Contrast-induced acute kidney injury after computed tomography prior to transcatheter aortic valve implantation.

AIM: To identify independent predictors of contrast medium-induced acute kidney injury (CI-AKI) after enhanced multidetector-row computed tomography (MDCT) prior to transcatheter aortic valve implantation (TAVI) in high-risk patients. MATERIALS AND METHODS: The present single-centre study analysed retrospectively 361 patients who were assessed using MDCT prior to TAVI. CI-AKI was defined as an increase in serum creatinine (SCr) of ≥ 25% or ≥ 0.5 mg/dl in at least one sample over baseline (24 h before MDCT) and at 24, 48, and 72 h after MDCT. RESULTS: A total of 38 patients (10.5%) experienced CI-AKI. As compared to patients without CI-AKI, they presented more frequently with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), (81.6% versus 64.4%, p = 0.045) and tended to receive higher volumes of iodinated contrast media (ICM; 55.3% versus 39%, p = 0.057). There was a significant interaction between baseline eGFR and the amount of intravenous ICM administered (pfor interaction = <0.001) identifying the amount of ICM >90 ml as independent predictive factor of CI-AKI only in patients with baseline eGFR <60 ml/min/1.73m(2) (OR 2.615; 95% CI: 1.21-5.64). CONCLUSION: One in ten elderly patients with aortic stenosis undergoing MDCT to plan a TAVI procedure experienced CI-AKI after intravenous ICM injection. Intravenous administration of <90 ml of ICM reduces this risk in patients with or without pre-existing impaired renal function. However, in the majority of patients renal function recovers before the TAVI procedure.

[Possibilities for exposure reduction in computed tomography examination of acute chest pain]. / Möglichkeiten der Dosisreduktion bei CT-Untersuchungen des akuten Thoraxschmerzes.

CLINICAL/METHODICAL ISSUE: Electrocardiogram-gated (ECG) computed tomography (CT) investigations can be accompanied by high amounts of radiation exposure. This is particularly true for the investigation of patients with unclear and acute chest pain. STANDARD RADIOLOGICAL METHODS: The common approach in patients with acute chest pain is standard spiral CT of the chest. METHODICAL INNOVATIONS: The chest pain or triple-rule-out CT protocol is a relatively new ECG-gated protocol of the entire chest. This article reviews and discusses different techniques for the CT investigation of patients with acute chest pain. PERFORMANCE: By applying the appropriate scan technique, the radiation exposure for an ECG-gated protocol must not necessarily be higher than a standard chest CT scan ACHIEVEMENTS: Aortic pathologies are far better depicted by ECG-gated scan protocols and depending on the heart rate coronary artery disease can also be detected at the same time. PRACTICAL RECOMMENDATIONS: The use of ECG-triggered scans will not support the diagnostics of the pulmonary arteries. However, in unspecific chest pain an ECG-triggered scan protocol can provide information on the differential diagnosis.

Comparative mapping of quantitative trait loci involved in heterosis for seedling and yield traits in oilseed rape (Brassica napus L.).

Little is known about the genetic control of heterosis in the complex polyploid crop species oilseed rape (Brassica napus L.). In this study, two large doubled-haploid (DH) mapping populations and two corresponding sets of backcrossed test hybrids (THs) were analysed in controlled greenhouse experiments and extensive field trials for seedling biomass and yield performance traits, respectively. Genetic maps from the two populations, aligned with the help of common simple sequence repeat markers, were used to localise and compare quantitative trait loci (QTL) related to the expression of heterosis for seedling developmental traits, plant height at flowering, thousand seed mass, seeds per silique, siliques per unit area and seed yield. QTL were mapped using data from the respective DH populations, their corresponding TH populations and from mid-parent heterosis (MPH) data, allowing additive and dominance effects along with digenic epistatic interactions to be estimated. A number of genome regions containing numerous heterosis-related QTL involved in different traits and at different developmental stages were identified at corresponding map positions in the two populations. The co-localisation of per se QTL from the DH population datasets with heterosis-related QTL from the MPH data could indicate regulatory loci that may also contribute to fixed heterosis in the highly duplicated B. napus genome. Given the key role of epistatic interactions in the expression of heterosis in oilseed rape, these QTL hotspots might harbour genes involved in regulation of heterosis (including fixed heterosis) for different traits throughout the plant life cycle, including a significant overall influence on heterosis for seed yield.

[C-arm CT-guided 3D navigation of percutaneous interventions]. / C-Bogen-CT-unterstützte 3D-Navigation perkutaner Interventionen.

So far C-arm CT images were predominantly used for a precise guidance of an endovascular or intra-arterial therapy. A novel combined 3D-navigation C-arm system now also allows cross-sectional and fluoroscopy controlled interventions. Studies have reported about successful CT-image guided navigation with C-arm systems in vertebroplasty. Insertion of the radiofrequency ablation probe is also conceivable for lung and liver tumors that had been labelled with lipiodol. In the future C-arm CT based navigation systems will probably allow simplified and safer complex interventions and simultaneously reduce radiation exposure.

Molecular characterisation and chromosomal localisation of a telomere-like repetitive DNA sequence highly enriched in the C genome of Brassica.

The aim of this work was to find C genome specific repetitive DNA sequences able to differentiate the homeologous A (B. rapa) and C (B. oleracea) genomes of Brassica, in order to assist in the physical identification of B. napus chromosomes. A repetitive sequence (pBo1.6) highly enriched in the C genome of Brassica was cloned from B. oleracea and its chromosomal organisation was investigated through fluorescent in situ hybridisation (FISH) in B. oleracea (2n = 18, CC), B. rapa (2n = 20, AA) and B. napus (2n = 38, AACC) genomes. The sequence was 203 bp long with a GC content of 48.3%. It showed up to 89% sequence identity with telomere-like DNA from many plant species. This repeat was clearly underrepresented in the A genome and the in situ hybridisation showed its B. oleracea specificity at the chromosomal level. Sequence pBo1.6 was localised at interstitial and/or telomeric/subtelomeric regions of all chromosomes from B. oleracea, whereas in B. rapa no signal was detected in most of the cells. In B. napus 18 to 24 chromosomes hybridised with pBo1.6. The discovery of a sequence highly enriched in the C genome of Brassica opens the opportunity for detailed studies regarding the subsequent evolution of DNA sequences in polyploid genomes. Moreover, pBo1.6 may be useful for the determination of the chromosomal location of transgenic DNA in genetically modified oilseed rape.

An Animal Model of Alcohol Dependence to Screen Medications for Treating Alcoholism.

Despite the high prevalence of alcohol use disorders in the United States, only a relatively small percentage of those afflicted seek treatment. This is further compounded by the fact that there are too few medications available to effectively treat this significant public health problem. The need for identifying and evaluating more effective treatments that aid in preventing relapse and/or tempering risky and harmful alcohol consumption cannot be overstated. Use of animal models represents a critical step in the process of screening, identifying, and informing plans for prioritizing the most promising candidate medications that can be advanced to the next stage of evaluation (clinical laboratory paradigms and controlled clinical trials). Numerous animal models have been developed to study excessive levels of alcohol self-administration. In recent years, a large literature has amassed of studies in which rodent models of dependence have been linked with alcohol self-administration procedures. This chapter focuses on studies employing a dependence model that involves chronic exposure to alcohol vapor by inhalation, which yields in both mice and rats significant escalation of voluntary alcohol consumption. These animal models of dependence and alcohol self-administration have revealed valuable insights about underlying mechanisms that drive excessive drinking. Additionally, this preclinical approach is useful in evaluating the effects of medications on escalated drinking associated with dependence vs more stable levels displayed by nondependent animals.

The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

Valproate potentiates and picrotoxin antagonizes the anxiolytic action of ethanol in a nonshock conflict task.

The purpose of this study was to examine the effects of the indirect GABA agonist valproate and the indirect GABA antagonist picrotoxin on the anxiolytic (anti-conflict) activity of ethanol in a behavioral conflict task that does not employ electroshock. This task (negative contrast) quantifies how animals respond to an abrupt, unexpected reduction in reward. Treatment with valproate alone did not elevated depressed behavior engendered by abrupt reduction in reward. However, when administered together with a sub-effective dose of ethanol (0.5 g/kg), valproate (50-200 mg/kg) dose-dependently potentiated the anxiolytic action of ethanol. Picrotoxin (2 mg/kg) antagonized the anxiolytic effects of a larger dose of ethanol (1.0 g/kg) given alone, as well as the ability of valproate to enhance the anxiolytic effects of smaller dose of ethanol (0.5 g/kg). As such, these data support a role for GABA in mediating the anxiolytic activity of ethanol.

Positive relationship between the number of prior ethanol withdrawal episodes and the severity of subsequent withdrawal seizures.

One factor that has been shown to influence the severity of an ethanol withdrawal syndrome is a history of prior experience with episodes of ethanol withdrawal. It has been hypothesized that the progressive intensification of withdrawal symptoms following repeated bouts of ethanol intoxication and withdrawal may represent the manifestations of a "kindling-like" process. In mice, repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures, even when the total amount of ethanol intoxication is equated across groups. In the current experiments, mice received 16-h bouts of continuous exposure to ethanol vapor in inhalation chambers separated by 8-h periods of abstinence. The withdrawal response was assessed by scoring handling-induced convulsions. The results demonstrated that a positive relationship exists between the number of prior episodes of ethanol withdrawal and the severity of subsequent withdrawal seizures. This conclusion was supported by both between-subject and within-subject comparisons. The difference in withdrawal severity does not appear to be related to differences in the level of intoxication, since blood ethanol levels immediately preceding withdrawal testing were similar for all groups. Further, the differential withdrawal response exhibited by multiple and single withdrawal groups cannot be explained by a difference in the rate of ethanol elimination. Although the mechanism(s) remain to be determined, taken together, these results provide support for the "kindling" hypothesis of ethanol withdrawal.

Ethanol-induced locomotor stimulation in C57BL/6 mice following RO15-4513 administration.

The purpose of this study was to examine the effects of two partial benzodiazepine inverse agonists, RO15-4513 and FG-7142, alone and in combination with ethanol on locomotor activity in C57BL/6 mice. When administered alone, 1.5 g/kg ethanol did not significantly influence activity, confirming previous reports indicating this mouse strain is relatively insensitive to the excitatory properties of ethanol. RO15-4513 treatment also did not significantly influence locomotor activity when administered alone. However, coadministration of RO15-4513 (1.5-6 mg/kg) and ethanol markedly increased locomotor activity. Moreover, the unmasking of ethanol's stimulant action by RO15-4513 (6 mg/kg) was completely reversed by pretreatment with the benzodiazepine receptor antagonist RO15-1788. In contrast, FG-7142 (10-20 mg/kg) increased activity to the same extent in both saline and ethanol-injected mice. This effect was blocked by RO15-1788 pretreatment as well. Neither RO15-4513, FG-7142, nor RO15-1788 significantly influenced blood ethanol concentrations. It is suggested that RO15-4513 unmasked the stimulant effects of ethanol by virtue of its ability to antagonize the depressant properties of ethanol in C57BL/6 mice.

Effects of prenatal ethanol exposure in C57BL mice on locomotor activity and passive avoidance behavior.

The purpose of this study was to examine the long-term behavioral effects of prenatal ethanol exposure in C57BL mice. Pregnant mice received free access to a liquid diet containing 25% ethanol-derived calories (EDC) from gestation days 6 to 18. Control animals were pair-fed an isocaloric 0% EDC diet during the same period of time. An additional control group was included that was maintained on standard lab chow and water throughout pregnancy. At 30 days of age, female offspring were tested for spontaneous locomotor activity in an open field under two lighting conditions (dim or bright illumination). Male offspring were tested in a passive avoidance task at 25 days of age. The activity results demonstrated that the 25% EDC female progeny were more active than controls. This hyperactivity was observed under both lighting conditions, despite the fact that all groups evidenced suppressed activity when tested under bright lights. With regard to passive avoidance behavior, male EtOH-exposed offspring required a greater number of trials to reach criterion than controls. Additionally, they exhibited shorter latencies to enter the shock-associated chamber after receiving a single shock. Taken together, these results confirm our previous findings and demonstrate that C57BL mice are sensitive to both the deleterious behavioral and morphological consequences of prenatal ethanol exposure.

Chlordiazepoxide and ethanol additively reduce gustatory negative contrast.

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose has been shown to be reduced by chlordiazepoxide (CDP) and ethanol (ETOH). In a previous experiment, doses of 0.75 and 1.0 g/kg ETOH substantially reduced contrast while doses of 0.25 and 0.5 g/kg ETOH were much less effective. In this study, doses of 6 and 8 mg/kg CDP were shown to attenuate the negative contrast effect while smaller doses (2 and 4 mg/kg) influenced contrast to a lesser degree. Evidence for an additive effect of CDP and ETOH on contrast reduction was obtained when 4 mg/kg CDP and 0.5 g/kg ETOH were administered together.

Influence of ethanol on contrast in consummatory behavior.

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose was reduced by IP injections of ethanol (1.0 g/kg) on postshift day 2, but not on postshift day 1. Smaller doses (0.25 and 0.5 g/kg) were ineffective, while larger doses (1.5 and 2 g/kg) produced sedation. A dose of 0.75 g/kg had effects similar to the 1.0 g/kg dose when administered on post-shift day 2. These results parallel those obtained with chlordiazepoxide and differ somewhat from amobarbital treatment.

Repeated ethanol withdrawal experience selectively alters sensitivity to different chemoconvulsant drugs in mice.

Repeated ethanol withdrawal experience has been shown to result in exacerbated seizures associated with future withdrawal episodes. This sensitization of the withdrawal response has been postulated to represent a "kindling" phenomenon. The present study employed an established model of repeated ethanol withdrawals to examine the potential role of GABA(A), and NMDA and non-NMDA glutamate receptor systems in mediating enhanced seizure activity, as assessed by sensitivity to seizures induced by pentylenetetrazol (PTZ), NMDA, and kainic acid (KA) i.v. infusions, respectively. Adult C3H mice were chronically exposed to ethanol vapor in inhalation chambers. A multiple withdrawal (MW) group received four cycles of 16-h ethanol vapor exposure interrupted by 8-h periods of abstinence; a single withdrawal (SW) group was tested after a single 16-h bout of ethanol intoxication; and the third group was ethanol-naive, serving as controls (C). Results indicated that the MW group evidenced significantly lower PTZ and NMDA seizure thresholds compared to SW and C groups at 8 and 24 h post-withdrawal. In contrast, MW and SW groups exhibited reduced sensitivity (higher seizure threshold) to KA in comparison to controls, and this effect only emerged at 24 h post-withdrawal. Further, MW mice required significantly less additional PTZ or NMDA to induce more severe convulsions once initial signs of seizures were elicited. Conversely, latency and amount of KA required to transition from initial seizure signs to more severe end-stage convulsions was significantly greater for MW and SW groups compared to controls. Taken together, these results suggest that repeated ethanol withdrawal experience does not result in a global non-specific lowering of threshold to convulsive stimuli, but rather, selective changes in CNS mechanisms associated with neural excitability may underlie potentiated withdrawal responses. Thus, reduced GABA(A) receptor function and increased NMDA receptor activity may become exaggerated as a consequence of repeated withdrawal experience, while reduced sensitivity to KA induced seizures may represent a compensatory response to withdrawal-related CNS hyperexcitability.

Indomethacin does not antagonize the anxiolytic action of ethanol in the elevated plus-maze.

The present study was designed to examine whether the prostaglandin (PG) synthesis inhibitor indomethacin (INDO) could antagonize the anxiolytic effects of ethanol (EtOH) in the elevated plus-maze test of anxiety. EtOH (1.6 g/kg) significantly increased the percentage of open arm entries and time spent on the open arms in both inbred C57BL/6J and outbred CD-1 mouse strains. However, this anxiolytic effect of EtOH was not significantly antagonized by pretreatment with INDO (5 and 10 mg/kg) in either strain. EtOH also significantly increased total arm entries in CD-1 mice, but not in the C57BL/6J strain. These data from C57BL/6J mice indicate that the low-dose stimulant properties of EtOH can be dissociated from the anxiolytic action of the drug in the plus-maze task. Finally, although INDO did not antagonize the stimulant effect of EtOH in the plus-maze task (in CD-1 mice), it did attenuate EtOH-induced stimulation of locomotor activity in an open-field arena. Taken together, these results suggest some specificity with regard to the role of PGs in mediating (or modulating) the neurobehavioral actions of EtOH, and further support the notion that the anxiolytic and stimulant effects of EtOH may be mediated by different mechanisms.

Single and repeated episodes of ethanol withdrawal increase adenosine A1, but not A2A, receptor density in mouse brain.

A history of multiple ethanol withdrawal experiences has been shown to exacerbate the severity of future withdrawal episodes, and this sensitization of the withdrawal response has been hypothesized to represent a 'kindling' phenomenon. Since adenosine functions as an inhibitory modulator of seizure activity and may interact with ethanol to influence neuronal excitability, the present study was conducted to examine the effects of single and repeated episodes of ethanol withdrawal on adenosine A1 and A2A receptors in adult C3H/He mice. Mice were chronically exposed to ethanol vapor in inhalation chambers and tested for withdrawal seizures following multiple withdrawal (MW) experience (four cycles of 16 h ethanol intoxication interrupted by 8 h periods of abstinence), single withdrawal experience following 16 h (SW) or 64 h (CE) continuous ethanol intoxication, or no ethanol exposure (controls). Separate groups of mice from each withdrawal condition were used to generate pooled cortical and striatal tissue for ligand saturation experiments using [3H]cyclohexyladenosine to label A1 receptors and [3H]CGS 21680 to label A2A receptors. Results indicated that withdrawal seizures were significantly more severe in mice with multiple withdrawal experience in comparison to animals that experienced only a single withdrawal episode, even when total amount of ethanol exposure was equated among groups. The density of A1 receptors in cerebral cortex was significantly increased over controls 8 h following final ethanol withdrawal by approximately 35% in SW and CE groups, with the largest increase observed in the MW group (56%). Withdrawal treatment groups did not differ in cortical A1 binding sites immediately upon withdrawal from ethanol, and no significant differences in binding of [3H]CGS 21680 to striatal A2A receptors were observed following ethanol withdrawal. Ethanol exposure and withdrawal did not significantly alter ligand affinity for either adenosine receptor. These results indicate that adenosine A1 receptors are selectively upregulated during ethanol withdrawal and that the degree of upregulation may be enhanced following multiple withdrawal episodes. Further, these observations suggest that the upregulation of brain A1 receptors during ethanol withdrawal may represent a compensatory inhibitory response to increased seizure severity associated with repeated episodes of ethanol withdrawal.

Chronic ethanol exposure selectively increases diazepam-insensitive [3H]RO15-4513 binding in mouse cerebellum.

The effect of chronic ethanol exposure and withdrawal on [3H]RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4] benzodiazepine-3-carboxylate) binding to diazepam-sensitive and diazepam-insensitive binding sites was determined in mouse brain. Neither chronic ethanol treatment nor withdrawal significantly altered total [3H]RO15-4513 binding in mouse cortex or cerebellum. However, diazepam-insensitive [3H]RO15-4513 binding density (Bmax) in cerebellum was significantly increased immediately following chronic ethanol treatment (60%) and at 8 h following withdrawal (75%). [3H]RO15-4513 binding affinity was not significantly influenced by chronic ethanol exposure or withdrawal. These results indicate that chronic ethanol treatment and withdrawal can selectively up-regulate diazepam-insensitive [3H]RO15-4513 binding sites and suggest that this unique GABAA receptor subtype may play some role in ethanol dependence and withdrawal.

Kindling in alcohol withdrawal.

In many alcoholics, the severity of withdrawal symptoms increases after repeated withdrawal episodes. This exacerbation may be attributable to a kindling process. Kindling is a phenomenon in which a weak electrical or chemical stimulus, which initially causes no overt behavioral responses, results in the appearance of behavioral effects, such as seizures, when it is administered repeatedly. Both clinical and experimental evidence support the existence of a kindling mechanism during alcohol withdrawal. Withdrawal symptoms, such as seizures, result from neurochemical imbalances in the brain of alcoholics who suddenly reduce or cease alcohol consumption. These imbalances may be exacerbated after repeated withdrawal experiences. The existence of kindling during withdrawal suggests that even patients experiencing mild withdrawal should be treated aggressively to prevent the increase in severity of subsequent withdrawal episodes. Kindling also may contribute to a patient's relapse risk and to alcohol-related brain damage and cognitive impairment.

Effects of the imidazobenzodiazepine RO15-4513 on the stimulant and depressant actions of ethanol on spontaneous locomotor activity.

The purpose of this study was to investigate the effects of the imidazobenzodiazepine RO15-4513, a partial inverse agonist at benzodiazepine (BDZ) receptors, on the stimulant and depressant actions of ethanol in mice. For comparative purposes, another BDZ inverse agonist, FG-7142, was examined as well. Neither RO15-4513 nor FG-7142 influenced the low-dose excitatory effects of ethanol on spontaneous locomotor activity. However, both RO15-4513 and FG-7142 significantly antagonized the depressant effects of ethanol, and this antagonism was completely reversed by pretreatment with the BDZ receptor antagonist, RO15-1788. These data suggest that RO15-4513 is capable of antagonizing only some of the behavioral effects of ethanol, and in particular, those responses to ethanol that are mediated by modulation of the GABA/BDZ-chloride channel receptor complex.

Effect of indomethacin on alcohol-induced morphological anomalies in mice.

The purpose of the present study was 1) to examine the effect of indomethacin (INDO), a prostaglandin synthesis inhibitor, on alcohol-induced growth and morphological impairment in C57BL/6J mice (Study 1) and 2) to determine if INDO crosses the placenta (Study 2). On day 10 of gestation, mice were injected (s.c.) acutely with either 0, 5, 10, or 20 mg/kg INDO, followed one hour later by alcohol (5.8 g/kg orally) or isocaloric sucrose. Fetuses were removed on day 19 of pregnancy, weighed, and examined for anomalous development. As expected, Study 1 demonstrated that maternal alcohol treatment decreased fetal weight and increased the number of fetuses with birth defects. INDO alone decreased fetal weight but did not affect morphologic development. More importantly, INDo antagonized alcohol-induced birth defects, but only at the highest dose. The results of Study 2 suggest that the relative ineffectiveness of INDO may be related to its inability to readily cross the placenta. Since high doses of INDO also caused maternal toxicity, the usefulness of this compound in future studies of this type was questioned.