bluuebunny/crossref_metadata_2025 huggingface dataset:
The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population
Authors: Johnstone EC , Yudkin P , Griffiths SE , Fuller A , Murphy M , Walton R
Published: October 2006

A single nucleotide polymorphism (SNP) in the Taq1A site near the DRD2 gene has been associated in several studies with smoking behaviour. We genotyped 732 current smokers (241 low, one to nine cigarettes a day, 250 mid, 10 ‐ 19 cigarettes, 241 high, 20 + cigarettes) and 243 never‐smokers at this site (C32806T), to test for effects on smoking initiation and amount of tobacco consumed. No significant association between minor allele frequency and smoking status was detected. Multiple regression analysis including DRD2 genotype, sex, age and alcohol consumption as predictors showed that level of cigarette consumption was associated with sex (p  = 0.003) and age (p  = 0.002) but not with alcohol consumption (p  = 0.25) or DRD2 genotype (p  = 0.76).
REVIEW: The alcohol‐preferring P rat and animal models of excessive alcohol drinking
Authors: Bell Richard L. , Rodd Zachary A. , Lumeng Lawrence , Murphy James M. , McBride William J.
Published: October 2006

The alcohol‐preferring, P, rat was developed by selective breeding to study ethanol drinking behavior and its consequences. Characterization of this line indicates the P rat meets all of the criteria put forth for a valid animal model of alcoholism, and displays, relative to their alcohol‐non‐preferring, NP, counterparts, a number of phenotypic traits associated with alcohol abuse and alcoholism. Behaviorally, compared with NP rats, P rats are less sensitive to the sedative and aversive effects of ethanol and more sensitive to the stimulatory effects of ethanol. Neurochemically, research with the P line indicates the endogenous dopaminergic, serotonergic, GABAergic, opiodergic, and peptidergic systems may be involved in a predisposition for alcohol abuse and alcoholism. Paralleling the clinical literature, genetically selected P rats display levels of ethanol intake during adolescence comparable to that seen during adulthood. Binge drinking has been associated with an increased risk for health and other problems associated with ethanol abuse. A model of binge‐like drinking during the dark cycle indicates that P rats will consume 6 g/kg/day of ethanol in as little as three 1‐hour access periods/day, which approximates the 24‐hour intake of P rats with free‐choice access to a single concentration of ethanol. The alcohol deprivation effect (ADE) is a transient increase in ethanol intake above baseline values upon re‐exposure to ethanol access after an extended period of deprivation. The ADE has been proposed to be an animal model of relapse behavior, with the adult P rat displaying a robust ADE after prolonged abstinence. Overall, these findings indicate that the P rat can be effectively used in models assessing alcohol‐preference, a genetic predisposition for alcohol abuse and/or alcoholism, and excessive drinking using protocols of binge‐like or relapse‐like drinking.
CLINICAL AND IMAGING STUDY: Imaging alcohol cue exposure in alcohol dependence using a PET 15O‐H2O paradigm: results from a pilot study
Authors: Lingford‐Hughes Anne R. , Daglish M. R. C. , Stevenson B. J. , Feeney A. , Pandit S. A. , Wilson Steven J. , Myles Judith , Grasby Paul M. , Nutt David J.
Published: October 2006

Craving is a commonly used term to describe an intense desire for a substance or behaviour; however, its underlying neurobiology is not fully characterized. We have successfully used a cue exposure paradigm with functional neuro‐imaging (H215O PET; PET, positron emission tomography) in abstinent opiate addicts. This study showed that salient cue exposure results in activation in the left anterior cingulate/mediofrontal cortex and elicited craving correlated with activity in the left orbitofrontal cortex. We therefore aimed to replicate this study in alcohol dependence to see if a similar pattern of neural activation occurred. We recruited six abstinent alcohol‐dependent and six non‐dependent subjects who each underwent a 12‐run PET scan using H215O to measure changes in regional blood flow during exposure to an alcoholic drink or its visually matched non‐alcoholic drink. Physiological data and subjective ratings were also recorded. Statistical parametric mapping (SPM99) was used to analyse the PET images. Compared with control subjects, abstinent alcohol‐dependent subjects rated their alcohol craving higher at baseline and throughout the study, but there was no significant change in the scores in response to the cues in either group. SPM analysis across all subjects showed significant activation in the occipital cortex in response to the alcohol cue as compared with the neutral one. Analysis of the same regions that were activated in the opiate study, revealed significant increases in signal activation in the left medial prefrontal area, but only in abstinent alcohol‐dependent subjects. In conclusion, in abstinent alcohol dependence we suggest that a simple cue exposure paradigm is not sufficiently powerful in functional imaging studies to determine the underlying neurobiology of subjective craving. Comparisons with the finding in opiate dependence suggest a shared region, the anterior cingulate/left medial prefrontal cortex is involved in the cue response in dependent subjects but not controls.
GENETIC STUDY: No association of dopamine receptor sensitivity in vivo with genetic predisposition for alcoholism and DRD2/DRD3 gene polymorphisms in alcohol dependence
Authors: Wiesbeck Gerhard A. , Dürsteler‐MacFarland Kenneth M. , Wurst Friedrich Martin , Walter Marc , Petitjean Sylvie , Müller Sandra , Wodarz Norbert , Böning Jobst
Published: October 2006

This study sought to examine dopamine receptor sensitivity among alcoholics in vivo and to explore whether this sensitivity might be associated with functional variations of dopamine D2 (DRD2) and D3 (DRD3) receptor genes along with a genetic predisposition for alcoholism as reflected by an alcohol‐dependent first‐degree relative. We analyzed the −141C Ins/Del polymorphism in the promoter region of the DRD2 gene and the Ser9Gly (BalI) polymorphism in exon 1 of the DRD3 gene in 74 alcohol‐dependent Caucasian men with or without genetic predisposition for alcoholism. In vivo dopamine receptor sensitivity was assessed by measuring apomorphine‐induced growth hormone release. A three‐way analysis of variance revealed no significant effects of DRD2, DRD3 genotypes and genetic predisposition on dopamine receptor sensitivity. Given the explorative and preliminary character of this investigation, we cannot provide evidence that in alcohol‐dependent Caucasian men a genetic predisposition for alcoholism along with functional variants of the DRD2 and DRD3 genes are associated with differences in dopamine receptor sensitivity.
CLINICAL AND IMAGING STUDY: Glucocorticoid negative feedback in methadone‐maintained former heroin addicts with ongoing cocaine dependence: dose–response to dexamethasone suppression
Authors: Aouizerate Bruno , Ho Ann , Schluger James H. , Perret Guillaume , Borg Lisa , Le Moal Michel , Piazza Pier V. , Kreek Mary Jeanne
Published: October 2006

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin‐addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone‐maintained former heroin addicts with ongoing cocaine dependence (C‐MM), 10 stabilized methadone‐maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C‐MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C‐MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C‐MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C‐MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long‐term treatment with methadone.
REVIEW: Behavioural assessment of drug reinforcement and addictive features in rodents: an overview
Authors: Sanchis‐Segura Carles , Spanagel Rainer
Published: October 2006

Some 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

The 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

This 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

Factors 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

Ethanol 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

Sardinian 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

Since 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.
Insect pollinators of the invasive plant, Rosa multiflora (Rosaceae), in Iowa, USA
Authors: JESSE LAURA C. , MOLONEY KIRK A. , OBRYCKI JOHN J.
Published: October 2006

Invasive species often require mutualistic relationships to successfully invade new environments. Insect pollination is an example of a mutualism that is required for seed‐set in the invasive species, Rosa multiflora Thunb. (Rosaceae), an obligate outcrosser. To determine the insect pollinators visiting R. multiflora flowers in Iowa, USA, we collected insects on yellow sticky traps placed on plants during the period of blooming and visually observed insects visiting the flowers. The common insect orders that were collected on the sticky traps included Coleoptera, Diptera, Hemiptera, Hymenoptera, Mecoptera, and Thysanoptera. Many of the insects found on the sticky cards were known to feed on pollen. However, we did not collect Apidae (bumble bees and honey bees) on the sticky cards. We observed Bombus spp. and Apis mellifera foraging on the flowers. Syrphid flies were the most commonly observed taxa visiting the flowers. Our results indicate that R. multiflora is utilizing common generalist insect pollinators in Iowa and that pollination is not a limiting factor for this invasive species.
Should central government seek to control the level of local authority expenditures?
Authors: Fender John , Watt Peter A.
Published: October 2006

Should 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.
Predicting Patient Survival from Microarray Data by Accelerated Failure Time Modeling Using Partial Least Squares and LASSO
Authors: Datta Susmita , Le‐Rademacher Jennifer , Datta Somnath
Published: October 2006

SummaryWe consider the problem of predicting survival times of cancer patients from the gene expression profiles of their tumor samples via linear regression modeling of log‐transformed failure times. The partial least squares (PLS) and least absolute shrinkage and selection operator (LASSO) methodologies are used for this purpose where we first modify the data to account for censoring. Three approaches of handling right censored data—reweighting, mean imputation, and multiple imputation—are considered. Their performances are examined in a detailed simulation study and compared with that of full data PLS and LASSO had there been no censoring. A major objective of this article is to investigate the performances of PLS and LASSO in the context of microarray data where the number of covariates is very large and there are extremely few samples. We demonstrate that LASSO outperforms PLS in terms of prediction error when the list of covariates includes a moderate to large percentage of useless or noise variables; otherwise, PLS may outperform LASSO. For a moderate sample size (100 with 10,000 covariates), LASSO performed better than a no covariate model (or noise‐based prediction). The mean imputation method appears to best track the performance of the full data PLS or LASSO. The mean imputation scheme is used on an existing data set on lung cancer. This reanalysis using the mean imputed PLS and LASSO identifies a number of genes that were known to be related to cancer or tumor activities from previous studies.
A Spatial Scan Statistic for Survival Data
Authors: Huang Lan , Kulldorff Martin , Gregorio David
Published: October 2006

SummarySpatial scan statistics with Bernoulli and Poisson models are commonly used for geographical disease surveillance and cluster detection. These models, suitable for count data, were not designed for data with continuous outcomes. We propose a spatial scan statistic based on an exponential model to handle either uncensored or censored continuous survival data. The power and sensitivity of the developed model are investigated through intensive simulations. The method performs well for different survival distribution functions including the exponential, gamma, and log‐normal distributions. We also present a method to adjust the analysis for covariates. The cluster detection method is illustrated using survival data for men diagnosed with prostate cancer in Connecticut from 1984 to 1995.
Enhanced Quantile Normalization of Microarray Data to Reduce Loss of Information in Gene Expression Profiles
Authors: Hu Jianhua , He Xuming
Published: October 2006

Summary In microarray experiments, removal of systematic variations resulting from array preparation or sample hybridization conditions is crucial to ensure sensible results from the ensuing data analysis. For example, quantile normalization is routinely used in the treatment of both oligonucleotide and cDNA microarray data, even though there might be some loss of information in the normalization process. We recognize that the ideal normalization, if it ever exists, would aim to keep the maximal amount of gene profile information with the lowest possible noise. With this objective in mind, we propose a valuable enhancement to quantile normalization, and demonstrate through three Affymetrix experiments that the enhanced normalization can result in better performance in detecting and ranking differentially expressed genes across experimental conditions.
STABILITY, PERIODIC SOLUTIONS AND NUMERICAL INTEGRATION IN THE KOWALEVSKI TOP DYNAMICS
Authors: ARON ANANIA , BIRTEA PETRE , PUTA MIRCEA , ŞUŞOI PAUL , TUDORAN RĂZVAN
Published: October 2006

The stability problem, the existence of periodic solutions, the Lax formulation and the numerical integration via the Lie–Trotter integrator of the Kowalevski top dynamics are discussed, and some of their properties are pointed out.
THE ENERGY OF A SOLUTION FROM DIFFERENT LAGRANGIANS
Authors: FATIBENE L. , FERRARIS M. , FRANCAVIGLIA M.
Published: October 2006

It is known that superpotentials of so-called higher-order theories of gravitation and Einstein theories with a cosmological constant are different in the "Palatini" formulation. However, these theories share a number of solutions, the energy of which should be defined out of superpotentials. We shall check that using augmented variational principles, recently introduced by us, the energy of a solution is defined regardless of the theory, and hence regardless of the superpotential used.
Why Does Pancreatic Overstimulation Cause Pancreatitis?
Authors: Saluja Ashok K. , Lerch Markus M. , Phillips Phoebe A. , Dudeja Vikas
Published: October 2006

Many animal models are available to investigate the pathogenesis of pancreatitis, an inflammatory disorder of the pancreas. However, the secretagogue hyperstimulation model of pancreatitis is the most commonly used. Animals infused with high doses of cholecystokinin (CCK) exhibit hyperamylasemia, pancreatic edema, and acinar cell injury, which closely mimic pancreatitis in humans. Intra-acinar zymogen activation is an essential early event in the pathogenesis of secretagogue-induced pancreatitis. Early in the course of pancreatitis, lysosomal hydrolases colocalize with digestive zymogens and activate them. These activated zymogens then cause acinar cell injury and necrosis, a characteristic of pancreatitis. Besides being the site of initiation of injury in pancreatitis, acinar cells also synthesize and release cytokines and chemokines very early in the course of pancreatitis, which then attract and activate inflammatory cells and initiate the disease's systemic phase.
Mitochondrial Ion Channels
Authors: O’Rourke Brian
Published: October 2006

In work spanning more than a century, mitochondria have been recognized for their multifunctional roles in metabolism, energy transduction, ion transport, inheritance, signaling, and cell death. Foremost among these tasks is the continuous production of ATP through oxidative phosphorylation, which requires a large electrochemical driving force for protons across the mitochondrial inner membrane. This process requires a membrane with relatively low permeability to ions to minimize energy dissipation. However, a wealth of evidence now indicates that both selective and nonselective ion channels are present in the mitochondrial inner membrane, along with several known channels on the outer membrane. Some of these channels are active under physiological conditions, and others may be activated under pathophysiological conditions to act as the major determinants of cell life and death. This review summarizes research on mitochondrial ion channels and efforts to identify their molecular correlates. Except in a few cases, our understanding of the structure of mitochondrial ion channels is limited, indicating the need for focused discovery in this area.
Genetic Defects in Ciliary Structure and Function
Authors: Zariwala Maimoona A. , Knowles Michael R. , Omran Heymut
Published: October 2006

Cilia, hair-like structures extending from the cell membrane, perform diverse biological functions. Primary (genetic) defects in the structure and function of sensory and motile cilia result in multiple ciliopathies. The most prominent genetic abnormality involving motile cilia (and the respiratory tract) is primary ciliary dyskinesia (PCD). PCD is a rare, usually autosomal recessive, genetically heterogeneous disorder characterized by sino-pulmonary disease, laterality defects, and male infertility. Ciliary ultrastructural defects are identified in ∼90% of PCD patients and involve the outer dynein arms, inner dynein arms, or both. Diagnosing PCD is challenging and requires a compatible clinical phenotype together with tests such as ciliary ultrastructural analysis, immunofluorescent staining, ciliary beat assessment, and/or nasal nitric oxide measurements. Recent mutational analysis demonstrated that 38% of PCD patients carry mutations of the dynein genes DNAI1 and DNAH5. Increased understanding of the pathogenesis will aid in better diagnosis and treatment of PCD.
Evidence that C-Reactive Protein or IL-6 Are Not Surrogates for All Inflammatory Cardiovascular Risk Factors in Hemodialysis Patients
Authors: Kaysen George A. , Levin Nathan W. , Mitch William E. , Chapman Anna L.P. , Kubala Lukas , Eiserich Jason P.
Published: October 2006

Background/Aims: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated with cardiovascular disease and have been linked to an inflammatory state. The presence of vascular disease is also associated with increased expression of adhesion molecules, including soluble intercellular adhesion molecule (sICAM), vascular endothelial growth factor (VEGF) and leukocyte-derived myeloperoxidase (MPO). These associations suggest potential mechanisms whereby inflammation may injure the vascular endothelium, but the recognition of how these mediators act in concert remain poorly characterized. That the prevalence of atherosclerosis and markers of inflammation are increased in renal failure patients suggests that inflammation causes accelerated vascular disease. Methods: In hemodialysis patients, we examined the relationships between plasma CRP and sICAM, VEGF and MPO longitudinally. We determined whether episodes of a high CRP value were paralleled by simultaneous increases in mediators of inflammatory injury or molecules associated with endothelial cell adhesion or growth and whether CRP levels correlated with those of VEGF and MPO. Results: Episodic increases in CRP were accompanied by higher levels of VEGF, sICAM and MPO. However, there was no correlation between serum CRP levels or other acute phase proteins and either MPO or VEGF, nor was there a constant temporal relationship between MPO and CRP. By contrast, MPO and VEGF levels were closely correlated with one another during episodes of inflammation (p = 0.0001), and CRP and interleukin-6 levels were also correlated. Increases in MPO tended to be restricted to patients with grafts or catheters, and not those with AV fistulas. Conclusions: These results suggest that high plasma levels of CRP or other acute phase proteins in cross-sectional studies should be interpreted cautiously when defining mechanisms underlying cardiovascular disease in the hemodialysis patient population. One, or more than one inflammatory repertoire may be activated, one involving hepatic acute phase proteins and the other neutrophil activation and each may contribute separately to outcomes. Better prognostic information may be obtained by measurement of more markers than CRP alone, such as MPO and VEGF.
Sequential Hemoperfusion and Continuous Venovenous Hemofiltration in Treatment of Severe Tetramine Poisoning
Authors: Dehua Gong , Daxi Ji , Honglang Xie , Bin Xu , Yun Liu , Leishi Li
Published: October 2006

Objective: It was the aim of this study to observe the effects of sequential hemoperfusion (HP) and continuous venovenous hemofiltration (CVVH) on patients with severe tetramine poisoning and to evaluate the ability of these modalities to remove tetramine. Methods: Eighteen patients diagnosed as having severe tetramine poisoning were treated by blood purification, additional to routine medical therapy. Blood purification procedures included HP using activated charcoal for 3–5 h and consecutive CVVH for 24–36 h. Patients’ clinical conditions, blood routine tests and serum chemical tests were evaluated every day after admission. Plasma tetramine concentrations were determined before and after HP. During CVVH, tetramine concentrations in plasma before and after passing through the filter and ultrafiltration at 2 and 12 h were also determined. Results: Eight patients received blood purification within 12 h after onset of poisoning, and 10 patients received blood purification more than 12 h later. Early-treated patients showed a higher cure rate (100 vs. 60.0%; p < 0.05, χ2 test) and shorter coma time than late-treated patients (26.0 ± 23.2 h, range 5–70, vs. 59.7 ± 27.7 h, range 20–96; p < 0.01, rank test). The mean plasma tetramine concentrations in early- and late-treated patients were comparable (0.095 ± 0.036 vs. 0.134 ± 0.110 mg/l; p > 0.05). Mean plasma tetramine concentration was reduced from 0.124 ± 0.082 to 0.080 ± 0.055 mg/l after HP. At 2 h of CVVH, mean plasma tetramine concentration was 0.078 ± 0.064 mg/l, at 12 h of CVVH, 0.074 ± 0.059 mg/l, and the ultrafiltration sieving coefficient at 2 and 12 h was 0.839 ± 0.409 and 0.686 ± 0.253 mg/l, respectively. Conclusion: Early sequential HP and CVVH therapy may significantly improve the outcome of patients with severe tetramine intoxication. HP can rapidly reduce the plasma concentration of tetramine, and CVVH can attenuate the plasma tetramine concentration rebound after HP by continuously removing tetramine from the plasma.
Tract Identification by Novel MRI Signal Changes following Stereotactic Anterior Capsulotomy
Authors: Hurwitz T.A. , Mandat T. , Forster B. , Honey C.
Published: October 2006

Background: Five patients underwent magnetic resonance imaging (MRI) following MRI-guided stereotactic bilateral anterior capsulotomy to detect lesion-related anatomic changes. Methods: Five disabled and treatment-resistant patients with major depression (n = 4) and obsessive-compulsive disorder (n = 1) underwent stereotactic bilateral anterior capsulotomy. All patients had postoperative MRI at 2 months and at 1–4 years after surgery. An additional patient who had a pure motor deficit following a spontaneous basal ganglia hemorrhagic stroke was imaged as a comparator. Results: The 2-month postcapsulotomy MRI showed a previously undescribed increase in T1-weighted signal within similar neural pathways for each patient. These pathways showed no changes in T2-weighted or fluid-attenuated inversion recovery sequences. The signal changes are different from the expected changes associated with anterograde Wallerian degeneration and identify retrograde changes in the proximal segment of the interrupted axon. Conclusion: Previously undescribed T1-weighted signal alterations following stereotactic surgery identify retrograde non-Wallerian changes in interrupted axons and provide a new method in identifying and tracing lesioned pathways.
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

Antibodies 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

Type 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

In 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

Vascular 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

Recent 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.