Volume 9, Issue 1, March 2007
Ágnes Szilágyi, Bernadett Blaskó, Dénes Szilassy, György Füst, Mária Sasvári-Székely and Zsolt Rónai
Recent findings revealed that the repetitions of long DNA sequences comprising the sequence of different genes (CNV – copy-number variations) are very common in the human genome. A well-known example for this type of variations is the “RCCX-module” that implies the tandem duplication of four genes – RP, 21-hydroxylase, complement component C4 and tenascin X – in a haplotype block. Only the C4 gene is active in each module, besides, each module may contain C4A or C4B gene encoding the two isoforms of complement C4. Copy number variation of C4 genes has functional relevance; specific combinations could be risk factors for autoimmune or other immunological diseases. We developed a new, real-time PCR based method for the quantification of C4A and C4B genes. This assay applies specific TaqMan probes, therefore combines the advantages of quantitative measurement (copy number determination) and SNP genotyping (for distinguishing the C4A and C4B isoforms) techniques. The developed real-time PCR methodology was used to determine C4A and C4B gene dosages in a healthy Hungarian population (N=118). The obtained data were compared to the results of an earlier study of the same population analyzed by different techniques. The novel method was demonstrated to be a simple, fast and reliable choice for studies of the complement C4 system, especially in large-scale populations screening.
Keywords: complement component C4, realtime PCR, copy number variations, SNP, immune system
Éva Kereszturi, Orsolya Király, Zsolt Csapó, Zsanett Tárnok, Júlia Gádoros, Mária Sasvári-Székely and Zsófia Nemoda
The human dopamine D4 receptor (DRD4) gene has been extensively studied as a candidate gene for attention deficit hyperactivity disorder (ADHD). Both the 5′ regulatory region and the coding sequence contain a number of polymorphisms. The most widely investigated polymorphism of the DRD4 gene is the 48 bp VNTR (Variable Number of Tandem Repeats) in the third exon. The promoter variants have received particular attention in the past few years due to their possible role in the regulation of gene expression. In this study we describe an association analysis of the 120 bp duplication and three sequence variations (SNPs, Single Nucleotide Polymorphism; -616 C/G, -615 A/G, -521 C/T) in the 5′ region of the DRD4 gene is presented among children with ADHD. In case-control approach, the 1-repeat form of the 120 bp duplication had a significantly higher frequency among ADHD children than controls, both in allele-(p=0.047), and genotype (p=0.019) distributions. There was no significant difference between the ADHD and control groups in the allele or genotype frequencies of the investigated SNPs. The transcriptional effect of the 120 bp duplication was analysed in luciferase reporter system. The different 120 bp duplication alleles (1-repeat, 2-repeat and the newly identified 4-repeat allele) was found to have an effect on transcriptional activity of the DRD4 gene in both neuroblastoma and retinoblastoma cell lines in a dose-dependent manner. The higher was the repeat number of the 120 bp sequence in the promoter, the stronger was the decrease of the gene transcription (1-repeat > 2-repeat > 4-repeat; p<0.01). These results of association and functional analyses suggest that the 1-repeat form of the 120 bp duplication might be a risk factor of ADHD.
Keywords: dopamine D4 receptor (DRD4), attention deficit hyperactivity disorder (ADHD), polymorphism, association-analysis
Levente Zsolt Juhász , György Bartkó
The disturbance of source-monitoring is one of the various impairments in cognitive functioning observed in schizophrenic patients. The process of source-monitoring allows individuals to distinguish self generated thoughts and behaviours from those generated by others. The aim of the present study is to review the general psychological definition of source memory and source-monitoring and its neurological basis as well as the models for explanation of source-monitoring deficits. The relationship between source-monitoring-deficits and psychopathological symptoms as well as the effect of antipsychotic treatment on source-monitoring disturbances are introduced. There is evidence suggesting, that a selective source-monitoring deficit is in the occurrence of auditory hallucinations. The disturbance of prospective memory may influence unfavorably the compliance. Administration of antipsychotics in general can improve source-monitoring deficits. The neuropsychiatric perspective provides a more accurate and comprehensive understanding of schizophrenia.
Keywords: schizophrenia, neuropsychiatry, source-monitoring deficit, antipsychotic
Atypical antipsychotics are now widely used in the acute and long-term treatment in bipolar disorder. The role of atypical antipsychotics as acute agents, add-on medications; or as primary mood stabilizers in different phases of bipolar disorder is an important current research tendency. However, in bipolar disorder the mostly used indication of quetiapine is the management of acute manic phases, clinical data and the actual research results suggest that it may have both antidepressant and long-term antimanic effects. Quetiapine enhances the transmission of the central serotonergic networks, by its high antagonistic affinity for 5-HT(2A) and partial agonistic activity for the 5-HT(1A) receptors. The 5HT(1A) partial agonism causes an increase in the dopaminergic neurotransmission of the prefrontal cortex, and also, the affinity for the alpha 2-adrenoceptor brings a relative increase in extracellular noradrenergic release an tone in the prefrontal cortex. Latest research shows that quetiapine’s main, active, human plasma metabolite, N-desalkyl quetiapine (norquetiapine), has a high inhibition affinity for the noradrenergic transporter. These data suggest that comparing to other atypical antipsychotics, norquetiapine may have a relatively strong antidepressant potential. Modifying the dopaminergic transmission by quetiapine’s D2 receptor blocking activity results indirect mediating the cAMP-PKA and the arrestin-Akt-GSK-3 intracellular signal transduction pathways, which process may explain its long-term antimanic and mood stabilizing capability. Quetiapine’s activity on nerve growth factors, histamine H1 receptor, proinflammatory networks may take an important additional part in its efficacy in bipolar depression. Its very fast dissociation from the D2 receptor is an important pharmakokinetic parameter for managing the optimal quetiapine dose in the daily clinical practice. This review tries to organize the actual information on quetiapine’s multiplex activity in bipolar disorder.
Keywords: quetiapine, bipolar disorder, serotonine, dopamine, noradrenaline, Akt, GSK-3, BDNF, fast dissociation
About 50 years of demolition work, it’s time now for a return to the grand syntheses. Two of the great syntheses of the 19th century have now been shattered. Marxism lies in fragments. And psychoanalysis has largely drifted outside of psychiatry to find a new and doubtless temporary home in departments of literary studies. To be sure, the third of the great syntheses, Darwin’s theory of evolution, remains intact. But otherwise, as far as the eye can see, there is rubble. The time for new attempts at synthesis is now nigh. After decades of pioneering work in the neurosciences, the fundamental importance of brain biology in the human condition has now become evident. Surely one of the new syntheses will draw upon neurochemistry and neurophysiology, and it is to the great credit of the Hungarian neurosciences that pharmacologist Joseph Knoll has now ventured a first attempt. This attempt will be widely discussed and will form the platform for other work that may end up building firm brigdes between „neuroenhancers” and behavior – and, what’s more, to show how this relationship has shaped the evolution of thousands of years of human destiny, a great synthesis indeed.
KEYWORDS: sexuality, enhancer mechanism, synthetic mesencephalic enhancer substances, innate and acquired drives
A pooled analysis of randomized placebo controlled antidepressant trials shows that the rate of antidepressant and placebo responders are 50% and 30% respectively. The traditional calculation of drug-placebo difference (50-30=20%) in these drug-trials is based on the assumption that all placebo responders should be antidepressant responders. However, it seems to be not the case, since about one-third of placebo responders are antidepressant nonresponders. Considering this, the fair calculation of antidepressant-placebo difference in randomized placebo controlled trials results in a 30% rather than 20% difference. The drug-placebo differences in all antidepressant drug trials should be re-calculated.
Keywords: antidepressants, placebo, antidepressant–placebo difference
Réka Szakács, János Kálmán, Pál Barzó, Katalin Sas, Zoltán Janka
The 53-year-old female patient had suffered massive subarachnoid bleeding due to rupture of left-localized aneurysm of the anterior communicant artery. Following the neurosurgical intervention, deterioration of consciousness related to strong vasospasm occurred. Cerebral CT examination was performed, showing a 0.5 cm ischaemic lesion of the left hippocampal fornix. Due to intensive therapy, the patient recovered gradually, however considerable short-time memory deficit and severe anterograde amnesia remained. Admission of the patient in psychiatric care 5 weeks after the operation was necessary since acute deterioration had been added to memory disturbance and anterograde amnesia. Clinical features included severe short-time memory deficit, continuous and severe anterograde amnesia, disorientation, alterations of verbal fluency and abstraction. The amnesic syndrome was probably related to the hippocampal damage, but considering the development of cognitive deficits, cerebral CT was performed again, which verified internal hydrocephalus. A ventriculo-peritoneal shunt has been implanted and the patient was re-admitted in psychiatry care because of her memory deficit, anterograde amnesia and disorientation. Thereafter, low doses of citalopram and donepezil therapy was started together with temporarily used antipsychotic medication (risperidone). Gradual, but continuous improvement of memory and cognitive function could be detected, with total recovery after one year. The deficits in long- and short-term memory, orientation and cognition were totally restored.
Keywords: hippocampal lesion, fornix, anterograde amnesia, memory deficit