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  • 1
    Keywords: RECEPTOR ; Germany ; MODEL ; MODELS ; SUPPORT ; COHORT ; DISEASE ; EPIDEMIOLOGY ; POPULATION ; RISK ; GENE ; SAMPLE ; SAMPLES ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; score ; PHENOTYPES ; SUBUNIT ; genetics ; smoking ; REGION ; PHENOTYPE ; VARIANT ; DEPENDENCE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; ADDICTION ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; pharmacogenomics ; pharmacology ; smoking cessation ; EXTENT ; Polymorphism,Single Nucleotide ; GENERAL-POPULATION ; genetic association ; NICOTINE DEPENDENCE ; Genetic ; Determination ; CHRNA4 ; Fagerstrom score ; TOBACCO DEPENDENCE
    Abstract: Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit alpha 4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N-1 = 1412; N-2 = 1855; N-3 = 2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (〈= 100 cigarettes over lifetime). We examined associations of the polymorphisms with smoking case-control status and with the extent of nicotine dependence as measured by the Fagerstrom test of nicotine dependence (FTND) score (N = 1030). The most significant association was observed between rs2236196 and FTND (P = 0.0023), whereas the closely linked rs1044396 had most statistical support in the case-control models (P = 0.0080). The consistent effect estimates across three independent cohorts elaborate on recently published functional studies of rs2236196 from the CHRNA4 3'-untranslated region and seem to converge with accumulating evidence to firmly implicate the variant G allele of this polymorphism in the intensification of nicotine dependence. The Pharmacogenomics Journal (2009) 9, 219-224; doi: 10.1038/tpj.2009.6; published online 17 March 2009
    Type of Publication: Journal article published
    PubMed ID: 19290018
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  • 2
    Abstract: Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5' untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerström index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically. (c) 2009 Wiley-Liss, Inc.
    Type of Publication: Journal article published
    PubMed ID: 19644963
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  • 3
    Keywords: brain ; CANCER ; human ; PHENOTYPES ; STRESS ; INSIGHTS ; CONSUMPTION ; GLUTAMATE ; DRINKING ; DEPENDENCE ; WIDE ASSOCIATION ; Alcoholism ; drug addiction ; genome-wide association study (GWAS) ; GLUTAMATERGIC NEUROTRANSMISSION ; imaging genetics ; NALTREXONE ; QTL analysis ; TRANSPORTER GENE
    Abstract: Alcohol drinking is highly prevalent in many cultures and contributes to the global burden of disease. In fact, it was shown that alcohol constitutes 3.2% of all worldwide deaths in the year 2006 and is linked to more than 60 diseases, including cancers, cardiovascular diseases, liver cirrhosis, neuropsychiatric disorders, injuries and foetal alcohol syndrome. Alcoholism, which has been proven to have a high genetic load, is one potentially fatal consequence of chronic heavy alcohol consumption, and may be regarded as one of the most prevalent neuropsychiatric diseases afflicting our society today. The aim of the integrated genome research network 'Genetics of Alcohol Addiction'-which is a German inter-/trans-disciplinary life science consortium consisting of molecular biologists, behavioural pharmacologists, system biologists with mathematicians, human geneticists and clinicians-is to better understand the genetics of alcohol addiction by identifying and validating candidate genes and molecular networks involved in the aetiology of this pathology. For comparison, addictive behaviour to other drugs of abuse (e.g. cocaine) is studied as well. Here, we present an overview of our research consortium, the current state of the art on genetic research in the alcohol field, and list finally several of our recently published research highlights. As a result of our scientific efforts, better insights into the molecular and physiological processes underlying addictive behaviour will be obtained, new targets and target networks in the addicted brain will be defined, and subsequently, novel and individualized treatment strategies for our patients will be delivered
    Type of Publication: Journal article published
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  • 4
    Abstract: Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression.
    Type of Publication: Journal article published
    PubMed ID: 20886544
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  • 5
    ISSN: 0167-8760
    Keywords: Age effect ; Auditory cortex ; Auditory evoked potential ; Augmenting/reducing ; Dipole source ; Serotonin
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine , Psychology
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0167-8760
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine , Psychology
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Der Nervenarzt 70 (1999), S. 206-215 
    ISSN: 1433-0407
    Keywords: Schlüsselwörter Iktale Angst ; Panikstörung ; Angst ; EEG-Veränderungen ; Übersichtsartikel ; Key words Ictal fear ; Panic disorder ; Anxiety ; EEG abnormalities ; Review article
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Episodes of anxiety have been reported to be the most common psychological symptoms in patients with partial seizures. They may occur before, during and after seizures and can also appear in isolation without any convulsive symptoms. The epileptic anxietysyndrome is strikingly similar to panic attacks, and panic disorder is an important differential diagnosis. The close relationship between epileptic seizures and panic attacks is of special interest for a better pathophysiological understanding of panic attacks. In the literature an epileptiform neuronal activity is discussed as a possible underlying mechanism for panic disorder. The finding that anxiety was the most common experiential phenomenon produced by electrical stimulation of amygdala and hippocampus with depth electrodes points in this direction. PET has demonstrated abnormalities of hippocampal structures during the nonpanic state of patients with panic disorder. In addition, some EEG studies have demonstrated a high incidence of epileptiform EEG patterns in patients with panic disorder with or without agoraphobia. This was the reason why several investigators proposed that a subset of panic attacks may be ralated to abnormal epileptiform neuronal activity in the limbic system. The size of this subset is difficult to determine because discharges in the depth of the limbic system often cannot be seen in the scalp EEG. Concerning the hypothetical pathophysiological mechanism of panic disorder therapeutic measures were taken with antiepileptic agents. The best results were obtained for valproic acid. It seems to be resonable to make a therapeutic trial with antiepileptic medication after nonresponse to standard pharmacotherapy.
    Notes: Zusammenfassung Angstanfälle zählen zu den häufigsten psychischen Symptomen im Rahmen epileptischer Anfälle und sind v.a. in Form einer Angstaura beobachtbar. Ebenso ist es möglich, daß Angstanfälle ohne konvulsive Symptome in Form einer isolierten Angstaura auftreten. Die epileptische Genese ist in solchen Fällen nicht ohne weiteres erkennbar, und die Symptomatik kann völlig mit den ICD-10-Kriterien einer Panikattacke übereinstimmen. Dementsprechend stellt die isolierte Angstaura in der psychiatrischen Diagnostik eine mögliche Differentialdiagnose zur Panikstörung dar. Von besonderem pathophysiologischen Interesse ist die enge Beziehung von epileptischer Erregungssteigerung und Panikattacken. Seit langem wird in der Literatur über eine gesteigerte Erregungsbildung limbischer Strukturen als biologisches Korrelat für anfallsartige Angst und Panik diskutiert. Intrazerebrale Stimulationsversuche belegen die besondere Bedeutung einer gesteigerten neuronalen Erregbarkeit im Mandelkern und Hippocampus. PET und EEG-Untersuchungen liefern eine Reihe von meist indirekten Hinweisen, daß auch bei einem Teil der Patienten mit der Diagnose Panikstörung nach ICD-10 eine gesteigerte Erregbarkeit limbischer Strukturen von pathophysiologischer Bedeutung ist. Dies legt die Vermutung nahe, daß die Panikstörung nach ICD-10 keine homogene Krankheitsentität darstellt, sondern eine Untergruppe mit gesteigerter zerebraler Erregbarkeit abgegrenzt werden kann. Ähnliche Überlegungen können für die ICD-10-Diagnose der Agoraphobie mit Panikstörung angestellt werden. Die Größe dieser Untergruppe ist nicht genau bestimmbar, da ein iktaler limbischer Prozeß durch die oberflächenferne Lokalisation dem Skalp-EEG häufig entgeht. Entsprechend der Hinweise auf gesteigerte limbische Erregbarkeit bei Panikstörung wurden ätiologiebezogene Behandlungsansätze mit Antiepileptika durchgeführt. Für Valproinsäure konnten bisher die besten Belege für eine günstige Wirkung erbracht werden. Es erscheint daher sinnvoll bei Nichtansprechen auf die herkömmliche Pharmakotherapie bei Panikstörung einen Behandlungsversuch mit einem Antiepileptikum zu unternehmen.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-055X
    Keywords: Schlüsselwörter Postoperatives Delir ; Postoperative psychiatrische Störungen ; Therapie ; Prophylaxe ; Key words Postoperative delirium ; Postoperative psychiatric disturbance ; Treatment ; Prophylaxis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract After surgical operations delirium can occur as a serious and possible lethal complication in about 5–15% of patients. Additionally, risk factors such as old age, polymedication, organic and psychiatric diseases raise the incidence. After open-heart- and orthopedic surgery more than half of the patients are affected. Delirium has negative effects on postoperative mobilization and reconvalescence and prolongs treatment on the ward. It is discussed in the literature that delirium may induce dementia in older patients. The correction of metabolic- and electrolyte imbalances, as well as the therapy of neurologic and psychiatric diseases, belongs to prophylactic treatment. Environmental conditions which facilitate reorientation of the patient after operation have beneficial effects. Some success has been achieved by using the nootropic substance piracetam as a prophylactic. In acute treatment, the butyrophenon-neuroleptic haloperidol is the drug of choice. In delirium caused by intoxication with anticholinergic agents, physostigmin is indicated. Benzodiazepines, clonidine and clomethiazole are used in particular for the treatment of withdrawal delirium.
    Notes: Zusammenfassung Nach operativen Eingriffen kommt es bei 5 bis 15% der Patienten zu einem Delir, welches eine ernste und potentiell tödliche Komplikation darstellt. Bei zusätzlich bestehenden Risikofaktoren wie hohem Alter, medikamentöser Mehrfachtherapie, somatischen und psychiatrischen Störungen findet sich eine noch wesentlich höhere Inzidenz. Bei Operationen am offenen Herzen und orthopädischen Eingriffen sind über die Hälfte der Patienten betroffen. Das Delir beeinträchtigt die postoperative Mobilisierung und Rekonvaleszenz der Patienten und führt zur Verlängerung des stationären Aufenthalts. Die Gefahr einer dementiellen Entwicklung als Spätfolge des Delir bei älteren Patienten wird in der Literatur diskutiert. Zu den Maßnahmen der Prophylaxe zählen die Behandlung von metabolischen Entgleisungen, Ausgleich von Elektrolytstörungen und Therapie von neurologischen und psychiatrischen Erkrankungen. Verhaltensmaßnahmen, die die Orientierung des Patienten nach der Operation erleichtern, haben eine günstige Wirkung. Erfolge wurden durch die prophylaktische Verabreichung des Nootropikums Piracetam berichtet. In der Akutbehandlung ist das Butyrophenon-Neuroleptikum Haloperidol Mittel der Wahl zur Sedierung. Bei Delirien auf der Grundlage einer Intoxikation mit anticholinerg wirkenden Pharmaka ist Physostigmin indiziert. Benzodiazepine, Clonidin und Clomethiazol kommen v.a. bei der Behandlung des Entzugsdelir zum Einsatz.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-2072
    Keywords: Key words Auditory evoked potentials ; Serotonin ; Depression ; Response prediction ; Augmenting/reducing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: A serotonergic dysfunction is supposed to play a pathogenetic role in depression, but there is a considerable number of non-responders in the acute treatment of depression with serotonergic agents like SSRI. Thus, an indicator of central serotonergic activity could lead to a more specific pharmacological treatment of depression. In animal and human data there is a growing amount of evidence that a strong loudness dependency of late auditory evoked potentials (LDAEP) is an indicator of low serotonergic activity and vice versa. Objective: In 29 depressive inpatients (DSM-III-R diagnosis 296.x in 28 patients, 300.4 in one patient), the hypothesis was tested that a strong LDAEP prior to treatment can predict a better clinical outcome under SSRI treatment over 4 weeks. Results: Patients with a strong pre-treatment LDAEP had a significantly greater decrease of depressive symptoms (Hamilton Scale for Depression) after 4 weeks than patients with a flat LDAEP. Significantly more responders fell into the group with a high LDAEP. Contrary to what might be expected, a second recording in a subsample of 19 patients after 4 weeks of treatment failed to show changes in the LDAEP. Conclusion: Our finding confirms the hypothesis that a strong LDAEP, indicating a low serotonergic activity, is related to a favorable response to acute SSRI treatment in depression. The LDAEP is a promising tool for the prediction of response to serotonin agonists in depression and it seems to be of clinical importance.
    Type of Medium: Electronic Resource
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