I resistance may represent a participating mechanism by which alcohol limits protein synthesis in heart.
Preclinical and Clinical Studies on Naltrexone: What Have They Taught Each Other?
Authors: Froehlich Janice , O'Malley Stephanie , Hyytiä Petri , Davidson Dena , Farren Conor
Published: November 2003

Proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, California; organized and co‐chaired by Janice C. Froehlich and Stephanie O'Malley. The presentations were (1) Introduction, by Janice C. Froehlich and Stephanie O'Malley; (2) Preclinical studies on naloxone: genetics and site of action, by Petri Hyytiä; (3) Clinical studies on naltrexone for treating hazardous drinkers, by Dena Davidson; (4) Clinical studies on naltrexone and sertraline in the treatment of alcohol dependence, by Conor Farren; and (5) Discussion by Janice D. Froehlich, Stephanie O'Malley, and Rainer Spanagel. Both preclinical and clinical studies are critical in the development of effective pharmacotherapeutic approaches for the treatment of alcoholism. Nowhere has this been more evident than in the development of naltrexone for the treatment of alcohol relapse. As research continues on the optimal use of naltrexone for modifying alcohol intake, a number of factors have emerged that are likely to determine the efficacy of naltrexone as a pharmacotherapeutic agent for the treatment of alcoholism. Some of these factors include dose, frequency and duration of treatment, pattern and severity of alcohol drinking prior to initiation of naltrexone treatment, genetic aspects of responsive subpopulations, degree of alcohol craving, and susceptibility to adverse effects of naltrexone. New, as well as established, animal models are being used to determine the parameters that optimize the ability of naltrexone to modify alcohol drinking in acute and chronic alcohol access paradigms, under conditions of intermittent versus continuous alcohol intake, and in populations that vary in genetic predisposition toward alcohol drinking. Current clinical studies are exploring the ability of naltrexone to alter alcohol drinking when delivered in combination with pharmacotherapeutic agents that act on nonopioid transmitter systems and the difference in efficacy of naltrexone when administered in populations that differ in drinking frequency and intensity, family history of alcoholism, and alcohol craving. This symposium presented new research findings from both preclinical and clinical studies with the aim of facilitating the development of treatment regimens that optimize the therapeutic potential of naltrexone in the treatment of alcoholism.
The Effect of Chronic Binge Ethanol Consumption on the Primary Stage of SIV Infection in Rhesus Macaques
Authors: Bagby Gregory J. , Stoltz David A. , Zhang Ping , Kolls Jay K. , Brown Julie , Bohm Rudolf P. , Rockar Richard , Purcell Jeanette , Murphey‐Corb Michael , Nelson Steve
Published: November 2003

Background: Alcohol abuse and infection with HIV individually compromise immune function, but the consequence of both conditions together is poorly understood owing to the difficulties of performing appropriate studies in human subjects. Simian immunodeficiency virus (SIV) infection of rhesus macaques is considered to closely model HIV disease in that the virus infects CD4+ cells and this infection leads to a similar AIDS state. This study was initiated to study the combined effects of chronic binge alcohol consumption on the primary stage of SIV infection.

Methods: Rhesus macaques were administered alcohol or isocaloric sucrose via a permanently indwelling intragastric catheter 4 consecutive days per week for the duration of the study. Doses were individualized to achieve plasma alcohol concentrations of 50–60 mM over a 5‐hr period. After 3 months, animals were inoculated intravenously with 10,000 times the ID50 (50% infective dose) of SIVDeltaB670 at the conclusion of an alcohol session and followed for 2 months postinoculation.

Results: At 1 week, plasma SIV RNA was greater than 60‐fold higher in alcohol‐consuming animals compared with sucrose controls. Likewise, alcohol consumption enhanced the SIV‐induced increase in cell cycling T lymphocytes (i.e., cells expressing Ki67 protein) in blood. These differences between alcohol‐ and sucrose‐treated animals were not sustained during the observation period. Peak viral load occurred 2 weeks post‐SIV inoculation at 7.6 ± 4.2 and 5.2 ± 3.1 × 106 copies/ml in alcohol‐ versus sucrose‐consuming animals, respectively. Blood CD4+ lymphocyte numbers were decreased 1 and 2 months after SIV inoculation to a similar degree in both sucrose‐control and alcohol‐treated animals.

Conclusions: The consequence of the early rise in viral load and increase in lymphocyte turnover seen with excess alcohol consumption is unknown. We hypothesize that alcohol intoxication may increase the susceptibility of the host to HIV/SIV infection. This possibility needs to be explored further.
Genetic Analyses of Ethanol‐Induced Hyperglycemia
Authors: Risinger Fred O.
Published: November 2003

Background: Genetic sensitivity to ethanol‐induced hyperglycemia was hypothesized to be related to sensitivity to ethanol‐induced hypothermia and conditioned taste aversion. These hypotheses were explored by characterizing blood glucose changes after ethanol exposure in BXD recombinant inbred mice.

Methods: Adult male and female BXD recombinant inbred mice were acutely exposed to 4 g/kg of ethanol or saline with the order of exposure counterbalanced, and separated by a 1‐week interval. Tail blood samples and rectal temperatures were determined immediately before ethanol/saline exposure and 2 hr after exposure.

Results: Substantial strain differences in ethanol‐induced hyperglycemia and hypothermia were noted. In addition, sex also determined sensitivity to ethanol‐induced hyperglycemia and interacted with strain. Correlational analyses using strain means indicated that ethanol‐induced hyperglycemia was genetically independent from ethanol‐induced hypothermia or conditioned taste aversion. Quantitative trait locus (QTL) analyses indicated provisional QTL for ethanol‐induced hyperglycemia on chromosomes 1, 3, 4, 6, 7, 9, 12, 14, and 18, which, in part, were sex specific.

Conclusions: These findings indicate important sex differences in the glycemic response to ethanol. In addition, multiple genes likely control this response, independent from genes that are important for the thermic or aversive effects of ethanol.
A 5‐Year Prospective Evaluation of DSM‐IV Alcohol Dependence With and Without a Physiological Component
Authors: Schuckit M. A. , Danko G. P. , Smith T. L. , Hesselbrock V. , Kramer J. , Bucholz K.
Published: November 2003

Background:The DSM‐III‐R removed tolerance and withdrawal as required elements for a diagnosis of alcohol dependence. Although this practice was continued in DSM‐IV, the more recent manual asked clinicians to note whether physiological aspects of withdrawal (tolerance and withdrawal) had ever been experienced. Few studies have determined the prognostic meaning of a history of a physiological component to DSM‐IV alcohol dependence.

Methods:Face‐to‐face structured interviews were used to evaluate the course of alcohol, drug, and psychiatric problems during the subsequent 5 years for 1094 alcohol‐dependent men and women. These subjects had been classified into subgroups at the time of initial interview regarding evidence of tolerance or withdrawal, and all evaluations were based on DSM‐IV criteria. At baseline, the application of DSM‐IV diagnostic guidelines resulted in 649 (59.3%) individuals having a history of an alcohol withdrawal syndrome, with or without tolerance (group 1); 391 (35.7%) with histories of tolerance but not withdrawal (group 2); and 54 (4.9%) with no lifetime histories of tolerance or withdrawal (group 3).

Results:During the 5‐year follow‐up, both the broad (group 1 plus 2 versus group 3) and narrow (group 1 versus group 2 plus group 3) definitions of physiological dependence were associated with more alcohol and drug problems. However, for most items, this differential primarily reflected differences between groups 1 and 3, with a less impressive effect by group 2. Although no group differences were noted for the rate of independent major depressive episodes, substance‐induced depressions did differentiate among groups, a finding also most closely related to the distinction between groups 1 and 3.

Conclusions:These data support the prognostic importance of noting the presence of a physiological component in alcohol dependence and indicate the potential relevance of limiting the definition of a physiological component to withdrawal.
Severe Alcoholic Hepatitis Successfully Treated by Leukocytapheresis: A Case Report
Authors: Tsuji Yoshiyasu , Kumashiro Ryukichi , Ishii Kunihide , Arinaga Teruko , Sakamoto Yoshihiro , Tanabe Ryo , Ogata Kei , Koga Yuriko , Ide Tatsuya , Ono Naofumi , Tanaka Eisuke , Abe Hirohiko , Sata Michio
Published: November 2003

Background: The prognosis of severe alcoholic hepatitis is poor, and there is no established method for a cure.

Methods: A 34‐year‐old man was admitted to Kurume University Hospital because of severe liver dysfunction due to excess alcohol intake. He was treated with prednisolone and two sessions of granulocyte and monocyte adsorption apheresis (GCAP) using an Adacolumn, which removes leukocytes—especially granulocytes and monocytes—from the peripheral blood. We evaluated the changes in the serum levels of interleukin‐6, interleukin‐8, tumor necrosis factor‐α, and soluble intercellular adhesion molecule‐1, as well as the conventional liver tests and peripheral white blood cell count.

Results: Prednisolone was effective in the short term but resulted in an increase in C‐reactive protein (CRP), peripheral leukocytes, and serum total bilirubin. GCAP performed on the 34th and 41th hospital days produced decreases in the white blood cell count, total bilirubin, and intercellular adhesion molecule‐1. The patient survived, despite the expected poor prognosis on admission.

Conclusions: GCAP is recommended as a potential therapeutic option for severe alcoholic hepatitis.
Analysis of Risk Factors for Hepatocellular Carcinoma in Patients With HBs Antigen‐ and Anti‐HCV Antibody‐Negative Alcoholic Cirrhosis: Clinical Significance of Prior Hepatitis B Virus Infection
Authors: Uetake Shinichiro , Yamauchi Masayoshi , Itoh Shuji , Kawashima Osamu , Takeda Kunihiko , Ohata Mitsuru
Published: November 2003

Background: The hepatitis B virus (HBV) or hepatitis C virus (HCV) markers frequently are detected in alcoholic patients with hepatocellular carcinoma (HCC). However, risk factors for the development of HCC in patients with HBs antigen (Ag)‐ and anti‐HCV antibody (anti‐HCV)‐negative alcoholic cirrhosis have not been clearly documented. The present study was conducted to elucidate the occurrence rates of HCC in HBs Ag‐ and anti‐HCV‐negative male alcoholic cirrhosis and to assess the risk factors for hepatocellular carcinogenesis.

Method: We prospectively studied 91 consecutive patients with HBs Ag‐ and anti‐HCV‐negative alcoholic cirrhosis for 0.5 to 12.5 years (median 5.9 years). Potential risk factors assessed for liver carcinogenesis included the following six variables: age, total alcohol intake, association of continuing alcohol intake after diagnosis, indocyanine green retention rate at 15 min, anti‐HB core antibodies (anti‐HBc), and association of diabetes mellitus.

Results: Cumulative occurrence rates of HCC were 6.4%, 18.9%, and 28.7% at the end of the 5th, 7th and 10th years, respectively. When classified by anti‐HBc, the occurrence rates of HCC in 31 patients with anti‐HBc and 60 patients without anti‐HBc were 15.6% and 2.9% at the 5th year, 28.4% and 13.5% at the 7th year, and 40.4% and 22.1% at the 10th year, respectively. The occurrence rates of HCC were also significantly related to the cumulative alcohol intake. Cox proportional hazard model identified that cumulative alcohol intake (p= 0.0047) and positive anti‐HBc antibodies (p= 0.0598) were independently associated with the occurrence rates of HCC.

Conclusion: These epidemiologic results suggest that heavy cumulative alcohol intake and prior exposure to HBV infection are risk factors for the development of HCC in patients with HBs Ag‐ and anti‐HCV‐negative alcoholic cirrhosis.
Critical Issues in the Development of Culturally Relevant Substance Abuse Treatments for Specific Minority Groups
Authors: Gonzàlez Castro Felipe , Garfinkle Julie
Published: November 2003

Contemporary substance abuse treatment providers are now recognizing the growing diversity within American society. This recognition includes a growing appreciation of racial/ethnic diversity, although few models exist to aid in conceptualizing this diversity as related to substance abuse treatment. This situation prompts the need to better understand the influences of cultural variables in the design and delivery of culturally‐responsive and effective substance abuse treatments. Culturally‐responsive treatments are those that are sensitive to the specific treatment needs of members of special populations. This article presents specific issues and provides directions for the design, development, and implementation of more effective substance abuse treatments for clients from special populations. These important issues include: (1) the development of provider cultural competence, (2) the need to incorporate cultural variables into treatment, (3) issues in program adaptation, and (4) issues in the transfer of science to practice. Strategic models are presented to aid in conceptualizing these issues, and to further understand relationships between important cultural variables. Finally, further scientific research is encouraged that will contribute an empirical database that will test and further develop these strategic models, in the interest of enhancing the efficacy and effectiveness of substance abuse treatments as delivered to racial/ethnic minority clients, and to clients from other special populations.
Comprehensive Assessment of Insomnia in Recovering Alcoholics Using Daily Sleep Diaries and Ambulatory Monitoring
Authors: Currie Shawn R. , Clark Stewart , Rimac Stephen , Malhotra Sonya
Published: November 2003

Background: Many alcoholics continue to experience disrupted sleep after quitting drinking. Previous studies with recovering alcoholics have relied on retrospective questionnaires and a single night of polysomnography to document sleep problems. In the present study, sleep was assessed at home over the course of a week using both subjective and objective sleep measures.

Methods: A mixed gender group of alcoholics in recovery (n= 63) experiencing insomnia underwent a multimodal sleep assessment including a structured interview, daily sleep diaries, questionnaires, and ambulatory sleep monitoring. Alcoholics with short‐term (<12 months) and long‐term (>12 months) abstinence had their sleep monitored prospectively and were compared.

Results: Over half of the participants reported sleep problems that predated the onset of alcohol dependence. Alcoholics with short‐ and long‐term abstinence had similarly disturbed sleep. Overall, problems with getting to sleep were worse than sleep maintenance difficulties. Severity of insomnia was unrelated to drinking history and modestly correlated with the current level of depressive symptoms. Poor sleep hygiene was evident in the sample.

Conclusions: Alcoholics can experience sleep problems for many months after quitting drinking. Implications for sleep interventions with this population are discussed.
Methodological Characterization of the 2‐Keto [1‐13C]isocaproate Breath Test to Measure in Vivo Human Mitochondrial Function: Application in Alcoholic Liver Disease Assessment
Authors: Parra Dolores , González Alvaro , García‐Villarreal Luis , Martínez J. Alfredo
Published: November 2003

Background: The 2‐keto[1‐13C]isocaproate oxidation measurement has been shown as a helpful tool in the in vivo assessment of liver mitochondrial function.

Methods: The aim of this work was to study the variability of the 2‐keto[1‐13C]isocaproate breath test in 24 healthy controls (8 men and 16 women) and to evaluate its clinical usefulness in 20 patients (14 men and 6 women) with liver disease (7 men with history of alcoholism). Breath test was performed by measuring 13CO2 enrichment in breath before and after the oral administration of the tracer and by using isotope ratio mass spectrometry.

Results: The intrasubject and intersubject variability of the percentage of tracer oxidized were 8 and 14%, respectively. The 2‐keto[1‐13C]isocaproate oxidation in women was faster (p= 0.004) and tended to be higher (p= 0.050) than in men. The percentage of oxidized tracer was lower in those patients with alcoholic liver disease than in healthy volunteers (p= 0.001) and in nonalcoholic patients (p= 0.003).

Conclusions: The percentage of tracer oxidized appears as a convenient parameter to detect impairment in liver mitochondrial oxidation related to alcoholism by the 2‐keto[1‐13C]isocaproate breath test, establishing different cutoff values depending on gender.