Genetic polymorphism of COMT in mental disorders

Many neurobiochemical studies show abnormalities within dopaminergic neuropathways, particularly altered dopamine transmission in etiopathogenesis of mental disorders. Evaluation of genes associated with the dopaminergic system include five well known subtypes of dopaminergic receptors, dopamine transporter and enzymes associated with the synthesis and degradation of dopamine, such as tyrosine hydroxylase, dopa decarboxylase, monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). None of these genes is 'a' pathognomonic factor of schizophrenia onset. In each sequence of the following genes 'a' functional polymorphism can occur. The polymorphisms of genes MAO-A and COMT have been described in relation to various expression or altered activity of these enzymes, their influence on cognitive functions, affective and anxiety disorders, learning disabilities, aggressive behaviour, eating disorders or gender differences.     

Neural mechanisms underlying trait impulsivity in non-clinical adults: stop-signal performance and event-related potentials

Impaired inhibitory processing has been implicated in clinical expressions of impulsivity, but it is unknown whether the same deficit underlies the personality trait in healthy, non-clinical populations. The present study examined performance and event-related potentials (ERPs) during a stop-signal task in non-clinical adults who scored in the top ("Low" n=20) and bottom 15% ("High" n=20) on Eysenck's Impulsiveness Questionnaire from a sample of 200 subjects. The stop-signal task consisted of a visual choice-RT task and auditory stop-signals presented on 30% of trials. While performance findings revealed no differences between groups, underlying ERPs revealed a number of quantitative differences. Lateralised readiness potential (LRP) amplitude on stop-signal trials was larger in the High than Low group, indicating greater response side-specific motor preparation in the primary motor cortex (PMC), while an N1/P3 complex was evoked on successful stop-signal trials and was also enhanced in the High than Low group. The centrally-maximal successful-stop P3 has previously been implicated as an index of inhibition in the PMC, suggesting enhanced inhibitory processing in the High group. Together these findings indicate that the High impulsivity group was able to counteract an impulsive response style on stop-signal trials with enhanced inhibitory activation, resulting in comparable overt performance to the Low group. These results provide a unique insight into the neural mechanisms underlying trait impulsivity in non-clinical adults.     

Screening of amide analogues of Trichostatin A in cultures of primary rat hepatocytes: search for potent and safe HDAC inhibitors

Summary  The vast majority of preclinical studies of HDAC inhibitors (HDAC-I) focus on the drug–target (cancer) cell interaction, whereas little attention is paid to the effects on non-target healthy cells, which could provide decisive information to eliminate potential cytotoxic compounds at a very early stage during drug development. In the current study we used cultures of primary rat hepatocytes as a read out system to select for the most potent HDAC-I in the group of structural analogues of an archetypal HDAC-I, namely Trichostatin A. This kind of approach allowed selecting compounds with high biological activity and with no apparent toxicity towards cultured hepatocytes. Joanna Fraczek and Sarah Deleu contributed equally to this article. T. Vanhaecke is a postdoctoral research fellow of the Fund for Scientific Research Flanders (FWO-Vlaanderen, Belgium)     

Continuous wavelet transform of laser-Doppler signals from facial microcirculation reveals vasomotion asymmetry

Facial laser Doppler flux (FLDF) consists of a mean value and complex oscillatory components called vasomotion. Vasomotion can be expressed as spectral amplitudes (SA) after the application of continuous wavelet transform. Vasomotion is influenced by cardiac activity (frequency interval I), respiration (interval II), intrinsic myogenic activity (interval III), neural mechanisms (interval IV) and endothelial mechanisms (intervals V and VI). Asymmetry of FLDF mean value was previously documented and hereby we present homogeneity assessment for FLDF vasomotion. Mean FLDF (p<0.001), total SA (p<0.001) and SA within frequency intervals I-VI were significantly higher in both cheeks compared to forehead. Total SA (p=0.009) and SA within frequency intervals I (p=0.041), II (p=0.005), III (p=0.009), IV (p=0.001) and V (p=0.036) were significantly higher in right than in left forehead. Human face is a heterogeneous microvascular region. Angiographic characteristics of deep horizontal sub-dermal plexus, endothelial and vascular smooth muscle cell heterogeneity, and plasticity of the microvasculature, autonomic asymmetry and facial neuropsychological asymmetry are possible causes of microvascular asymmetry. The origin and significance of microvascular imbalance need to be elucidated further.     

Individual differences in the perception of temporal order: the effect of age and cognition

Temporal-order judgements in the time range of some milliseconds were assessed by using two auditory tasks in 86 participants, aged from 20 to 69 years. Two stimulus presentation modes, binaural versus monaural, were compared. Elderly participants performed worse than the younger participants; however, different patterns of age-related declines were observed, depending on the presentation mode. In the monaural mode considerable deterioration was observed beyond 60 years of age, whereas in the binaural mode declines were found much earlier, from 40 years of age. Performance of the monaural task correlated with cognitive competences and provided important insight into neuronal timing mechanisms. In contrast, the binaural mode reflected a bias towards an integrated perception of sequential stimuli and was less related to cognitive resources. These findings provide evidence that age-related declines in human sequencing abilities involve, besides temporal mechanisms, also a mode-specific processing, presumably associated with different neuronal mechanisms.     

Teat tablet with sodium ibuprofen: the effect of sorbitol on therapeutic agent pharmaceutical availability and on physicochemical parameters of a drug form

Dosing pediatric drugs available on pharmaceutical markets of analgesic, antifebrile and anti-inflammatory activity to children up to 3 years of age is not precise and frequently causes problems. The aim of the study was to work out a pediatric teat form of a drug with sodium ibuprofen and to determine the effect of sorbitol content on pharmaceutical availability of the therapeutic agent. Three variants of tablets containing 50 mg of sodium ibuprofen differing in the percentage content of sorbitol (from 37% - batch I to 79% - batch III) were produced. Quality tests of the produced forms of drugs (PPVI) were performed and the tests of therapeutic agent pharmaceutical availability by spatula method and by a method with a teat. Tablets of all batches had a smooth surface and same shape. The content of the therapeutic agent was within the limit of 95-105% of the declared value. The highest value of Q coefficient in the release test by pharmacopeal method and the shortest disintegration time (12 minutes) were obtained for tablets with 79% content of sorbitol. In conclusion, teat tablets with sodium ibuprofen of the highest sorbitol content (79%) demonstrated the expected physicochemical parameters and high pharmaceutical availability.     

Subacute toxicity of polychlorinated naphthalenes and their effect on cytochrome P-450

The aim of the study was to investigate the subacute toxicity of a polychlorinated naphthalene (PCN) mixture and its effect on cytochrome P-450 levels in rats. The animals were administered PCNs intragastrically in repeated daily doses of 1, 10, and 100 mg/kg. The animals were dissected after 7, 14, or 21 doses. Doses of 10 and 100 mg/kg induced a significant decrease in the body weight at all time points of the experiment compared with the control group. The exposure to PCNs increased both the level of total cytochrome P-450 and the activity of CYP 1A at the same time points. In the groups of rats given PCNs in doses of 10 and 100 mg/kg, an evident dose- and time-dependent increase in malondialdehyde (MDA) level was observed throughout the experiment. The correlation between the increased MDA and decreased glutathione (GSH) levels in the liver was also observed.     

p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis

p38alpha is a stress-activated protein kinase that negatively regulates malignant transformation induced by oncogenic H-Ras, although the mechanisms involved are not fully understood. Here, we show that p38alpha is not a general inhibitor of oncogenic signaling, but that it specifically modulates transformation induced by oncogenes that produce reactive oxygen species (ROS). This inhibitory effect is due to the ROS-induced activation of p38alpha early in the process of transformation, which induces apoptosis and prevents the accumulation of ROS and their carcinogenic effects. Accordingly, highly tumorigenic cancer cell lines have developed a mechanism to uncouple p38alpha activation from ROS production. Our results indicate that oxidative stress sensing plays a key role in the inhibition of tumor initiation by p38alpha.