bluuebunny/crossref_metadata_2025 huggingface dataset:
A new benzoxazine compound blocks KATP channels in pancreatic β cells: molecular basis for tissue selectivity in vitro and hypoglycaemic action in vivo
Authors: Rolland J‐F , Tricarico D , Laghezza A , Loiodice F , Tortorella V , Camerino D Conte
Published: October 2006

Background and purpose:

The 2‐propyl‐1,4 benzoxazine (AM10) shows a peculiar behaviour in skeletal muscle, inhibiting or opening the ATP‐sensitive K+ (KATP) channel in the absence and presence of ATP, respectively. We focused on tissue selectivity and mechanism of action of AM10 by testing its effects on pancreatic KATP channels by means of both in vitro and in vivo investigations.

Experimental approach:

In vitro, patch‐clamp recordings were performed in native pancreatic beta cells and in tsA201 cells expressing the Kir6.2ΔC36 channel. In vivo, an intraperitoneal glucose tolerance test was performed in normal mice.

Key results:

In contrast with what observed in the skeletal muscle, AM10, in whole cell perforated mode, did not augment KATP current (IKATP) of native beta cells but it inhibited it in a concentration‐dependent manner (IC50: 11.5 nM; maximal block: 60%). Accordingly, in current clamp recordings, a concentration‐dependent membrane depolarization was observed. On excised patches, AM10 reduced the open‐time probability of KATP channels without altering their single channel conductance; the same effect was observed in the presence of trypsin in the bath solution. Moreover, AM10 inhibited, in an ATP‐independent manner, the K+ current resulting from expressed Kir6.2ΔC36 (maximal block: 60% at 100 μM; IC50: 12.7 nM) corroborating an interaction with Kir. In vivo, AM10 attenuated the glycemia increase following a glucose bolus in a dose‐dependent manner, without, at the dose tested, inducing fasting hypoglycaemia.

Conclusion and implications:

Altogether, these results help to gain insight into a new class of tissue specific KATP channel modulators.

British Journal of Pharmacology (2006) 149, 870–879. doi:10.1038/sj.bjp.0706895
Evidence that corticotropin‐releasing factor receptor type 1 couples to Gs‐ and Gi‐proteins through different conformations of its J‐domain
Authors: Berger H , Heinrich N , Wietfeld D , Bienert M , Beyermann M
Published: October 2006

Background and purpose:

According to the two‐domain model for the corticotropin‐releasing factor receptor type 1 (CRF1), peptide antagonists bind to the N‐terminal domain (N‐domain), non‐peptide antagonists to the transmembrane region (J‐domain), whereas peptide agonists attach to both the N‐ and J‐domain of the receptor to express activity. The aim of this study was to search for possible differences in the antagonism of the Gs‐ and Gi‐protein coupling of CRF1 by a peptide (α‐helical CRF(9–41)) and non‐peptide antagonist (antalarmin), to determine whether the conformational requirements of the activated CRF1 states for Gs and Gi coupling are similar or different.

Experimental approach:

We studied the inhibitory effect of α‐helical CRF(9–41) and antalarmin on the coupling of CRF1 to Gs‐ and Gi‐protein in human embryonic kidney cells, using the [35S]‐GTPγS binding stimulation assay.

Key results:

The non‐peptide antagonized the receptor coupling to Gs competitively but that to Gi noncompetitively, and its antagonistic potency was different for urocortin‐ and sauvagine‐evoked G‐protein activation. In contrast, the peptide antagonist exhibited uniformly competitive antagonism.

Conclusions and Implications:

The results allow us to extend the two‐domain model of CRF1 activation by assuming that CRF1 agonists activate the receptor by binding to at least two ensembles of J‐domain configurations which couple to Gs or Gi, that are in turn antagonized by a non‐peptide antagonist competitively and allosterically, respectively. It is further concluded that the allosteric mechanism of non‐peptide antagonism is not valid for the Gs‐mediated physiological activities of CRF1.

British Journal of Pharmacology (2006) 149, 942–947. doi:10.1038/sj.bjp.0706926
Teamwork in the Operating Room
Authors: Sexton J Bryan , Makary Martin A. , Tersigni Anthony R. , Pryor David , Hendrich Ann , Thomas Eric J. , Holzmueller Christine G. , Knight Andrew P. , Wu Yun , Pronovost Peter J.
Published: October 2006

Background

The Joint Commission on Accreditation of Healthcare Organizations is proposing that hospitals measure culture beginning in 2007. However, a reliable and widely used measurement tool for the operating room (OR) setting does not currently exist.

Methods

OR personnel in 60 US hospitals were surveyed using the Safety Attitudes Questionnaire. The teamwork climate domain of the survey uses six items about difficulty speaking up, conflict resolution, physician-nurse collaboration, feeling supported by others, asking questions, and heeding nurse input. To justify grouping individual-level responses to a single score at each hospital OR level, the authors used a multilevel confirmatory factor analysis, intraclass correlations, within-group interrater reliability, and Cronbach's alpha. To detect differences at the hospital OR level and by caregiver type, the authors used multivariate analysis of variance (items) and analysis of variance (scale).

Results

The response rate was 77.1%. There was robust evidence for grouping individual-level respondents to the hospital OR level using the diverse set of statistical tests, e.g., Comparative Fit Index = 0.99, root mean squared error of approximation = 0.05, and acceptable intraclasss correlations, within-group interrater reliability values, and Cronbach's alpha = 0.79. Teamwork climate differed significantly by hospital (F59, 1,911 = 4.06, P < 0.001) and OR caregiver type (F4, 1,911 = 9.96, P < 0.001).

Conclusions

Rigorous assessment of teamwork climate is possible using this psychometrically sound teamwork climate scale. This tool and initial benchmarks allow others to compare their teamwork climate to national means, in an effort to focus more on what excellent surgical teams do well.
Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects
Authors: Snapir Amir , Posti Jussi , Kentala Erkki , Koskenvuo Juha , Sundell Jan , Tuunanen Helena , Hakala Kristo , Scheinin Harry , Knuuti Juhani , Scheinin Mika
Published: October 2006

Background

Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects.

Methods

The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine.

Results

The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate.

Conclusions

In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.
Nonlinear Changes in Brain Dynamics during Emergence from Sevoflurane Anesthesia
Authors: Walling Peter T. , Hicks Kenneth N.
Published: October 2006

Background

New software was used during a pilot study of nonlinear changes in the electroencephalogram during emergence from sevoflurane anesthesia.

Methods

Digitized electroencephalographic signals were recorded from bipolar forehead electrodes between 1.2 and 40 k s/sec. Trajectories derived from underlying attractors were displayed continuously, and attractor dimensions were estimated. Observations are reported from 13 patients emerging from sevoflurane anesthesia.

Results

Qualitative observations and quantitative analysis of the data demonstrated four dynamical stages during emergence from deep anesthesia to consciousness.

Conclusions

The dynamical stages of emergence from sevoflurane anesthesia into consciousness demonstrate a classic route toward chaos, but the presence of chaos in the conscious state remains unproven. These stages are apparent both pictorially and analytically. Pre-emergent attractor patterns are usually distinctive; their real-time display could be a useful adjunct to depth of anesthesia monitors because they may provide warning of an imminent return to consciousness.
Positron Emission Tomography Study of Regional Cerebral Metabolism during General Anesthesia with Xenon in Humans
Authors: Rex Steffen , Schaefer Wolfgang , Meyer Philipp H. , Rossaint Rolf , Boy Christian , Setani Keyvan , Büll Ulrich , Baumert Jan H.
Published: October 2006

Background

The precise mechanism by which the gaseous anesthetic xenon exerts its effects in the human brain remains unknown. Xenon has only negligible effects on inhibitory gamma-aminobutyric acid receptors, one of the putative molecular targets for most general anesthetics. Instead, xenon has been suggested to induce anesthesia by inhibiting excitatory glutamatergic signaling. Therefore, the authors hypothesized that xenon, similar to ketamine and nitrous oxide, increases global and regional cerebral metabolism in humans.

Methods

The regional cerebral metabolic rate of glucose (rcMRGlu) was sequentially assessed in two groups of six volunteers each, using F-fluorodeoxyglucose as tracer. In the xenon group, rcMRGlu was determined at baseline and during general anesthesia induced with propofol and maintained with 1 minimum alveolar concentration xenon. In the control group, rcMRGlu was measured using the identical study protocol but without administration of xenon. rcMRGlu was assessed after the plasma concentration of propofol had decreased to subanesthetic levels (< 1.0 microg/ml). rcMRGlu was quantified in 10 cerebral volumes of interest. In addition, voxel-wise changes in rcMRGlu were analyzed using statistical parametric mapping.

Results

Xenon reduced whole-brain metabolic rate of glucose by 26 +/- 7% (from 43 +/- 5 micromol x 100 g x min to 31 +/- 3 micromol x 100 g x min; P < 0.005) and significantly decreased rcMRGlu in all volumes of interest compared with the control group receiving propofol only. Voxel-based analysis revealed metabolic depression within the orbitofrontal, frontomesial, temporomesial, occipital, dorsolateral frontal, and lateral temporal cortices and thalami. No increases in rcMRGlu were detected during xenon anesthesia.

Conclusions

Xenon induces metabolic depression in the human brain, suggesting that the inhibition of the glutamatergic system is likely to be of minor significance for the anesthetic action of xenon in vivo.
Performance Characteristics of Five New Anesthesia Ventilators and Four Intensive Care Ventilators in Pressure-support Mode
Authors: Jaber Samir , Tassaux Didier , Sebbane Mustapha , Pouzeratte Yvan , Battisti Anne , Capdevila Xavier , Eledjam Jean-Jacques , Jolliet Philippe
Published: October 2006

Background

During the past few years, many manufacturers have introduced new modes of ventilation in anesthesia ventilators, especially partial-pressure modalities. The current bench test study was designed to compare triggering and pressurization of five new anesthesia ventilators with four intensive care unit ventilators.

Methods

Ventilators were connected to a two-compartment lung model. One compartment was driven by an intensive care unit ventilator to mimic "patient" inspiratory effort, whereas the other was connected to the tested ventilator. The settings of ventilators were positive end-expiratory pressures of 0 and 5 cm H2O, and pressure-support ventilation levels of 10, 15, and 20 cm H2O with normal and high "patient" inspiratory effort. For the anesthesia ventilators, all the measurements were obtained for a low (1 l/min) and a high (10 l/min) fresh gas flow. Triggering delay, triggering workload, and pressurization at 300 and 500 ms were analyzed.

Results

For the five tested anesthesia ventilators, the pressure-support ventilation modality functioned correctly. For inspiratory triggering, the three most recent anesthesia machines (Fabius, Drägerwerk AG, Lübeck, Germany; Primus, Drägerwerk AG; and Avance, GE-Datex-Ohemda, Munchen, Germany) had a triggering delay of less than 100 ms, which is considered clinically satisfactory and is comparable to intensive care unit machines. The use of positive end-expiratory pressure modified the quality of delivered pressure support for two anesthesia ventilators (Kion, Siemens AG, Munich, Germany; and Felix, Taema, Antony, France). Three of the five anesthesia ventilators exhibited pressure-support ventilation performance characteristics comparable to those of the intensive care unit machines. Increasing fresh gas flow (1 to 10 l/min) in the internal circuit did not influence the pressure-support ventilation performance of the anesthesia ventilators.

Conclusion

Regarding trigger sensitivity and the system's ability to meet inspiratory flow during pressure-supported breaths, the most recent anesthesia ventilators have comparable performances of recent-generation intensive care unit ventilators.
Epinephrine Increases the Extracellular Lidocaine Concentration in the Brain
Authors: Takahashi Ryota , Oda Yutaka , Tanaka Katsuaki , Morishima Hisayo O. , Inoue Koki , Asada Akira
Published: October 2006

Background

Local anesthetics exert central nervous system (CNS) toxicity by inhibiting intracerebral neuronal activity, while epinephrine augments the CNS toxicity of intravenously administered local anesthetics. Viewed together, increases of extracellular concentrations of local anesthetics in the brain may be directly associated with increased CNS toxicity. The authors examined the hypothesis that epinephrine enhances the CNS toxicity of lidocaine by increasing the extracellular concentration in the brain.

Methods

An awake, spontaneously breathing rat model was used. Twenty male Sprague-Dawley rats received an intravenous infusion of lidocaine (3 mg x kg x min; group C) or lidocaine with epinephrine (3 mg x kg x min and 2 microg x kg x min, respectively; group E) for 10 min (n = 10 in each group). Effects of epinephrine on the convulsive dose and concentrations of total (protein-bound and unbound) and unbound lidocaine in plasma were examined. Concentrations of extracellular lidocaine in the cerebral nucleus accumbens were quantitatively determined by a microdialysis method.

Results

The convulsive dose of lidocaine was significantly lower in group E than in group C (22.4 +/- 5.5 vs. 27.9 +/- 3.1 mg/kg, respectively; P < 0.05). Overall concentrations and area under the plasma concentration-versus-time curve of unbound lidocaine in group E were significantly higher than those in group C. Concentrations of extracellular lidocaine in the nucleus accumbens in group E were comparable to those of unbound fraction in plasma and were also significantly higher than those in group C.

Conclusions

Concomitant administration of epinephrine significantly enhanced the CNS toxicity of intravenously administered lidocaine. Increased extracellular concentration in the brain would be related to this mechanism.
Sevoflurane Protects Rat Mixed Cerebrocortical Neuronal–Glial Cell Cultures against Transient Oxygen–Glucose Deprivation
Authors: Canas Paula T. , Velly Lionel J. , Labrande Christelle N. , Guillet Benjamin A. , Sautou-Miranda Valérie , Masmejean Frédérique M. , Nieoullon André L. , Gouin François M. , Bruder Nicolas J. , Pisano Pascale S.
Published: October 2006

Background

The purpose of this study was to clarify the role of glutamate and reactive oxygen species in sevoflurane-mediated neuroprotection on an in vitro model of ischemia-reoxygenation.

Methods

Mature mixed cerebrocortical neuronal-glial cell cultures, treated or not with increasing concentrations of sevoflurane, were exposed to 90 min combined oxygen-glucose deprivation (OGD) in an anaerobic chamber followed by reoxygenation. Cell death was quantified by lactate dehydrogenase release into the media and cell viability by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium by mitochondrial succinate dehydrogenase. Extracellular concentrations of glutamate and glutamate uptake were assessed at the end of the ischemic injury by high-performance liquid chromatography and incorporation of L-[H]glutamate into cells, respectively. Free radical generation in cells was assessed 6 h after OGD during the reoxygenation period using 2',7'-dichlorofluorescin diacetate, which reacts with intracellular radicals to be converted to its fluorescent product, 2',7'-dichlorofluorescin, in cell cytosol.

Results

Twenty-four hours after OGD, sevoflurane, in a concentration-dependent manner, significantly reduced lactate dehydrogenase release and increased cell viability. At the end of OGD, sevoflurane was able to reduce the OGD-induced decrease in glutamate uptake. This effect was impaired in the presence of threo-3-methyl glutamate, a specific inhibitor of the glial transporter GLT1. Sevoflurane counteracted the increase in extracellular level of glutamate during OGD and the generation of reactive oxygen species during reoxygenation.

Conclusion

Sevoflurane had a neuroprotective effect in this in vitro model of ischemia-reoxygenation. This beneficial effect may be explained, at least in part, by sevoflurane-induced antiexcitotoxic properties during OGD, probably depending on GLT1, and by sevoflurane-induced decrease of reactive oxygen species generation during reoxygenation.
Ambulatory Continuous Interscalene Nerve Blocks Decrease the Time to Discharge Readiness after Total Shoulder Arthroplasty
Authors: Ilfeld Brian M. , Vandenborne Krista , Duncan Pamela W. , Sessler Daniel I. , Enneking F Kayser , Shuster Jonathan J. , Theriaque Douglas W. , Chmielewski Terese L. , Spadoni Eugene H. , Wright Thomas W.
Published: October 2006

Background

A continuous interscalene nerve block (CISB) may be used to provide analgesia after shoulder arthroplasty. Therefore, inpatient stays may be shortened if CISB (1) provides adequate analgesia without intravenous opioids and (2) improves shoulder mobilization. This study investigated the relationship between ambulatory CISB and the time to reach three discharge criteria after shoulder arthroplasty.

Methods

Preoperatively, patients received a CISB. All patients received a perineural 0.2% ropivacaine infusion from surgery until 06:00 the following morning, at which time they were randomly assigned either to continue perineural ropivacaine or to switch to normal saline. The primary endpoint was the time from the end of surgery until three discharge criteria were attained (adequate analgesia, independence from intravenous analgesics, and tolerance to 50% of shoulder motion targets). Patients were discharged home as early as the afternoon after surgery with their CISB using a portable infusion pump.

Results

Patients receiving perineural ropivacaine (n = 16) attained all three discharge criteria in a median (10th-90th percentiles) of 21 (16-41) h, compared with 51 (37-90) h for those receiving perineural normal saline (n = 13, P < 0.001). Unlike patients receiving perineural ropivacaine, patients receiving perineural normal saline often required intravenous morphine, but still experienced a higher degree of pain and tolerated less external rotation.

Conclusions

An ambulatory CISB considerably decreases the time until readiness for discharge after shoulder arthroplasty, primarily by providing potent analgesia that permits greater passive shoulder movement and the avoidance of intravenous opioids. Additional research is required to define the appropriate subset of patients and assess the incidence of complications associated with earlier discharge.
Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by Parecoxib in Humans
Authors: Tröster Andreas , Sittl Ruth , Singler Boris , Schmelz Martin , Schüttler Jürgen , Koppert Wolfgang
Published: October 2006

Background

Numerous experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. It is suggested that spinal cyclooxygenase activity may contribute to the development and expression of opioid tolerance. The aim of the investigation was to determine analgesic and antihyperalgesic properties of the cyclooxygenase-2 inhibitor parecoxib on remifentanil-induced hypersensitivity in humans.

Methods

Fifteen healthy male volunteers were enrolled in this randomized, double-blind, placebo-controlled study in a crossover design. Transcutaneous electrical stimulation at high current densities was used to induce spontaneous acute pain (numeric rating scale 6 of 10) and stable areas of pinprick hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during, and after a 30-min intravenous infusion of remifentanil (0.1 microg x kg x min) or placebo (saline). Parecoxib (40 mg) was administered intravenously either with onset of electrical stimulation (preventive) or in parallel to the remifentanil infusion.

Results

Remifentanil reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level. Preventive administration of parecoxib led to an amplification of remifentanil-induced antinociceptive effects during the infusion (71.3 +/- 7 vs. 46.4 +/- 17% of control) and significantly diminished the hyperalgesic response after withdrawal. In contrast, parallel administration of parecoxib did not show any modulatory effects on remifentanil-induced hyperalgesia.

Conclusion

The results confirm clinically relevant interaction of mu opioids and prostaglandins in humans. Adequate timing seems to be of particular importance for the antihyperalgesic effect of cyclooxygenase-2 inhibitors.
Neurotoxicity of Lidocaine Involves Specific Activation of the p38 Mitogen-activated Protein Kinase, but Not Extracellular Signal–regulated or c-jun N-Terminal Kinases, and Is Mediated by Arachidonic Acid Metabolites
Authors: Haller Ingrid , Hausott Barbara , Tomaselli Bettina , Keller Christian , Klimaschewski Lars , Gerner Peter , Lirk Philipp
Published: October 2006

Background

Pharmacologic inhibition of the p38 mitogen-activated protein kinase (MAPK) leads to a reduction in lidocaine neurotoxicity in vitro and in vivo. The current study investigated in vitro the hypotheses that lidocaine neurotoxicity is specific for dorsal root ganglion cells of different size or phenotype, involves time-dependent and specific activation of the p38 MAPK, that p38 MAPK inhibitors are only effective if applied with local anesthetic, and that p38 MAPK activation triggers activation of lipoxygenase pathways.

Methods

The authors used primary sensory neuron cultures and pheochromocytoma cell line cultures to detect time-dependent activation of the p38 MAPK or related pathways such as extracellular signal-regulated kinases and c-jun N-terminal kinases. Cells were divided by size or by immunoreactivity for calcitonin gene-related peptide or isolectin B4, indicative of nociceptive phenotype. The authors also investigated whether arachidonic acid pathways represent a downstream effector of the p38 MAPK in local anesthetic-induced neurotoxicity.

Results

All types of dorsal root ganglion cells were subject to neurotoxic effects of lidocaine, which were mediated by specific activation of the p38 MAPK but not extracellular signal-regulated kinases or c-jun N-terminal kinases. Neuroprotective efficacy of p38 MAPK inhibitors declined significantly when administered more than 1 h after lidocaine exposure. Activation of p38 MAPK preceded activation of arachidonic acid pathways. Neurotoxicity of lidocaine, specific activation of p38 MAPK, and neuroprotective effects of a p38 MAPK inhibitor were further confirmed in pheochromocytoma cell line cultures.

Conclusions

Specific and time-dependent activation of the p38 MAPK is involved in lidocaine-induced neurotoxicity, most likely followed by activation of lipoxygenase pathways.
Do Antifibrinolytics Reduce Allogeneic Blood Transfusion in Orthopedic Surgery?
Authors: Zufferey Paul , Merquiol Fanette , Laporte Silvy , Decousus Hervé , Mismetti Patrick , Auboyer Christian , Samama Charles Marc , Molliex Serge , Warltier David C.
Published: October 2006

Studies have shown that antifibrinolytic (aprotinin, tranexamic acid, epsilon-aminocaproic acid) reduce blood loss in orthopedic surgery. However, most lacked sufficient power to evaluate the efficacy and safety on clinical outcomes. This meta-analysis aims to evaluate whether intravenous antifibrinolytics, when compared with placebo, reduce perioperative allogeneic erythrocyte transfusion requirement in adults undergoing orthopedic surgery and whether it might increase the risk of venous thromboembolism. From MEDLINE, EMBASE, and the Cochrane Controlled Trials Register, the authors identified 43 randomized controlled trials in total hip and knee arthroplasty, spine fusion, musculoskeletal sepsis, or tumor surgery performed to July 2005 (for aprotinin, 23 trials with 1,268 participants; tranexamic acid, 20 with 1,084; epsilon-aminocaproic acid, 4 with 171). Aprotinin and tranexamic acid reduced significantly the proportion of patients requiring allogeneic erythrocyte transfusion according to a transfusion protocol. The odds ratio was 0.43 (95% confidence interval, 0.28-0.64) for aprotinin and 0.17 (0.11-0.24) for tranexamic acid. Results suggest a dose-effect relation with tranexamic acid. Epsilon-aminocaproic acid was not efficacious. Unfortunately, data were too limited for any conclusions regarding safety. Although the results suggest that aprotinin and tranexamic acid significantly reduce allogeneic erythrocyte transfusion, further evaluation of safety is required before recommending the use of antifibrinolytics in orthopedic surgery.
Peptide signaling paths related to intoxication, memory and addiction
Authors: Lands William E. M.
Published: October 2006

Many peptides bind to G protein‐coupled receptors and activate intracellular signaling paths for adaptive cellular responses. The components of these paths can be affected by signals from other neurotransmitters to produce overall integrated results not easily predicted from customary a priori considerations. This intracellular cross‐talk among signaling paths provides a “filter” through which long‐term tonic signals affect short‐term phasic signals as they progress toward the nucleus and induce long‐term adaptation of gene expression which provide enduring attributes of acquired memories and addictions. Peptides of the PACAP family provide intracellular signaling that involves kinases, scaffolding interactions, Ca2 + mobilization, and gene expression to facilitate development of tolerance to alcohol and development of associative memories. The peptide‐induced enhancement of NMDA receptor responses to extracellular glutamate also may increase behavioral sensitization to the low doses of alcohol that occur at the onset of each bout of drinking. Because many gene products participate in each signaling path, each behavioral response to alcohol is a polygenic process of many steps with no single gene product sufficient to interpret fully the adaptive response to alcohol. Different susceptibility of individuals to alcohol addiction may be a cumulative result of small differences among the many signaling components. Understanding this network of signals may help interpret future “magic bullets” proposed to treat addiction.
Susceptibility for alcoholism: DRD4 exon III polymorphism: a case–control and a family‐based association approach
Authors: Franke Petra , Wang Tao , Möthen Markus M. , Knapp Michael , Neith Helge , Lichtermann Dirk , Capellen Kathrin Meyer Zur , Sander Thomas , Propping Peter , Maier Wolfgang
Published: October 2006

The present investigation explored whether the 7‐repeat allele of the exon III polymorphism in the dopamine D4 receptor gene confers to susceptibility of alcoholism. Using a classical case‐control approach we first compared DRD4 exon III VNTR frequencies between alcoholics and ethnically matched controls (sample I). Secondly, we applied a family‐based association approach in an independent parent‐offspring sample of alcoholics (sample II). All patients underwent an inpatient treatment for alcohol detoxification: sample I comprised 218 alcoholics and 197 ethnically matched controls, sample II included 76 alcoholics plus their biological parents. A higher proportion of addicted individuals in sample I revealed the 7‐repeat allele compared to the control sample yielding an odds ratio (OR) of 1.43 (individuals homozygous for 7‐repeat allele) and an OR of 1.69 (homozygous and heterozygous 7‐repeat allele individuals together). However, we failed to detect preferential transmission from parents to offspring of either the 7‐repeat allele or the long alleles (5–7 repeats) of the DRD4 exon III VNTR in the family‐based association approach (sample II). The impact of the DRD4 exon III polymorphism on susceptibility to addictive behaviour putatively plays only a minor role in our sample of alcohol‐dependent patients, since we were not able to replicate our findings by the family‐based association approach. However, a larger sample size by the family‐based approach would be needed (approximately > 300 parent‐offspring trios) to definitely corroborate or reject the findings from our case‐control sample.
Possible association between loudness dependence of auditory evoked potentials and tryptophan hydroxylase‐alleles in alcoholics
Authors: Preuss U. W. , Bondy B. , Zill P. , Frodl T. , Soyka M. , Möller H. J. , Hegerl U.
Published: October 2006

The serotonergic neurotransmission was suggested to play an important role in the aetiology of alcoholism. This study explores the association between tryptophan hydroxylase (TPH)‐alleles and Loudness Dependence of Auditory Evoked N1/P2 Potentials (LDAEP). The TPH is the rate‐limiting biosynthetic enzyme in serotonergic pathway. The LDAEP is one of the best validated non‐invasive indicators for serotonergic neurotransmission. A sample of 54 alcoholics was recruited. N1/P2 potentials were evoked by five different sound intensities. A dipole source analysis using BESA (brain electric signal topography) was performed and intensity dependence was computed. The TPH intron 7 polymorphism was determined by using PCR in DNA samples. There was a weak but significant association between low LDAEP and the L‐TPH allele. No influence from an individual's history of alcohol dependence or a positive family history of alcohol dependence on LDAEP was found. The weak but significant relationship found between L‐TPH‐allele and high serotonergic neurotransmission may contribute to a more detailed neurobiological characterization of alcohol dependents using functional and genetic parameters.
Relevance of urinalysis monitoring of methadone maintenance patients: a clinical–biological agreement on 41 patients
Authors: Fellous J. , Lowenstein W. , Gourarier L. , Bonan B. , Manuel N. , Dauphin A. , Fermanian J. , Durand H.
Published: October 2006

This study evaluated the concordance of concomitant urinalysis and clinical assessments of drug abusers included in a methadone maintenance programme. The agreement between a clinical subjective score and an objective biological score, both measuring the evolution of illicit substance consumption over 12 months, was analysed. The clinical score, established by physicians and applied during patient interviews, was determined at entry into the programme and re‐evaluated after 6 and 12 months. Forty‐one patients were evaluated. The urinalysis score was based on regular screening of urine samples with the EMIT method. Agreement between the two scores was determined by using the kappa coefficient for each substance (opiates, benzodiazepines and cocaine) for each time‐point. The calculated kappa coefficients showed poor agreement between the two scores, but could indicate the complementarity of these clinical and biological appraisals. Indeed, the urinalysis objectively detected change in drug use before the clinician. Thus, urinalysis monitoring should be considered as an additional and complementary biological procedure for patient follow‐up by physicians.
Ofloxacin causes false‐positive immunoassay results for urine opiates
Authors: Backmund Markus , Meyer Kirsten , Von Zielonka Michael , Eichenlaub Dieter
Published: October 2006

Immunoassay drug screening tests are usually used as a control during methadone maintenance programmes, to check cleanliness of drugs during detoxification treatment and abstinence programmes. False‐positive results can have catastrophic consequences for the patient, as shown in the case report. False‐positive results were reported for opioids following ofloxacin or rifampicin and for LSD following mucolytic. Since inpatient and outpatient units usually employ an urine quick test (immunoassay), positive results should be checked with gas chromatography/mass spectroscopy (GC‐MS) or high pressure liquid chromatography (HPLC) before conclusions from the positive urine screening results can be drawn.
A role for glutamate transmission in addiction to psychostimulants
Authors: Kalivas Peter W.
Published: October 2006

Psychostimulant addiction results in the emergence of undesirable behaviors such as drug craving and paranoia. Using animal models of addiction the neurobiological substrates mediating these behaviors have been examined. Studies have focused on cellular adaptations within the motive circuit that contains the nucleus accumbens, ventral tegmental area, ventral pallidum and prefrontal cortex. While long‐term alterations in dopamine transmission have been clearly characterized, more recent studies reveal that important neuroadaptations are also produced in glutamate transmission.This short review provides a description of these neuroadaptations and a discussion of how these psychostimulant‐induced changes may synergize to elicit addiction‐related behaviors.
Role of peroxynitrite in methamphetamine‐induced dopaminergic neurotoxicity and sensitization in mice
Authors: Ali Syed F. , Haung Paul , Itzhak Yossef
Published: October 2006

Methamphetamine (METH)‐induced dopaminergic neurotoxicity is thought to be associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recently, we have reported that copper/zinc(CuZn)‐superoxide dismutase transgenic mice are resistant to METH‐induced neurotoxicity. In the present study, we examined the role of the neuronal nitric oxide synthase (nNOS), susceptibility of nNOS knockout (KO) mice and sensitization to psychostimulants after neurotoxic doses of METH. Male SwissWebster mice were treated with or without 7‐nitroindazole (7‐NI) along with METH (5 mg/kg,ip,q 3h × 3) and were sacrificed 72 h after the last METH injection. Dopamine (DA) and dopamine transporter (DAT) binding sites were determined in striatum from saline and METH‐treated animals. 7‐NI completely protected against the depletion of DA, and DAT in striatum. In follow‐up experiments nNOS KO mice along with appropriate control (C57BL/6N, SV129 and B6JSV129) mice were treated with METH (5 mg/kg,ip, q 3h × 3) and were sacrificed 72 h after dosing. This schedule of METH administrations resulted in only 10–20% decrease in tissue content of DA and no apparent change in the number of DAT binding sites in nNOS KO mice. However, this regime of METH resulted in a significant decrease in the content of DA as well as DAT binding sites in the wild‐type animals. Pre‐exposure to single or multiple doses of METH resulted in a marked locomotion sensitization in response to METH. However, the nNOS KO mice show no sensitization in response to METH after single or multiple injections of METH. Therefore, these studies strongly suggest the role of peroxynitrite, nNOS and DA system in METH‐induced neurotoxicity and behavioral sensitization.
Molecular and regional targets of cocaine in primate brain: liberation from prosaic views
Authors: Madras Bertha K. , Miller Gregory M. , Meltzer Peter C. , Brownell Anna‐Liisa , Fischman Alan J.
Published: October 2006

The neurochemical processes underlying initial exposure to and reinforcing effects of cocaine are not fully understood. An enduring hypothesis of cocaine addiction is based on an underlying premise that dopamine is the acute mediator of the rewarding effects of cocaine and this nefarious role extends through each phase of addiction. Cocaine is an effective inhibitor of the dopamine transporter, thereby increasing extracellular dopamine levels. Euphoria is attributed to the cocaine‐induced inundation of extracellular dopamine and the withdrawal and craving for cocaine after cessation of drug use are attributed to neuroadaptive processes to dampen dopaminergic transmission. Nevertheless, our understanding of the role of dopamine transporter blockade in cocaine addiction is not fully understood. The objectives of this laboratory are to investigate the primary targets of cocaine in the brain, those associated with the initial phase of cocaine use and that can provide leads for investigating neuroadaptive processes that may trigger addiction. Two prosaic views of the neurobiology of cocaine addiction are examined in this review. The first is based on the assumption that the dopamine transporter contributes significantly to the stimulant and reinforcing effects of cocaine, and focuses on how stimulant drugs of abuse such as cocaine bind to the dopamine transporter. We present evidence that the widespread assumption that dopamine transporter blockers require an amine nitrogen in their structure is incorrect as non‐amines are effective blockers of transporters. The second prosaic view, based on the assumption that the dopamine transporter fulfills a paramount role in cocaine addiction, is assessed in view of mounting evidence that the transporter may not account for the full spectrum of cocaine's effects. Other targets of cocaine, which may be relevant to the acute and chronic effects of cocaine, are presented.
Book and media reviews
Authors: COOK CHRIS
Published: October 2006

Books reviewed in this article:

Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, significant titles of general relevance to the addictions field will also be included, even if they are not “biologi cal”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CDs, videos, etc). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggesti ons of any items suitable for reviews, but especially software and other media of specific relevance to the addictions. Please contact: Dr David Ball, National Addiction Centre, 4 Windsor Walk, London SE5 8AF, UK.

Evaluating the Treatment of Drug Abuse in the European Union. EMCDDA scientific monograph series no. 3

Genetics and Criminality. The Potential Misuse of Scientific Information in Court JEFFREY R. BOTKIN, WILLIAM M. McMAHON & LESLIE PICKERING

Dimensions of Forgiveness, Psychological Research and Theological Perspectives EVERETT L. WORTHINGTON Jr

Handbook of Psychiatry for Primary Care C. W. ALLWOOD & C. A. GAGIANO

Scientific Unit Conversion, 2nd edn FRANÇOIS CARDARELLI (English translation by M.J. SHIELDS)
Gamma‐hydroxybutyric acid in alcohol preference, dependence and withdrawal
Authors: Colombo Giancarlo , Gessa Gian Luigi
Published: October 2006

Gamma‐hydroxybutyric acid (GHB) is an endogenous constituent of the mammalian brain, where it likely functions as a neurotransmitter or a neuromodulator. Its exogenous administration exerts a number of pharmacological effects, including reduction of intensity of alcohol withdrawal syndrome and alcohol consumption in both laboratory animals and human alcoholics.The clinical studies conducted to date, although often testing samples of limited size, feature GHB as an effective, well‐tolerated and safe drug for the treatment of alcohol dependence. Behavioural data in rats suggest that GHB may produce alcohol‐like effects. This similarity may explain why GHB produces positively reinforcing properties, being subsequently self‐administered by rodents and sometimes abused by humans (although episodes of self‐directed intake of GHB appear to be a limited phenomenon in alcoholics); in addition it provides support to the hypothesis that GHB constitutes for alcoholism a replacement therapy similar to methadone in heroin addiction.
Harman and norharman plasma levels in weaned alcoholics: correlations with depression and tobacco smoking
Authors: Kiefer F. , Krödel A. , Jahn H. , Wolf K. , Barocka A.
Published: October 2006

Based on the hypothesis that β‐carbolines are involved in the pathogenesis of alcohol‐related mood disturbance, harman and norharman levels were assayed in the blood plasma of alcoholics and correlated to the Hamilton Depression (HAM‐D) scores after 3 and 5 weeks post‐admission. Tobacco smoking was co‐evaluated since it is known to influence β‐carboline levels. After a 3‐week period, plasma harman but not norharman was increased in depressed alcoholics and positively related to the HAM‐D sum‐score (r = 0.47; p < 0.04) and to tobacco smoking (r = 0.56; p < 0.02). Since no correlation between depression and smoking was found, these data could account for the higher incidence of depressive symptoms in withdrawn alcoholics with increased harman levels. The partial correlations support this hypothesis.
A compressed opiate detoxification regime with naltrexone maintenance: patient tolerance, risk assessment and abstinence rates
Authors: Beaini A. Y. , Johnson T. S. , Langstaff P. , Carr M. P. , Crossfield J. N. , Sweeney R. C.
Published: October 2006

Opiate detoxification using methadone programmes are inefficient and expensive. Rapid and ultra‐rapid detoxification using precipitated withdrawal under heavy sedation or anaesthesia provide increased efficiency and speed, but are limited by the requirement for high‐dependency facilities and are perceived as high‐risk procedures. Procedures using precipitated withdrawal over longer periods with lower sedation are safer, but 20% of patients fail to tolerate these. Here we evaluate a naltrexone compressed opiate detoxification (NCOD) protocol. We investigated patient acceptance, organ function and abstinence rates on 504 consecutive patients undergoing treatment at the Harrogate Detox5 centre between February 1996 and January 1999. Ninety‐eight per cent of patients completed the procedure; 81% of patients reported withdrawal was “better than expected”. Only 3% of patients reported any pain. Laboratory investigations demonstrated no organ dysfunction. Abstinence rates post‐detox were high with 71%, 61% and 51% of patients free of opiates 3, 6 and 12 months post‐detox, respectively. Compliance with the naltrexone maintenance in abstinent patients was 66%, 68% and 30% at these time points. This NCOD protocol provides an efficient method of detoxifying opiate abusers with little patient discomfort or risk to health. Abstinence rates are better than those in comparable studies using other programmes.
Chronic ethanol treatment and GABA A receptor a6 subunit gene expression: a study using a6 subunit‐deficient mice
Authors: Vekovischeva Olga Y. , Uusi‐Oukari Mikko , Korpi Esa R.
Published: October 2006

Chronic alcohol administration increases the expression of cerebellum‐specific GABA A receptor α6 subunit mRNA, protein and selective autoradiographical fingerprint on rat and mouse brain sections. We have tested whether the α6 gene is activated by chronic alcohol administration (daily p.o. injection of 2 g/kg during the first 3 days and 2.5 g/kg during the next 17 days) that produced tolerance in the rotarod test to motor impairment by acute challenge of ethanol (2 g/kg, i.p.). We utilized a mouse line engineered to express E. coli b‐galactosidase enzyme and an unfunctional truncated α6 subunit under the control of the α6 gene promoter. Chronic ethanol treatment failed to alter the cerebellar b‐galactosidase activity when compared with no treatment and isocaloric sucrose treatment in groups of α6 subunit‐deficient mice. The results suggest that tolerance to motor‐impairing effects of ethanol can be achieved in the absence of α6 subunit‐containing GABA A receptors, but that the reported upregulation of α6 gene transcription by ethanol treatment requires functional α6 subunits.
Leptin is associated with craving in females with alcoholism
Authors: Kraus T , Reulbach U , Bayerlein K , Mugele B , Hillemacher T , Sperling W , Kornhuber J , Bleich S
Published: October 2006

The appetite and weight regulating peptide leptin was associated recently with alcohol craving during withdrawal. Nevertheless, correlations were only significant with craving displayed on the visual analogue scale for maximum craving during the previous week (VAS), and not if assessed with the highly validated Obsessive Compulsive Drinking Scale (OCDS). The objective of the following study, therefore, is to elucidate further the associations between the leptin system and craving concepts during alcohol withdrawal. A sufficiently large sample size should allow multiple statistical subgroup and confounder analyses. We prospectively investigated 102 chronic alcoholic inpatients (23 females, 79 males) during withdrawal on days 0 (admission), 1, 2 and days 7 ‐ 10. In addition to the statistical analysis of the total sample, females and males were to be analysed separately. For detecting associations between leptin levels and craving scores multiple regression analysis was performed. Plasma leptin levels were determined, and craving for ethanol was assessed by both the OCDS and the VAS. Leptin plasma levels significantly increased during alcohol withdrawal compared to day 0, while all craving scores decreased. Body mass corrected leptin plasma levels predicted craving on day 0 in the OCDS total score (R  = 0.55, F  = 7.91, df = 1.19, p  < 0.05) and in the OCDS obsessive subscore (R  = 0.57, F < = 8.48, df = 1.19, p  < 0.05) in females. Neither in males nor in the total population did multiple regression analysis reveal any significant results. Leptin levels seem to change during inpatient alcohol withdrawal. In a multivariate model, correlations between leptin levels and the highly validated craving scores of the OCDS can only be assumed in females. Hence, gender differences have to be taken into account when searching for neurobiological models of alcohol craving.