bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Levels of Coenzyme Q10 in Children with Hyperthyroidism
Authors: Menke Thomas , Niklowitz Petra , Reinehr Thomas , de Sousa Gideon John , Andler Werner
Published: December 2003

Objectives: In hyperthyroidism, increased oxygen consumption and free radical production in the stimulated respiratory chain leads to oxidative stress. Apart from its antioxidative function, coenzyme Q10 (CoQ10) is involved in electron transport in the respiratory chain. The aim of this study was to determine whether there is a correlation between an increased respiratory chain activity and the state of CoQ10 in children with hyperthyroidism. Methods: The CoQ10 plasma concentration was measured by high-performance liquid chromatography in 12 children with hyperthyroidism before and after treatment. Results: In the hyperthyroid state, the plasma level of CoQ10 was significantly decreased in comparison with the level in the euthyroid state. The correction of the hyperthyroid state resulted in a normalization of the CoQ10 level. Conclusion: Plasma CoQ10 deficiency appears to be related to the stimulated respiratory chain activity in children with hyperthyroidism.
Cortical Orofacial Motor Representation in Old World Monkeys, Great Apes, and Humans
Authors: Sherwood Chet C. , Holloway Ralph L. , Erwin Joseph M. , Schleicher Axel , Zilles Karl , Hof Patrick R.
Published: December 2003

Social life in anthropoid primates is mediated by interindividual communication, involving movements of the orofacial muscles for the production of vocalization and gestural expression. Although phylogenetic diversity has been reported in the auditory and visual communication systems of primates, little is known about the comparative neuroanatomy that subserves orofacial movement. The current study reports results from quantitative image analysis of the region corresponding to orofacial representation of primary motor cortex (Brodmann’s area 4) in several catarrhine primate species (Macaca fascicularis, Papio anubis, Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, and Homo sapiens) using the Grey Level Index method. This cortical region has been implicated in the execution of skilled motor activities such as voluntary facial expression and human speech. Density profiles of the laminar distribution of Nissl-stained neuronal somata were acquired from high-resolution images to quantify cytoarchitectural patterns. Despite general similarity in these profiles across catarrhines, multivariate analysis showed that cytoarchitectural patterns of individuals were more similar within-species versus between-species. Compared to Old World monkeys, the orofacial representation of area 4 in great apes and humans was characterized by an increased relative thickness of layer III and overall lower cell volume densities, providing more neuropil space for interconnections. These phylogenetic differences in microstructure might provide an anatomical substrate for the evolution of greater volitional fine motor control of facial expressions in great apes and humans.
Brain Architecture and Social Complexity in Modern and Ancient Birds
Authors: Burish Mark J. , Kueh Hao Yuan , Wang Samuel S.-H.
Published: December 2003

Vertebrate brains vary tremendously in size, but differences in form are more subtle. To bring out functional contrasts that are independent of absolute size, we have normalized brain component sizes to whole brain volume. The set of such volume fractions is the cerebrotype of a species. Using this approach in mammals we previously identified specific associations between cerebrotype and behavioral specializations. Among primates, cerebrotypes are linked principally to enlargement of the cerebral cortex and are associated with increases in the complexity of social structure. Here we extend this analysis to include a second major vertebrate group, the birds. In birds the telencephalic volume fraction is strongly correlated with social complexity. This correlation accounts for almost half of the observed variation in telencephalic size, more than any other behavioral specialization examined, including the ability to learn song. A prominent exception to this pattern is owls, which are not social but still have very large forebrains. Interpolating the overall correlation for Archaeopteryx, an ancient bird, suggests that its social complexity was likely to have been on a par with modern domesticated chickens. Telencephalic volume fraction outperforms residuals-based measures of brain size at separating birds by social structure. Telencephalic volume fraction may be an anatomical substrate for social complexity, and perhaps cognitive ability, that can be generalized across a range of vertebrate brains, including dinosaurs.
Stabilitätserhaltende Reduktion nichtlinearer Modelle (Stability-Preserving Nonlinear Model Reduction)
Authors: Wolf P. , Renninger H. , Rehfus B.
Published: December 2003

Wir haben ein allgemeines Reduktionsverfahren für Modelle nichtlinearer Systeme auf ein komponentenorientiertes Simulationsmodell angewendet und sind dabei auf einige Nachteile dieser Methode gestoßen. Beispielsweise gehen die physikalische Interpretierbarkeit der Variablen und Konstanten sowie Stabilitätseigenschaften des Modells verloren. Diese Probleme können umgangen werden, indem Teilsysteme des Modells auf Standardkomponenten des Ausgangsmodells projiziert werden. Dadurch wird die physikalische Bedeutung der Variablen und Konstanten automatisch erhalten. Werden bei der Projektion Nebenbedingungen berücksichtigt, kann sogar Stabilität gewährleistet werden. Wir haben unsere Methode auf ein hydrodynamisches Modell angewendet und konnten hinreichende Stabilitätsbedingungen formulieren.
Rekonfiguration linearer Systeme bei Aktor- und Sensorfehlern (Reconfiguration of Linear Systems with Actuator and Sensor Faults)
Authors: Lunze Jan , Steffen T.
Published: December 2003

Dieser Beitrag befasst sich mit der Frage, wie nach dem Ausfall von Aktoren oder Sensoren eine Regelung durch Rekonfiguration wieder hergestellt und das System in den nominalen Arbeitspunkt zurückgeführt werden kann. Bei Aktorfehlern ist dieses Ziel nur in speziellen Fällen erreichbar. Die Lösung besteht dann in einer statischen Kopplung der verbleibenden Eingänge. Der allgemeine Ansatz zur Behandlung von Sensorsfehlern ist der Einsatz eines reduzierten Beobachters. Beide Fälle werden detailliert untersucht und die Ergebnisse an einem Anwendungsbeispiel illustriert.
Ein Beitrag zur Systemtheorie ereignisdiskreter Systeme – Teil 1: Der Zeitbereich (A Note on System Theoretic Elements of Discrete Event Systems – Part 1: Time Domain)
Authors: Jäkel H. , Kiencke Uwe
Published: December 2003

Der Beitrag beschreibt einen elementaren Zugang zur ereignisdiskreten Systemtheorie. Die Definitionen und Eigenschaften lassen sich aufgrund des hohen Wiedererkennungseffektes leicht verinnerlichen. Nach den Definitionen zur Systemtheorie werden Beispiele zur Anwendung der Begriffe bei existierenden Systemen diskutiert. Der in diesem Artikel definierte Begriff der Ereigniserhaltung definiert eine Charakteristik ereignisdiskreter Systeme und wird ebenfalls anhand eines Beispiels dargestellt. Die Ereigniserhaltung kann durch Betrachtung der Impulsantwort des Systems charakterisiert werden.
Reaktive Kontrolle komplexer autonomer Systeme in einer agentenorientierten Mehrschichtenarchitektur (Reactive Control of Autonomous Systems within an Agent-oriented Multi-layer Architecture)
Authors: Martens C. , Gräser A.
Published: December 2003

Bei dem Entwurf einer Kontrollarchitektur für komplexe autonome Systeme, wie Roboter- oder Fertigungssysteme sind eine Vielzahl von Anforderungen zu berücksichtigen. Diese Systeme müssen Befehle auf hohem Abstraktionsniveau entgegennehmen, verarbeiten und sich während der Befehlsausführung automatisch auf Änderungen in der Umwelt einstellen. In diesem Beitrag wird der Entwurf einer agentenorientierten Mehrschichtenarchitektur für den Rehabilitationsroboter FRIEND vorgestellt. Schwerpunkt des Beitrags ist die detaillierte Beschreibung der reaktiven Schicht und deren Integration in die vorgestellte Mehrschichtenarchitektur.
Eine neue Kaskadenstruktur (A New Structure for Cascade Control)
Authors: Graf Klemens , Wurmthaler C.
Published: December 2003

Der Entwurf und die Inbetriebnahme von Kaskadenregelungen wird durch die in der üblichen Struktur stets vorhandene Abhängigkeit zwischen den Regelkreisen erschwert. Dieser Beitrag stellt eine aus Steuerungsüberlegungen gewonnene neue Kaskadenstruktur vor, die voneinander unabhängige Regelkreise aufweist. Die neue Struktur besitzt dadurch den wesentlichen Vorteil, dass Entwurf und Inbetriebnahme der Regler voneinander unabhängig und in beliebiger Reihenfolge vorgenommen werden können.
Strukturierte Polvorgabe für PMD Prozesse (Structural Pole Assignment for PMD Processes)
Authors: Lampe B. P. , Rosenwasser E. N.
Published: December 2003

Der Artikel behandelt das Problem der strukturierten Polvorgabe für PMD (Polynomial Matrix Description) Prozesse, das im Zusammenhang mit dem Entwurf von Regelgesetzen entsteht, wenn die Lage der Eigenwerte der charakteristischen Matrix des geschlossenen Systems in der komplexen Ebene und außerdem die Struktur der Menge ihrer invarianten Polynome vorgegeben wird.
Ein Beitrag zur Systemtheorie ereignisdiskreter Systeme – Teil 2: Der Bildbereich (A Note on System Theoretic Elements of Discrete Event Systems – Part 2: Range Domain)
Authors: Jäkel H. , Kiencke Uwe
Published: December 2003

Dieser Beitrag erweitert den ersten Teil der Beitragsreihe um die Darstellung von ereignisdiskreten Signalen im Bildbereich. Hierzu werden algebraische Verfahren verwendet, die anschaulich interpretiert werden und sich somit leicht nachvollziehen lassen. Die Beschreibung der Systeme erfolgt mittels einer Systemfunktion. Dies geschieht analog zur Signaldefinition durch die Betrachtung der Auftretenszeitpunkte einzelner Ereignisse. In einem Beispiel wird eine Systemfunktion berechnet und deren Aussage unter praktischen Gesichtspunkten diskutiert.
Verifikation von Funktionsbausteinadaptern durch Modelchecking (Verification of Function Block Adapters through Modelchecking)
Authors: Heverhagen Torsten
Published: December 2003

Die Unified Modeling Language (UML) gewinnt in der Automatisierungstechnik immer mehr an Bedeutung. In der Version 2.0 enthält die UML so genannte “Ports”, die unter anderem eine Integration der UML in ein stark heterogenes automatisierungstechnisches Umfeld erleichtern. Speziell zur Integration mit Sprachen für speicherprogrammierbare Steuerungen wurden Ports der UML als Schnittstelle zu Funktionsbausteinen der IEC 61131-3 eingesetzt. Die Umsetzung der unterschiedlichen Protokollarten erfolgt hierbei durch Funktionsbausteinadapter (FBAs). In diesem Artikel wird das logische, plattformunabhängige Verhalten von FBAs mit Hilfe kommunizierender endlicher Automaten beschrieben. Durch symbolisches Modelchecking wird dieses Automatenmodell anschließend auf häufige Spezifikationsfehler überprüft.
Optimale Parametrisierung eines Triebwerksreglers (Optimal Parameterisation of a Jet Engine Controller)
Authors: Lachmann Stefan , Giesa Dennis , Dlabka Michael
Published: December 2003

In dieser Arbeit wird ein Verfahren zur Auslegung eines robusten, optimalen, linearen Reglers für ein nichtlineares System vorgestellt. Das nichtlineare System wird durch ein nominelles lineares Modell mit Unsicherheiten dargestellt. Im Gegensatz zur μ-Synthese können bei diesem Verfahren beliebige feste Reglerstrukturen vorgegeben werden. Die Bestimmung der Parameter des Reglers erfolgt dabei mittels Optimierung bezüglich vorgegebener Zeit- und Frequenzbereichskriterien. Zur Bewertung der robusten Performanz wird die μ-Analyse als weiteres Kriterium eingesetzt. Die Leistungsfähigkeit des Verfahrens wird anhand der Auslegung einer Drehzahlregelung eines Strahltriebwerkes demonstriert.
Ein neues Verfahren zur Ermittlung aktueller Betriebszustände bei selbsteinstellenden multi-modell-gestützten Regelungssystemen (A New Method for Determining Current Operating Points in Adaptive Control Systems based on Multi-models)
Authors: Feng Zhengyuan , Schöne Armin
Published: December 2003

Um multi-modell-gestützte adaptive Regelungssysteme anwenden zu können, muss man den Betriebszustand, der das jeweils aktuelle Submodell kennzeichnet, im laufenden Prozess zuverlässig erkennen. Es ist üblich, hierzu fortlaufend ermittelte Schätzwerte der Modellparameter zu verwenden. Bei schwachen Eingangsanregungen weichen diese stark von den wahren Werten ab. Mit den bekannten Verfahren kann dann der jeweilige Betriebszustand nicht mehr bestimmt werden. In der Arbeit wird nachgewiesen, dass aus dem für die linearen Submodelle verwendeten Ansatz eine Funktion der Parameterschätzwerte abgeleitet werden kann, die auch bei schwachen Eingangsanregungen identifizierbar ist. Damit ist in großen Anwendungsbereichen auch aus ungenauen Parameterschätzwerten eine sichere und vor allem auch schnelle Erkennung des gültigen Betriebszustandes möglich.
The OECD Nuclear Energy Agency Thermochemical Database Project
Authors: Mompeán Federico J. , Wanner Hans
Published: December 2003

The OECD Nuclear Energy Agency (NEA) Thermochemical Database Project aims at making available a comprehensive, internally consistent and quality assured chemical thermodynamic database of selected chemical elements. This database should meet the specialized modeling requirements for safety assessments of radioactive waste disposal systems. This paper describes the evolution of the project from its inception in 1984 to the present organization as a semi-autonomous project under the aegis of the OECD NEA. The scientific principles behind the project organization have not been altered and the effort has resulted in the publication of five major reviews on the chemical thermodynamics of inorganic species and compounds of U, Np, Pu, Am and Tc. Currently, a second series of reviews is being prepared updating the existing, CODATA compatible, database and extending it to include selected data on inorganic species of compounds of Ni, Se and Zr as well as organic complexes with citrate, oxalate, EDTA and iso-saccharinic acid with U, Np, Pu, Am, Tc, Ni, Se, Zr and some other competing cations.
The supramolecular speciation: a key for improved understanding and modelling of chemical reactivity in complex systems
Authors: Cote Gérard
Published: December 2003

The objective of this paper is to show through various examples that the "supramolecular" speciation is a key for the understanding and modelling of phenomena as varied as unusually rapid mass transfers in solvent extraction, organic phase splitting in liquid-liquid systems and complex behaviours of the organic matter in the environment.
Actinide speciation in the environment
Authors: Choppin Gregory R.
Published: December 2003

The chemical behavior of the actinide elements in the environment depends upon their oxidation state and chemical species. Plutonium is the major transuranic element in the environment due to releases in nuclear weapons testing. The major factors influencing environmental behavior of plutonium, including redox, compexation, colloid formation, solubility,etc.are discussed. The strong hydrolysis and low solubility of Pu(OH)4limits the solubility concentrations of plutonium in the other, more soluble oxidation states and results in plutonium in environmental waters being mainly present in colloids. To perform valid modeling, it is necessary to have reliable knowledge on the nature of plutonium present, the oxidation state (or states) and reliable stability constants for the complexes which may be formed in these oxidation states. These problems and possible approaches to their solution are the main focus of this paper.
On the use of time-resolved laser-induced fluorescence (TRLIF) and electrospray mass spectrometry (ES-MS) for speciation studies
Authors: Moulin Christophe
Published: December 2003

Time-Resolved Laser Induced fluorescence (TRLIF) and ElectroSpray Mass Spectrometry (ES-MS) are used for speciation studies. While the former has been used for long time, the latter is rather new in the field of speciation. These two techniques have different advantages such as sensitivity (especially for TRLIF), selectivity and multielement capabilities (in case of ES-MS). Examples obtained from studies carried out within the CEA are presented. Concerning TRLIF, emphasis is put on uranyl ion speciation in nitric acid to phosphoric acid going through hydroxo complexes. Concerning ES-MS, humic substances identification as well as speciation of cesium, zirconium, thorium and uranyl ions in various complexing media are presented. Comparisons of TRLIF and ES-MS results are made in the case of uranyl hydroxo complexes and favourably compared with OECD data. Trends for these two techniques are also discussed.
Dimerization of Np(V) and media effects in concentrated solutions
Authors: Gregoire-Kappenstein A. C. , Moisy Ph. , Cote Gerard , Blanc P.
Published: December 2003

Highly concentrated (up to 3.56mol L-1) binary solutions of NpO2NO3 were prepared to investigate the self-association of Np(V). By using visible/NIR absorption spectrophotometry and chemometric techniques, Np(V) was shown to be only monomeric below 0.2mol L-1, to exist under its monomeric and dimeric forms between 0.2 and 2mol L-1, to begin to form self-associates of higher degrees above 2mol L-1. In the range 0.2mol L-1 < C
Np(V)<2mol L-1, the neptunium distribution between the free NpO2
+ and dimeric (NpO2)2
2+ forms was determined by Raman spectroscopy. The simple solution concept was used to establish the activity function for the reaction of dimerization. Such a water activity function can be used to calculate the apparent dimer formation constant for any solution of known composition and water activity, provided that this solution is simple.
Speciation and mobility of uranium(VI) in humic-containing soils
Authors: Crançon Pierre , van der Lee J.
Published: December 2003

Uranium is known to easily form stable complexes with both organic and inorganic ligands in natural aquatic environments. The potential mobility of U(VI), and particularly the role of humic substances, has been investigated for a sandy podzol. Adsorption of U(VI) at equilibrium was experimentally investigated, comparatively for a pure quartz sand as well as a sandy podzolic soil from Landes Gascony, France, containing 0.6 wt. organic matter. Uranium is strongly retained by the bulk soil, mainly due to organic aggregates (<50μm) and organic coatings on quartz grains. A large fraction of U(VI) is found to be associated to humic colloids in soil, thus forming a potential mobile uranium phase. For the soil, the U(VI) adsorption isotherm is linear for relatively low U(VI) total aqueous concentration, ranging from 15 to 40000μg/L. This indicates that the functional groups of humic matter are far from saturated for aqueous concentrations close to U(VI) solubility in soil pore-water. The speciation of uranium in soil pore water and the interactions between U(VI) species and the reactive sites of the soil material were evaluated using the speciation code CHESS [1]. Comparison between the model and experimental results show that complexation of U(VI) by humic substances tends to immobilise uranium in soils with a pH below 5, when the reactive surface of quartz grains and aggregates are entirely coated by humic matter. In soil pore-water, the presence of mobile organic ligands competing with surface-bound organics for U(VI) complexation must be included in the speciation modelling. Without the mobile organic phase, the model overestimates the actual bound fraction, thus underestimating the actual amount of mobile U(VI).
Association between the TPH gene A218C polymorphism and suicidal behavior: A meta‐analysis
Authors: Bellivier Frank , Chaste Pauline , Malafosse Alain
Published: December 2003

Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of suicidal behavior. The tryptophan hydroxylase (TPH) gene, which codes for the rate‐limiting enzyme of serotonin biosynthesis, is a major candidate gene and has been extensively studied in association studies of suicidal behavior, providing conflicting results. It is difficult to interpret these conflicting results due to lack of power, ethnic heterogeneity, and variations in the sampling strategies (in particular for controls) and in the polymorphism of the TPH gene studied. Meta‐analyses can improve the statistical power for the analysis of the effects of candidate vulnerability factors. The analysis of the sources of heterogeneity that contribute to these conflicting results is an important step in the interpretation of these conflicting association results and in the interpretation of the results of a meta‐analysis. We selected all of the published association studies between the TPH gene polymorphism and suicidal behavior. Nine association studies between the A218C TPH polymorphism and suicidal behavior fulfilled the inclusion criteria. A significant association was observed between the A218C polymorphism and suicidal behavior using the fixed effect method (odds ratio (OR) = 1.62; 95% confidence interval (CI) = [1.26; 2.07]) and the random effect method (OR = 1.61; 95% CI = [1.11; 2.35]). The analysis of the sources of heterogeneity showed that two studies (one positive and one negative) significantly deviated from the calculated global effect. The meta‐analysis performed after removing those two studies also revealed a significant association between the TPH A218C polymorphism and suicidal behavior. Both analyses suggested that the A allele has a dose‐dependent effect on the risk of suicidal behavior. © 2004 Wiley‐Liss, Inc.
Variation in the urokinase‐plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD
Authors: Myers Amanda J. , Marshall Helen , Holmans Peter , Compton Danielle , Crook Richard J.P. , Mander Adrian P. , Nowotny Petra , Smemo Scott , Dunstan Melanie , Jehu Luke , Wang Jen C. , Hamshere Marian , Morris John C. , Norton Joanne , Chakraventy Sumi , Tunstall Nigel , Lovestone Simon , Petersen Ronald , O'Donovan Michael , Jones Lesley , Williams Julie , Owen Michael J. , Hardy John , Goate Alison
Published: December 2003

Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Aβ42 levels suggesting that a single locus may influence risk for AD by elevating plasma Aβ42 [Ertekin‐Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase‐plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family‐based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data. © 2004 Wiley‐Liss, Inc.
Nature and nurture: Interaction and coaction
Authors: McClearn Gerald E.
Published: December 2003

The sophistry of the “Nature versus Nurture” formulation is becoming ever more apparent as a consequence of the rapid advances in understanding of the basic mechanisms of heredity and in the application of this knowledge to a wide spectrum of issues of human health and welfare. It is clear that a more accurate formulation would emphasize the interaction and coaction of genetic and environmental factors in their influence on complex phenotypes. Furthermore, the potential dependence of the influence of a particular gene on other genes in the system is increasingly realized. This paper documents these perspectives by examples of gene‐environment interaction and gene‐gene interaction both from animal model and from human research that reveal both the potential power and subtlety of these interactive effects. © 2004 Wiley‐Liss, Inc.
Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia
Authors: Szekeres György , Kéri Szabolcs , Juhász Anna , Rimanóczy Ágnes , Szendi István , Czimmer Csongor , Janka Zoltán
Published: December 2003

Molecular components of the dopaminergic system may play an important role in the pathophysiology of schizophrenia. In this study, we investigated the relationship of the Ser9Gly (S/G) polymorphism of the dopamine D3 receptor (DRD3) and the variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) with therapeutic response to atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone) and cognitive functions. No associations were found between the DRD3 and DAT polymorphisms and schizophrenia. The S/S genotype and the S allele were more frequent in the non‐responder patients (n = 28) than in the group of responders (n = 47) (cut‐off: >20‐point improvement in Global Assessment of Functioning (GAF) scale). The patients with S/S genotype completed fewer categories and had more perseverative errors in the Wisconsin Card Sorting Test (WCST) compared with the S/G patients. The S/S and S/G patients did not differ in positive and negative symptoms, GAF scores, WCST failure to maintain set, and verbal learning. No differences in symptoms or WCST measures were observed in the patients with different DAT genotypes. These results suggest that the S/S genotype of the DRD3 is associated with worse therapeutic response and more severe executive dysfunctions in patients with schizophrenia. © 2003 Wiley‐Liss, Inc.
Personality traits in young female apolipoprotein E (apoE) ε4 and non‐ε4 carriers
Authors: Tsai Shih‐Jen , Yu Younger W.‐Y. , Hong Chen‐Jee
Published: December 2003

Apolipoprotein E (apoE) is the major brain apolipoprotein, and is related to the functional integrity of the central nervous system. It has been reported that the apoE genetic polymorphism is associated with several components of childhood and adolescent temperament. To study the effect of the presence of the apoE ε4 allele on adult personality factors, tridimensional personality questionnaire (TPQ) scores were compared for ε4 and non‐ε4 carriers in a sample population consisting of 135 young females. No significant differences were demonstrated comparing the scores for the two groups. Our findings suggest that the investigated apoE polymorphism does not play a major role in personality trait factors, as assessed by TPQ. © 2004 Wiley‐Liss, Inc.
Mutation screen of the glutamate decarboxylase‐67 gene and haplotype association to unipolar depression
Authors: Lappalainen Jaakko , Sanacora Gerard , Kranzler Henry R. , Malison Robert , Hibbard Ellen S. , Price Lawrence H. , Krystal John , Gelernter Joel
Published: December 2003

Abnormally low concentrations of brain gamma‐aminobutyric acid (GABA) have been reported in unipolar depression. Almost all of the brain GABA is synthesized by glutamate decarboxylase (GAD) enzymes (GAD67 and GAD65). These enzymes, therefore, play a central role in brain GABA homeostasis. We screened all the 17 exons of the GAD67 gene for mutations using single strand conformation polymorphism (SSCP) or denaturing high pressure liquid chromatography (dHPLC) in a sample of 43 individuals diagnosed with major unipolar depression or other disorders with putative GABAergic dysfunction. We identified eight novel variants (five synonymous base substitutions, two insertion/deletions and one tandem repeat). Three relatively common (minor allele frequency >20%) single nucleotide polymorphisms (SNPs), located in the 5′ non‐coding region (exon 0), intron 8, and the 3′ non‐coding region (exon 16) of the gene, were genotyped in 103 European‐American (EA) subjects with depression and 125 EA psychiatrically screened controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated using the 3LOCUS program. Significant LD was observed between the intron 8 SNP and the exon 16 SNP and between the exon 0 SNP and the exon 16 SNP. Three common GAD67 haplotypes were observed in this population, which accounted for >90% of the possible GAD67 three‐locus haplotypes. Comparison of SNP and haplotype frequencies between individuals with depression and controls revealed no differences. These results demonstrate a significant within‐gene LD for GAD67 in the EA population and begin to establish a haplotype map for this gene. Furthermore, these results suggest that common genetic variation within the GAD67 gene does not play a major role in the predisposition to unipolar depression. © 2003 Wiley‐Liss, Inc.
Re‐Screening serotonin receptors for genetic variants identifies population and molecular genetic complexity
Authors: Glatt Charles E. , Tampilic Maricel , Christie Carroll , DeYoung Joe , Freimer Nelson B.
Published: December 2003

We have re‐screened the genes for the 5‐HT1A, 5‐HT2A, 5‐HT2C, and 5‐HT7 serotonin receptors for genetic variants in a large African‐American and Caucasian‐American population sample. We have identified eight novel variants in these genes including four that are predicted to cause amino acid substitutions. These variants are additional candidates for association studies of behavioral disorders such as depression and schizophrenia as well as quantitative personality traits. We have also detected some, but not all, previously identified variants in these genes suggesting that many previously identified variants are unique to specific populations. The results of this study, and previous screens of serotonin receptors, demonstrate that the genes for serotonin receptors display marked population and molecular genetic complexity. These levels of complexity may have a substantial effect on genetic association studies of human behavioral variability related to these genes. We discuss the implications of these findings and propose methods to address complexity in genetic association studies. © 2003 Wiley‐Liss, Inc.
Novel CAG/CTG repeat expansion mutations do not contribute to the genetic risk for most cases of bipolar disorder or schizophrenia
Authors: Tsutsumi T. , Holmes S.E. , McInnis M.G. , Sawa A. , Callahan C. , DePaulo J.R. , Ross C.A. , DeLisi L.E. , Margolis R.L.
Published: December 2003

The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia.© 2003 Wiley‐Liss, Inc.
An indirect test of the new mutation hypothesis associating advanced paternal age with the etiology of schizophrenia
Authors: Pulver Ann E. , McGrath John A. , Liang Kung‐Yee , Lasseter Virginia K. , Nestadt Gerald , Wolyniec Paula S.
Published: December 2003

Two studies by Malaspina et al. [2001: Arch Gen Psychiatr 58:361–367]; [2002: Am J Med Genet 114:299–303] have put forward the hypothesis that advanced paternal age with concomitant mutations in the male germ line is associated with sporadic schizophrenia in offspring. The hypothesis was supported by an observation of a monotonic increase in the risk for schizophrenia with increased paternal age, and a second observation in a separate sample of greater paternal mean age at birth among cases of apparent sporadic schizophrenia. The present study did not test the association of the risk of schizophrenia with advanced paternal age, but repeated the test of paternal age at birth among sporadic versus familial schizophrenic probands. We also examined the risk of schizophrenia, psychosis, and broad psychosis among paternal 1st and 2nd degree relatives of schizophrenic probands as a function of paternal age at birth of the proband, reasoning that if probands born to older fathers are more likely to be sporadic cases, the risk of schizophrenia (or psychosis) should be lower on the paternal side of the family. Results indicate a lack of support for the previous finding that sporadic probands tend to have older fathers at birth than familial probands. Results also failed to support the related hypothesis that increased paternal age is associated with the lower risk of schizophrenia (or psychosis) in the relatives of schizophrenic probands. The failure to support the paternal age hypothesis may be a function of heterogeneous samples, but calls for further research in the context of family studies. © 2003 Wiley‐Liss, Inc.
Interleukin‐1β (IL‐1β) gene and increased risk for the depressive symptom‐dimension in schizophrenia spectrum disorders
Authors: Rosa Araceli , Peralta Victor , Papiol Sergi , Cuesta Manuel J. , Serrano Fermín , Martínez‐Larrea Alfredo , Fañanás Lourdes
Published: December 2003

Interleukin‐1β (IL‐1β), as well as other cytokines, has been classically implicated in the pathophysiology of major psychiatric disorders such as schizophrenia and major depression, and recent studies have implicated the IL‐1β gene and schizophrenia. Nevertheless, new approaches to this complex phenotype are necessary to clarify the risk conferred by this gene, either to the disorder or to its clinical manifestations. The aim of the present study was to explore the effect of a genetic polymorphism of the promoter region of the IL‐1β gene, in schizophrenia defined with: (i) a categorical diagnosis and (ii) a multidimensional symptom approach. We studied 356 individuals from 89 nuclear families consisting of one affected individual and the unaffected father, mother, and sib, in a family‐based association study design. We find a trend for biased transmission of allele 2 from heterozygous parents to affected offspring, categorically defined (P = 0.07). This tendency was not observed in the healthy offspring. Using a multidimensional symptom approach to the diagnosis, the association was confirmed in psychotic patients showing the depressive symptom‐dimension (P = 0.02). © 2003 Wiley‐Liss, Inc.
No evidence of linkage or association between the norepinephrine transporter (NET) gene MnlI polymorphism and adult ADHD
Authors: De Luca Vincenzo , Muglia Pierandrea , Jain Umesh , Kennedy James L.
Published: December 2003

Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow‐up studies have indicated that one to two thirds of patients continue to suffer from ADHD during late adolescence and adulthood. The mechanism of action of the new selective noradrenergic reuptake inhibitor, atomoxetine, efficacious in the treatment of ADHD symptoms, suggests that the norepinephrine transporter (NET) may be involved in ADHD. The aim of this study was to investigate for the presence of linkage disequilibrium between the MnlI RFLP in the NET gene and adult ADHD in a sample of nuclear families. The MnlI polymorphism was typed in 128 trios and analyzed using the transmission disequilibrium test (TDT). There was no preferential transmission of either allele (χ2 = 0.209, df = 1, P = 0.647). © 2003 Wiley‐Liss, Inc.
Co‐occurrence of ADHD and low IQ has genetic origins
Authors: Kuntsi J. , Eley T.C. , Taylor A. , Hughes C. , Asherson P. , Caspi A. , Moffitt T.E.
Published: December 2003

Previous studies show that the symptoms of attention deficit hyperactivity disorder (ADHD) and lower intelligence quotient (IQ) covary in children. We investigated the aetiology of this association in a large population‐based sample of 5‐year‐old twins. The twins were individually assessed on an IQ test, and data on ADHD symptoms were obtained from mother interviews and teacher ratings. Confirming previous studies, the phenotypic correlation between ADHD symptom scores and IQ was −0.3 and, in a categorical analysis, children with a Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) ADHD research diagnosis obtained IQ scores nine points lower, on average, than comparison children. We show here that the co‐occurrence of ADHD and lower IQ has genetic origins: 86% of the association between ADHD symptom scores and IQ, and 100% of the association between ADHD diagnosis and IQ, was accounted for by genetic influences that are shared by ADHD and IQ. Some candidate genes for ADHD could also contribute to variation in IQ or vice versa. © 2003 Wiley‐Liss, Inc.
Effects of dopamine receptor D4 variation on alcohol and tobacco use and on novelty seeking: Multivariate linkage and association analysis
Authors: Luciano Michelle , Zhu G. , Kirk K.M. , Whitfield J.B. , Butler R. , Heath A.C. , Madden P.A.F. , Martin N.G.
Published: December 2003

The dopamine D4 receptor gene contains a polymorphic sequence consisting of a variable number of 48‐base‐pair (bp) repeats, and there have been a number of reports that this polymorphism is associated with variation in novelty seeking or in substance abuse and addictive behaviors. In this study we have assessed the linkage and association of DRD4 genotype with novelty seeking, alcohol use, and smoking in a sample of 377 dizygotic twin pairs and 15 single twins recruited from the Australian Twin Registry (ATR). We found no evidence of linkage or association of the DRD4 locus with any of the phenotypes. We made use of repeated measures for some phenotypes to increase power by multivariate genetic analysis, but allelic effects were still non‐significant. Specifically, it has been suggested that the DRD4 7‐repeat allele is associated with increased novelty seeking in males but we found no evidence for this, despite considerable power to do so. We conclude that DRD4 variation does not have an effect on use of alcohol and the problems that arise from it, on smoking, or on novelty seeking behavior. © 2003 Wiley‐Liss, Inc.
Association between brain‐derived neurotrophic factor 196 G/A polymorphism and personality traits in healthy subjects
Authors: Itoh Kanako , Hashimoto Kenji , Kumakiri Chikara , Shimizu Eiji , Iyo Masaomi
Published: December 2003

Several lines of evidence suggest that a certain type of personality or temperament is at risk for developing neuropsychiatric diseases, and that brain‐derived neurotrophic factor (BDNF) might be involved in pathophysiology of neuropsychiatric diseases such as mood disorders. Considering the role of BDNF and personality traits in the neuropsychiatric diseases, it is of interest to examine the association between BDNF gene polymorphism and personality test scores. In this study, we examined the association between 196 G/A the polymorphism in the coding region of the BDNF gene and personality traits scores (temperament and character inventory (TCI) and NEO personality inventory (NEO‐PI)) in Japanese healthy subjects. We found that female, but not male, subjects with BDNF genotype A/A have high scores in reward dependence on TCI and high scores in extraversion on NEO‐PI as compared with other genotypes (G/A or G/G), suggesting an association between reward dependence (or extraversion) personality traits and BDNF genotype in female subjects. Our findings suggest that BDNF 196 A/G polymorphism might be associated with personality traits in female, but not male, healthy subjects. © 2003 Wiley‐Liss, Inc.
Linkage disequilibrium analysis of polymorphisms in the gene for myelin oligodendrocyte glycoprotein in Tourette's syndrome patients from a Chinese sample
Authors: Huang Yi , Li Tao , Wang Yun , Ansar Jawaid , Lanting Guo , Liu Xiehe , Zhao Jing Hua , Hu Xun , Sham Pak C. , Collier David
Published: December 2003

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterised by multiple motor and phonic tics, which wax and wane. Recently, evidence has accumulated supporting the role of autoimmune mechanisms in the aetiology of GTS, suggesting that it is within the paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) spectrum of childhood neurobehavioural disorders. An immunopathogenic role of antibodies against myelin oligodendrocyte glycoprotein (MOG) has been suggested in this syndrome. In this study, we investigate the association of three microsatellite polymorphisms (MOGa, MOGb, MOGc) in the gene for MOG with GTS in 197 family trios collected from southwest China. Linkage disequilibrium between these three markers was observed with the strongest between MOGa and MOGc (D′ = 0.541, P = 0.000). We did not find overall significant evidence for distorted transmission of any of these three markers of MOG gene in GTS, although we observed a weak preferential transmission of the 148 bp allele of MOGc (χ2 = 4.000, P = 0.046) which did not survive correction for multiple testing. Our results suggest that there is no association between the MOG gene polymorphisms we tested and GTS. © 2003 Wiley‐Liss, Inc.
Ethnicity‐independent genetic basis of functional psychoses: A genotype‐to‐phenotype approach
Authors: Stassen H.H. , Bridler R. , Hell D. , Weisbrod M. , Scharfetter C.
Published: December 2003

The functional psychoses schizophrenia, schizoaffective disorder, and bipolar illness represent complex clinical syndromes that are characterized by phenotypic heterogeneity. Yet evidence from numerous studies suggests that (1) the prevalence of schizophrenia and bipolar illness is with 1% very similar across ethnicities, and (2) a strong genetic component is involved in the disorders' pathogenesis. Using data from different US‐American ethnicities (77 families with a total of 17 unaffected and 170 affected sib pairs; 276 marker loci), we searched for ethnicity‐independent oligogenic susceptibility loci for which the between‐sib genetic similarity in affected sib pairs deviated from the expected values. Specifically, we addressed the question of the extent to which genetic risk factors and their interactions constitute multigenic inheritance of functional psychoses across populations and might constitute universal targets for treatment. Our novel multivariate genotype‐to‐phenotype search strategy was based on a genetic similarity function that allowed us to quantify the inter‐individual genetic distances d(xi, xj) between the allelic genotype patterns xi, xjof any two subjects i, j with respect to n loci l1, l2, … ln. Thus, we were able to assess the between‐ethnicity, the within‐ethnicity, and the within‐family genetic similarities. The problem of ethnicity‐independent vulnerability was addressed by treating the Afro‐American families as “training” samples, while the non‐Afro‐American families served as independent “test” samples. We evaluated the between‐sib similarities, which were expected to deviate from “0.5” in affected sib pairs if the region of interest contained markers close to vulnerability genes. The reference value “0.5” was derived from the parent–offspring similarities that are always 0.5, irrespective of the affection status of parents and offspring. We found 12 vulnerability loci on chromosomes 1, 4, 5, 6, 13, 14, 18, and 20, that were reproducible across the two samples under comparison and therefore, likely to constitute an ethnicity‐independent, oligogenic vulnerability model of functional psychoses. The elevated vulnerability appeared to be unspecific and to act in such a way that exogenous factors become more likely to trigger the onset of psychiatric illnesses. © 2003 Wiley‐Liss, Inc.
Combined family trio and case‐control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa
Authors: Gabrovsek M. , Brecelj‐Anderluh M. , Bellodi L. , Cellini E. , Di Bella D. , Estivill X. , Fernandez‐Aranda F. , Freeman B. , Geller F. , Gratacos M. , Haigh R. , Hebebrand J. , Hinney A. , Holliday J. , Hu X. , Karwautz A. , Nacmias B. , Ribases M. , Remschmidt H. , Komel R. , Sorbi S. , Tomori M. , Treasure J. , Wagner G. , Zhao J. , Collier D.A.
Published: December 2003

The high activity Val158 (H) allele of the dopamine‐metabolizing enzyme catechol‐O‐methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio‐based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case‐control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (χ2 = 0, ns). Allele‐wise case‐control analysis using separate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78–1.24). Analysis by genotype was likewise not significant (overall χ2 = 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample. © 2003 Wiley‐Liss, Inc.
Association between interleukin 1‐β promoter (−511) polymorphism and depressive symptoms in Alzheimer's disease
Authors: McCulley Michelle C. , Day Ian N.M. , Holmes Clive
Published: December 2003

Depressive symptoms have been associated with raised interleukin 1‐β (IL‐1β) plasma levels. The presence of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease, including depressive symptoms, have been shown to be influenced by common genetic polymorphisms. A common polymorphism in the promoter region of IL‐1β has been linked to altered synthesis of IL‐1β. We hypothesize that this common genetic polymorphism is a risk factor for the appearance of depressive symptoms in AD. A total of 133 subjects, diagnosed as probable AD and 156 controls were genotyped for the −511 variant of IL‐1β. Neither genotype or allele frequencies differed between the AD and control group. However, an allelic association was found between the T variant and the symptoms of depression in AD subjects. Genotypic analysis showed that heterozygotes were three times more likely to develop depressive symptoms than CC homozygotes. © 2003 Wiley‐Liss, Inc.
The 1239G/C polymorphism in exon 5 of BACE1 gene may be associated with sporadic Alzheimer's disease in Chinese Hans
Authors: Shi Jiajun , Zhang Sizhong , Tang Mouni , Liu Xiehe , Li Tao , Wang Yingcheng , Han Haiying , Guo Yangbo , Hao Yuantao , Zheng Keqin , Kong Xiangdong , Su Zhiguang , Tong Yu , Ma Cui
Published: December 2003

Beta‐site amyloid‐precursor protein cleaving enzyme (BACE1) is a candidate risk factor for Alzheimer's disease (AD) because of involving in generating β‐amyloid peptide, which is thought to play a central role in the pathogenesis of the disease. A single nucleotide polymorphism 1239G/C in exon 5 of BACE1 gene and a weak association between this polymorphism and AD in Caucasian APOEε4 allele carriers has been reported. To examine possible association of the polymorphism with sporadic AD, two Chinese Han cohorts including 257 patients and 242 age‐matched controls in Guangzhou and 112 patients and 113 controls in Chengdu were genotyped using PCR‐RFLP techniques. The frequency of the C allele in controls of both cohorts was 0.65, which was higher than that in Caucasian populations [0.39 by Nowotny et al. 2001: Neuroport 12:1799–1802; 0.44 by Nicolaou et al. 2001: Neurogenetics 3:203–206]. There was a significant excess of C allele among the patients in both cohorts (Guangzhou, 0.71 vs. 0.65, χ2 = 5.20, P = 0.02; Chengdu, 0.74 vs. 0.65, χ2 = 4.36, P = 0.04). The CC genotype was found to be associated with AD (Guangzhou cohort, OR = 1.56, 95% CI = 1.09–2.23; Chengdu cohort, OR = 1.74, 95% CI = 1.03–2.95; combined sample: OR = 1.61, 95% CI = 1.20–2.17). The association remained in non‐APOE ε4 allele carriers when all subjects were divided on the basis of the APOEε4 status. Our findings suggest that the 1239G/C polymorphism in exon 5 of BACE1 gene may be associated with sporadic AD in Chinese Hans. © 2003 Wiley‐Liss, Inc.