bluuebunny/crossref_metadata_2025_split huggingface dataset:
REVIEW: Behavioural assessment of drug reinforcement and addictive features in rodents: an overview
Authors: Sanchis‐Segura Carles , Spanagel Rainer 
Published: October 2006

ABSTRACTSome psychoactive drugs are abused because of their ability to act as reinforcers. As a consequence behavioural patterns (such as drug‐seeking/drug‐taking behaviours) are promoted that ensure further drug consumption. After prolonged drug self‐administration, some individuals lose control over their behaviour so that these drug‐seeking/taking behaviours become compulsive, pervading almost all life activities and precipitating the loss of social compatibility. Thus, the syndrome of addictive behaviour is qualitatively different from controlled drug consumption. Drug‐induced reinforcement can be assessed directly in laboratory animals by either operant or non‐operant self‐administration methods, by classical conditioning‐based paradigms such as conditioned place preference or sign tracking, by facilitation of intracranial electric self‐stimulation, or, alternatively by drug‐induced memory enhancement. In contrast, addiction cannot be modelled in animals, at least as a whole, within the constraints of the laboratory. However, various procedures have been proposed as possible rodent analogues of addiction’s major elements including compulsive drug seeking, relapse, loss of control/impulsivity, and continued drug consumption despite negative consequences. This review provides an extensive overview and a critical evaluation of the methods currently used for studying drug‐induced reinforcement as well as specific features of addictive behaviour. In addition, comic strips that illustrate behavioural methods used in the drug abuse field are provided given for free download under http://www.zi‐mannheim/psychopharmacology.de
CLINICAL STUDY: Suppression of cue‐induced heroin craving and cue‐reactivity by single‐trial transcutaneous electrical nerve stimulation at 2 Hz
Authors: Zhong Fei , Wu Liu‐Zhen , Han Ji‐Sheng 
Published: October 2006

ABSTRACTThe purpose of the present study was to investigate the efficacy of 2 Hz transcutaneous electrical nerve stimulation (TENS) to reduce cue‐induced heroin craving and the corresponding cardiovascular responses. Seventy heroin addicts with at least 1 month of abstinence were enrolled and randomly divided into two groups of 35, to receive single‐trial 2 Hz TENS (TENS group) or mock TENS (mock group) during experimental procedure, respectively. They were required to express their degree of craving by visual analog scale before and after the presentation of a video‐cue, and after TENS treatment, which lasted for 30 minutes. Heart rate and arterial blood pressure were simultaneously monitored in 56 cases, with 28 in each group. Results show that in mock group, video‐cue induced a dramatic increase of craving score, which did not return to baseline in 150 minutes, whereas in the TENS group, 2 Hz TENS treatment produced a significant decrease of craving, reaching baseline in 90 minutes. Video‐cue induced a significant increase of heart rate and systolic and diastolic blood pressure, which remained elevated for at least 60 minutes in the mock group; whereas in the TENS group, they returned to baseline immediately after the termination of TENS. These results indicate that the craving induced by a heroin‐related cue can be immediately and significantly suppressed, and the cardiovascular activation totally abolished by a single‐trial 2 Hz TENS for 30 minutes
CLINICAL STUDY: Endocrine alterations during a detoxification treatment with carbamazepine in male alcoholics
Authors: Krüger Tillmann H. C. , Brink Paul , Goebel Marion U. , Schiffer Boris , Schedlowski Manfred , Hartmann Uwe , Schneider Udo 
Published: October 2006

ABSTRACTThis study aimed to evaluate the prevalence and time‐course of endocrine alterations in male alcohol addicts during a detoxification treatment and to examine a possible relation between endocrine alterations and depressive symptoms and overall mental distress. Blood samples were drawn in 54 male alcohol addicts on admission, at day 7 of treatment and at day 14 on discharge. Endocrine analysis was performed for cortisol, luteinizing hormone, prolactin, androgens, free testosterone and 17β‐estradiol. Psychometric measures (Beck’s depression inventory and the symptom checklist‐90‐R) were taken on admission and on discharge and were correlated with endocrine measures. Cortisol plasma levels were substantially increased at the beginning of the detoxification, whereas all other endocrine parameters were within the normal range. Although subjects depicted mild to moderate levels of depressive symptoms and mental distress, there were no correlations with endocrine variables. Further analysis revealed a high variation in sex steroid levels with approximately 55% of participants showing initial (n = 19) or developing (n = 11) hypogonadal values during detoxification. In conclusion, chronic alcohol consumption induces disturbances of gonadal function which are reversible in the majority of cases. However, few patients develop a hypogonadal state during detoxification. Initially increased cortisol levels indicate a bodily stress response with the onset of alcohol withdrawal but are not related to mental disturbances.
PRECLINICAL STUDY: Long‐term voluntary consumption of MDMA and THC in rats is modified by individual and situational factors
Authors: Reinhard Carola , Wolffgramm Jochen 
Published: October 2006

ABSTRACTFactors influencing long‐term voluntary intake of 3,4‐methylenedioxymethamphetamine (MDMA; ecstasy) and Δ9‐tetrahydrocannabinol (THC; cannabis) were studied in a rat model. Sixty‐four male Wistar rats were given free choice for 49 weeks between (1) water and MDMA solution, (2) water and THC solution or (3) water, MDMA solution and THC solution. After the first experiences with the drugs, animals of both monodrug and polydrug group developed an individually stable pattern of MDMA consumption, whereas the individual predictability of THC consumption remained poor. While THC consumption was maintained for the whole experimental period, MDMA consumption decreased with time and was nearly ceased after 3–7 months. Intake of both drugs was adapted to social changes, with THC consumption being more sensitive to social changes than MDMA consumption. In the re‐test after 4 months of abstinence, all animals ceased drug consumption when the drug solutions were adulterated with bitter tasting quinine. The results show that the rats had maintained a flexible mode of drug consumption and had not become addicted. Response to novelty of the rats in test trials before the start of drug supply correlated with later MDMA intake. In conclusion, although very low amounts of MDMA and/or THC were consumed, the findings that drug‐experienced animals responded differentially to a stressor and that housing conditions influenced drug intake suggests that MDMA and THC can induce psychopharmacological effects in our long‐term voluntary consumption paradigm.
REVIEW: The UChA and UChB rat lines: metabolic and genetic differences influencing ethanol intake
Authors: Quintanilla María E. , Israel Yedy , Sapag Amalia , Tampier Lutske 
Published: October 2006

ABSTRACTEthanol non‐drinker (UChA) and drinker (UChB) rat lines derived from an original Wistar colony have been selectively bred at the University of Chile for over 70 generations. Two main differences between these lines are clear. (1) Drinker rats display a markedly faster acute tolerance than non‐drinker rats. In F2 UChA × UChB rats (in which all genes are ‘shuffled’), a high acute tolerance of the offspring predicts higher drinking than a low acute tolerance. It is further shown that high‐drinker animals ‘learn’ to drink, starting from consumption levels that are one half of the maximum consumptions reached after 1 month of unrestricted access to 10% ethanol and water. It is likely that acquired tolerance is at the basis of the increases in ethanol consumption over time. (2) Non‐drinker rats carry a previously unreported allele of aldehyde dehydrogenase‐2 (Aldh2) that encodes an enzyme with a low affinity for Nicotinamide‐adenine‐dinuclectide (NAD+) (Aldh22), while drinker rats present two Aldh2 alleles (Aldh21 and Aldh23) with four‐ to fivefold higher affinities for NAD+. Further, the ALDH2 encoded by Aldh21 also shows a 33% higher Vmax than those encoded by Aldh22 and Aldh23. Maximal voluntary ethanol intakes are the following: UChA Aldh22/Aldh22 = 0.3–0.6 g/kg/day; UChB Aldh23/Aldh23 = 4.5–5.0 g/kg/day; UChB Aldh21/Aldh21 = 7.0–7.5 g/kg/day. In F2 offspring of UChA × UChB, the Aldh22/Aldh22 genotype predicts a 40–60% of the alcohol consumption. Studies also show that the low alcohol consumption phenotype of Aldh22/Aldh22 animals depends on the existence of a maternally derived low‐activity mitochondrial reduced form of nicotinamide‐adenine‐dinucleotide (NADH)‐ubiquinone complex I. The latter does not influence ethanol consumption of animals exhibiting an ALDH2 with a higher affinity for NAD+. An illuminating finding is the existence of an ‘acetaldehyde burst’ in animals with a low capacity to oxidize acetaldehyde, being fivefold higher in UChA than in UChB animals. We propose that such a burst results from a great generation of acetaldehyde by alcohol dehydrogenase in pre‐steady‐state conditions that is not met by the high rate of acetaldehyde oxidation in mitochondria. The acetaldehyde burst is seen despite the lack of differences between UChA and UChB rats in acetaldehyde levels or rates of alcohol metabolism in steady state. Inferences are drawn as to how these studies might explain the protection against alcoholism seen in humans that carry the high‐activity alcohol dehydrogenase but metabolize ethanol at about normal rates.
REVIEW: Phenotypic characterization of genetically selected Sardinian alcohol‐preferring (sP) and ‐non‐preferring (sNP) rats
Authors: Colombo Giancarlo , Lobina Carla , Carai Mauro A. M. , Gessa Gian Luigi 
Published: October 2006

ABSTRACTSardinian alcohol‐preferring (sP) and ‐non‐preferring (sNP) rats are one of the pairs of rat lines selectively bred for high and low alcohol preference and consumption, respectively, under the homecage, continuous two‐bottle choice regimen. sP rats meet most of the fundamental criteria for an animal model of alcoholism, in that they voluntarily consume sufficient amounts of alcohol to achieve significant blood alcohol levels and produce psychopharmacological effects, including anxiolysis and motor stimulation. sP rats are also willing to ‘work’ (such as lever‐pressing) for alcohol. Chronic alcohol drinking in sP rats results in the development of tolerance to a given effect of alcohol (specifically, motor incoordination) and relapse‐like drinking (the alcohol deprivation effect). Conversely, sNP rats avoid alcohol virtually completely; their avoidance for alcohol being resistant even to an environmental manipulation such as long‐term exposure to alcohol plus sucrose. sP and sNP rats have been characterized for different phenotypes, possibly associated to their different alcohol preference and consumption. In comparison with sNP rats, alcohol‐naive sP rats displayed (1) more anxiety‐related behaviors; (2) higher initial sensitivity to the locomotor stimulating and sedative/hypnotic effects of alcohol; and (3) lower sensitivity to the aversive effects of alcohol. The present paper reviews the data collected to date on alcohol drinking behavior and other alcohol‐related behaviors in sP and sNP rats. The behavioral profile of sP rats is also compared with that of other lines of selectively bred alcohol‐preferring rats and the heterogeneity resulting from this comparison is discussed in terms of different animal models for the different forms of alcoholism.
REVIEW: Alcohol‐related genes: contributions from studies with genetically engineered mice
Authors: Crabbe John C. , Phillips Tamara J. , Harris R. Adron , Arends Michael A. , Koob George F. 
Published: October 2006

ABSTRACTSince 1996, nearly 100 genes have been studied for their effects related to ethanol in mice using genetic modifications including gene deletion, gene overexpression, gene knock‐in, and occasionally by studying existing mutants. Nearly all such studies have concentrated on genes expressed in brain, and the targeted genes range widely in their function, including most of the principal neurotransmitter systems, several neurohormones, and a number of signaling molecules. We review 141 published reports of effects (or lack thereof) of 93 genes on responses to ethanol. While most studies have focused on ethanol self‐administration and reward, and/or sedative effects, other responses studied include locomotor stimulation, anxiolytic effects, and neuroadaptation (tolerance, sensitization, withdrawal). About 1/4 of the engineered mutations increase self‐administration, 1/3 decrease it, and about 40% have no significant effect. In many cases, the effects on self‐administration are rather modest and/or depend on the specific experimental procedures. In some cases, genes in the background strains on which the mutant is placed are important for results. Not surprisingly, review of the systems affected further supports roles for serotonin, γ‐aminobutyric acid, opioids and dopamine, all of which have long been foci of alcohol research. Novel modulatory effects of protein kinase C and G protein‐activated inwardly rectifying K+(GIRK) channels are also suggested. Some newer research with cannabinoid systems is promising, and has led to ongoing clinical trials.
Should central government seek to control the level of local authority expenditures?
Authors: Fender John , Watt Peter A. 
Published: October 2006

AbstractShould local authorities be free to determine their expenditure, provided they finance changes in spending by changes in local taxation? We set up a theoretical framework to analyse this issue, and discuss three arguments that have been put forward for central control of such spending. The first relates to tax spillovers, the second to distributional effects combined with imperfect local democracy and the third considers self‐interested local politicians. While these arguments cannot be entirely dismissed, they are subject to numerous qualifications and, if correct, would imply the desirability of a number of policies other than expenditure capping.
Amino acid regions 572–579 and 657–666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP
Authors: Luken Brenda , Turenhout Ellen , Kaijen Paul , Greuter Mascha , Pos Wouter , van Mourik Jan , Fijnheer Rob , Voorberg Jan 
Published: October 2006

SummaryAntibodies directed against ADAMTS13 have been detected in the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP). We have previously localized a major antigenic determinant within the spacer domain of ADAMTS13. To identify the amino acid residues of the spacer domain that are involved in binding of anti-ADAMTS13 antibodies, we constructed a series of fifteen hybrids (designated A-O) in which 5–10 amino acids of the spacer domain were exchanged for the corresponding region of ADAMTS1. Plasma from six patients with antibodies directed against the spacer domain was analyzed for reactivity with the ADAMTS13/ADAMTS1 chimeras. Exchange of amino acid residues 572–579 (hybrid C) and 657–666 (hybrid M) completely abolished the binding of antibodies from all six patients analyzed. Regions 580–587 (D), 602–620 (G, H), 629–638 (J), and 667–767 (N) contributed to binding of antibodies from patients 2, 4, and 5 (epitope present within regions CDGHJMN). Antibodies derived from patient 1 required region 602–620 (G, H) for binding (CGHM-epitope). For antibodies of patient 3, residues 564–571 (B), 580–587 (D), and 629–638 (J) were required (BCDJM-epitope), whereas replacement of residues 602–610 (G) and 629–638 (J) greatly diminished binding of antibodies from patient 6 (CGJM-epitope). Despite the presumably polyclonal origin of the antibodies present in plasma of patients, our results suggest that residues 572–579 (C) and 657–666 (M) comprise a common antigenic core region that is crucial for binding of anti-ADAMTS13 antibodies. Other regions that spatially surround this antigenic core further modulate binding of antibodies to the spacer domain.
Type 2N von Willebrand disease due to compound heterozygosity for R854Q and a novel R763G mutation at the cleavage site of von Willebrand factor propeptide
Authors: Nurden Paquita , Caron Claudine , Nurden Alan , Goudemand Jenny , Meyer Dominique , Fressinaud Edith , Mazurier Claudine , Hilbert Lysiane ,   and the INSERM Network on Molecular Abnormalities in von Willebrand Disease
Published: October 2006

SummaryType 2N von Willebrand disease (VWD) is characterized by a markedly decreased affinity of von Willebrand factor (VWF) for factorVIII (FVIII) and is caused by mutations in the D’ or D3 domain of mature VWF. We now report a French patient with an atypical 2N VWD phenotype associating FVIII deficiency with plasmaVWF unable to bind FVIII (undetectableVWF:FVIIIB) but with an abnormal multimeric profile. This patient is heterozygous for both the frequent R854Q type 2NVWD mutation and a novel R763G mutation at the cleavage site betweenVWF propeptide and mature VWF. Four children of the patient displayed moderately decreased VWF:FVIIIB of plasma VWF and were heterozygous for either the R763G or the R854Q mutation. Children with the R763G mutation displayed the same abnormal multimeric profile as their father. Recombinant VWF (rVWF) expression studies performed in COS-7 cells showed that the R763G mutation subtly affects its multimeric profile and dramatically impairs its FVIII binding function. Furthermore, the characteristics of hybrid G763/Q854 rVWF resulting from cotransfection experiments were in agreement with the type 2N VWD diagnosis of the patient. We conclude that R763G is a new type 2N VWD mutation located in the VWF propeptide which alters the proteolytic processing of VWF and consequently its binding to FVIII.
Fibrinolytic efficacy of Amediplase, Tenecteplase and scu-PA in different external plasma clot lysis models
Authors: Guimarães Ana , Barrett-Bergshoeff Marrie , Criscuoli Marco , Evangelista Stefano , Rijken Dingeman 
Published: October 2006

SummaryIn this study, the in-vitro fibrinolytic efficacy of Tenecteplase, Amediplase and scu-PA was investigated in different external lysis models by measuring the lysis of human plasma clots after the addition of the plasminogen activators (PAs) to the surrounding plasma. The effect ofTAFI was examined for each PA by neutralizing TAFI a with potato carboxypeptidase inhibitor (PCI). The lytic efficacy of Amediplase was lower than that of Tenecteplase at low PA concentrations but slightly higher at therapeutic concentrations. The activity of scu-PA was clearly lower than that of either Tenecteplase or Amediplase. The TAFI system inhibited external clot lysis mediated by all the PAs when thrombomodulin was present in the model. In the therapeutic range (5–10 µg/ml) however, the TAFIa effect was negligible for both Amediplase and Tenecteplase. At lower PA concentrations the effect of TAFI on Amediplase was slightly stronger than that on Tenecteplase. Under static conditions the lysis rates were lower than with stirring. The role of TAFI was similar under both conditions. In conclusion, at therapeutic concentrations Amediplase was slightly more active than Tenecteplase and scu-PA under all conditions used. Therefore, Amediplase might possibly be a more potent thrombolytic agent at these concentrations and increase the efficacy of thrombolysis. The potential of TAFI for inhibiting thrombolytic therapy is probably low. However in conditions where the local PA concentrations are sub-optimal TAFI might affect the lysis rate.
A novel mechanism of transcriptional repression of p27kip1
through Notch/HRT2 signaling in vascular smooth muscle cells
Authors: Havrda Matthew , Johnson Michael , O’Neill Christine , Liaw Lucy 
Published: October 2006

SummaryVascular smooth muscle cell (VSMC) proliferation occurs in vascular obstructive events such as atherosclerosis and restenosis. We previously showed that Notch receptors are induced in smooth muscle cells during vascular remodeling. Our goal was to determine the mechanisms employed by Notch signaling to regulate proliferation. Activation of Notch1 and Notch4 induced the VSMC-selective target genes HRT1 and HRT2, promoted cell cycle transit in smooth muscle cells, and led to loss of density-dependent growth inhibition. This was associated with a reduction in levels of the cyclin-dependent kinase inhibitor (cdk) p27kip1.Over-expression of p27 kip1 resulted in a dose-dependent rescue of the Notch-induced phenotype and exit from the cell cycle. In addition, HRT2 expression was sufficient to promote S-phase entry, and we demonstrate that HRT2 interacts directly with the p27 kip1 promoter to repress transcription. Transcriptional repression occurred within the ∼774bp minimal p27kip1 promoter region and mutational analysis demonstrated that repression is largely dependent on a conserved class-C domain. Our data show that Notch signaling acts to promote a proliferative phenotype in VSMC by modulation of the G1/S-phase checkpoint. In addition, we define a novel mechanism by which the Notch effector, HRT2, interacts directly with the class-C domain of the p27kip1 promoter, repressing its expression. These studies identify a novel transcriptional target of HRT2, and show that Notch effectors directly control cell cycle regulatory components. We suggest that this mechanism is relevant to hyperproliferative states in VSMC seen during vascular remodeling and repair.
New concepts in optimal management of anticoagulant therapy for extended treatment of venous thromboembolism
Authors: Ögren Mats , Schulman Sam 
Published: October 2006

SummaryRecent trials on secondary prophylaxis after venous thromboembolism (VTE) have provided a wealth of data on the risk factors for recurrence and, to some extent, also for bleeding. Some of the results are consistent across the studies, but there are also conflicting data. Certain risk factors, such as pulmonary embolism versus deep vein thrombosis or presence of cardiolipin antibodies, have a more pronounced influence on the risk early in the course of disease. Others, such as hereditary throm- bophilic defects, seem to gain importance over many years of follow-up. Therefore, it can be difficult to make decisions on an individual patient basis. In this article,data from important and illustrative trials have been extracted and compared and controversies highlighted. The conclusions drawn should help clinicians make balanced decisions on the optimal duration of anticoagulation after an episode of VTE.
Initial treatment of venous thromboembolism
Authors: Becattini Cecilia , Emmerich Joseph , Bura Alessandra , Weitz Jeffrey , Agnelli Giancarlo 
Published: October 2006

SummaryImmediate anticoagulant treatment is essential to reduce morbidity and mortality in patients with acute venous thromboembolism (VTE). Currently, rapid anticoagulation can only be achieved with parenteral anticoagulants, such as heparin or low-molecular-weight heparin (LMWH).Weight-adjusted LMWH is the treatment of choice, because it produces predictable anticoagulation and does not require coagulation monitoring. If heparin is used, the activated partial thromboplastin time must be monitored and the heparin dose adjusted to ensure a therapeutic level of anticoagulation. Heparin is recommended for patients with renal impairment and for those at high risk of bleeding. The selective factor Xa inhibitor fondaparinux is a recently introduced alternative to heparin or LMWH for initial VTE treatment. Heparin, LMWH, or fondaparinux should be given for at least five to seven days. Vitamin K antagonists should be initiated on the first day, or as soon as possible, in patients who are candidates for an oral anticoagulant. An oral anticoagulant agent to be used without laboratory monitoring for both acute and long-term treatment of VTE remains an unsolved clinical need in the treatment of VTE.