Positionsklonierung eines Kandidatengens für chronisch entzündliche Darmerkrankungen auf dem humanen Chromosom 16

Die chronisch entzündlichen Darmerkrankungen (CED) zählen mit ihren beiden Subphänotypen Morbus Crohn (MC) und Colitis ulcerosa (CU) zu den komplexen Erkrankungen, denen eine polygenetische und umweltbedingte Ätiologie zu Grunde liegt. Das bisher stärkste Risikogen für die CED konnte in Form von NOD2 auf der Basis einer Kopplungsregion (IBD1) auf dem Chromosom 16 identifiziert werden. Eine Stratifizierung gegen die NOD2-Riskovarianten in unabhängigen Kopplungsanalysen erbrachte den Hinweis auf ein weiteres, NOD2-unabhängiges Krankheitsgen auf dem Chromosom 16q; dieses galt es in einer Kandidatengenstudie zu identifizieren. In einem umfassenden Feinkartierungsexperiment wurden 436 SNP-Marker einer 35Mb großen Region in insgesamt 6.688 Individuen genotypisiert. Das Studiendesign war als familien- und populationsbasierte Assoziationsstudie angelegt und die Auswertung über die TDT- und Fall-Kontroll-Statistik konnte die Gene BRD7, GPR56, ZFP90, ZNF19 und ZNF23 als Kandidatengene ausweisen. Ein 5-Marker-Haplotyp des ZFP90-Gens zeigte eine deutliche CED-Assoziation (p=0,00035) basierend auf einer gerichteten Vererbung in den Patienten. Desweiteren konnte eine statistische Erhöhung des Krankheitsrisikos für den Phänotyp MC um den Faktor 1,4 (OR=0,74, 95%-KI 0,61-0,91) für einzelne Varianten der Gene ZNF19 und ZNF23 identifiziert werden. Zwei Mutationen der 5’-UTR-Region des GPR56-Locus zählten durch eine starke allelische Assoziation in der Fall-Kontroll-Statistik (p=0,0009 und p=0,0008) ebenfalls zu den ermittelten Risikovarianten für diesen Krankheitsphänotyp. Das Gen BRD7 erhielt den bedeutesten Kandidatengenstatus in dieser Studie, da eine Replikation der assoziierten Genvarianten in einer unabhängigen Studienpopulation erbracht werden konnte. Fünf Einzelbasenpolymorphismen (SNPs) des BRD7-Locus zeigten sowohl in der familien- als auch populationsbasierten Teststatistik eine starke Assoziation mit dem Phänotyp CED (p=0,006-0,003) und eine moderate Bedeutung für die Subphänotypen MC und CU (p=0,03-0,003). Die physikalische Nähe (328Kb) des BRD7-Locus zu dem MC-Krankheitsgen NOD2 wurde als potentieller Einflussfaktor auf die BRD7-Assoziation betrachtet und mittels einer LD-Block-basierten Genotypenpaarung der Patienten und Kontrollindividuen als nicht relevant für den Phänotyp CED und CU beurteilt. Die D’-basierte LD-Analyse der BRD7-NOD2-Region unterstrich diese Annahme durch eine schwache Kopplung der beiden Genloci (D’<=0,2). Einen funktionellen Risikostatus konnte auf der Basis der vorliegenden Untersuchung bisher keinem der fünf Gene zugesprochen werden. Folgestudien zur Untersuchung der Krankheitsrelevanz des BRD7-Locus für die Colitis ulcerosa könnten jedoch insbesondere vor dem Hintergrund der für diesen Phänotyp nicht vorhandenen Assoziation des NOD2-Krankheitsgens von größter Bedeutung sein

Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data.

BACKGROUND The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). METHODS We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. RESULTS We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. CONCLUSIONS Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives

Controversies regarding lithium-associated weight gain: case–control study of real-world drug safety data

Background: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). Methods: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. Results: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. Conclusions: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives

General synovitis score and immunologic synovitis score reflect clinical disease activity in patients with advanced stage rheumatoid arthritis

The purpose of this study was to investigate the relationship between clinical disease activity in patients with advanced stage rheumatoid arthritis (RA) on treatment with Disease Modifying Antirheumatic Drugs (DMARDs) and histopathological scores of synovial inflammation. To this end, synovial biopsies of 62 RA patients who underwent surgery for either synovectomy or total joint arthroplasty were assessed by a general synovitis score (GSS) and an immunologic synovitis score (IMSYC). The clinical disease activity index (CDAI) was significantly correlated with both the GSS and the IMSYC (r = 0.65, p = &lt;0.001, r = 0.68, p = &lt;0.001). Compared to patients with moderate and high disease activity, there was a significantly lower expression of T cell (CD3), B cell (CD20) and neutrophil (CD15) markers in synovial tissue of patients with low activity, but similar expression of the macrophage marker CD68. Subgroup analyses revealed no differences between small and large joints, seropositive and seronegative RA and patients with or without prednisolone treatment. However, we found a significantly stronger correlation of CDAI with IMSYC in patients undergoing arthroplasty (r = 0.82) than in patients undergoing synovectomy (r = 0.55). In addition, there was a stronger correlation of CDAI with GSS in patients treated with methotrexate (r = 0.86) than in patients with TNFα blockade (r = 0.55). In summary, the present study demonstrates that the histopathological scores GSS and IMSYC in general reflect clinical disease activity in patients with advanced stage rheumatoid arthritis, but that there is some heterogeneity between subgroups of patients within the cohort. In the future, molecular characterization of synovial inflammatory cell populations, including plasma cell infiltrates, will help to further defined clinically important subtypes of RA and treatment response

Looking While Unhappy: A Mood-Congruent Attention Bias Toward Sad Adult Faces in Children

A negative mood-congruent attention bias has been consistently observed, for example, in clinical studies on major depression. This bias is assumed to be dysfunctional in that it supports maintaining a sad mood, whereas a potentially adaptive role has largely been neglected. Previous experiments involving sad mood induction techniques found a negative mood-congruent attention bias specifically for young individuals, explained by an adaptive need for information transfer in the service of mood regulation. In the present study we investigated the attentional bias in typically developing children (aged 6–12 years) when happy and sad moods were induced. Crucially, we manipulated the age (adult vs. child) of the displayed pairs of facial expressions depicting sadness, anger, fear and happiness. The results indicate that sad children indeed exhibited a mood specific attention bias toward sad facial expressions. Additionally, this bias was more pronounced for adult faces. Results are discussed in the context of an information gain which should be stronger when looking at adult faces due to their more expansive life experience. These findings bear implications for both research methods and future interventions

Apolipoprotein E-dependent load of white matter hyperintensities in Alzheimer’s disease: a voxel-based lesion mapping study

Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer’s disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD. Methods: WM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE ε4 risk allele) was determined globally as well as regionally with voxel-based lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network. Results: WM hyperintensity volume was significantly greater in non-carriers of the APOE ε4 allele. Lesion distribution was similar among ε4 carriers and non-carriers. Only ε4 non-carriers showed a correlation between lesion volume and cognitive performance. Conclusion: The current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE ε4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE ε4-mediated risk

Prefrontal Cortex Glutamate Correlates with Mental Perspective-Taking

Background: Dysfunctions in theory of mind and empathic abilities have been suggested as core symptoms in major psychiatric disorders including schizophrenia and autism. Since self monitoring, perspective taking and empathy have been linked to prefrontal (PFC) and anterior cingulate cortex (ACC) function, neurotransmitter variations in these areas may account for normal and pathological variations of these functions. Converging evidence indicates an essential role of glutamatergic neurotransmission in psychiatric diseases with pronounced deficits in empathy. However, the role of the glutamate system for different dimensions of empathy has not been investigated so far. Methodology/Principal Findings: Absolute concentrations of cerebral glutamate in the ACC, left dorsolateral PFC and left hippocampus were determined by 3-tesla proton magnetic resonance spectroscopy (1H-MRS) in 17 healthy individuals. Three dimensions of empathy were estimated by a self-rating questionnaire, the Interpersonal Reactivity Index (IRI). Linear regression analysis showed that dorsolateral PFC glutamate concentration was predicted by IRI factor ‘‘perspective taking’’ (T = 22.710, p = 0.018; adjusted alpha-level of 0.017, Bonferroni) but not by ‘‘empathic concern’ ’ or ‘‘personal distress’’. No significant relationship between IRI subscores and the glutamate levels in the ACC or left hippocampus was detected. Conclusions/Significance: This is the first study to investigate the role of the glutamate system for dimensions of theory of mind and empathy. Results are in line with recent concepts that executive top-down control of behavior is mediated b

Flüsse als Grenzen und Bindeglieder. Zur Wiederentdeckung des Raumes in der Geschichtswissenschaft

Rüther A. Flüsse als Grenzen und Bindeglieder. Zur Wiederentdeckung des Raumes in der Geschichtswissenschaft. Jahrbuch für Regionalgeschichte . 2007;25:29-44

Reformchronik und Schwesternbuch des St. Galler Katharinenklosters. Möglichkeiten und Aufgaben einer kommentierten Edition

Rüther A. Reformchronik und Schwesternbuch des St. Galler Katharinenklosters. Möglichkeiten und Aufgaben einer kommentierten Edition. In: Miszellen aus dem Schülerkreis. Kaspar Elm dargebracht zum 23. September 1994. Berlin : Freie Universität; 1994: 137-152