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Chronic severe somatoform disorder (SFD) is resistant to treatment. In a prospective observational study, we evaluated an intensive multidisciplinary treatment focusing on body-related mentalization and acceptance. Patients included in the study were 183 (146 women, 37 men) of 311 eligible patients with chronic severe SFD, referred consecutively to a specialized tertiary care center between 2002 and 2009. Primary outcome measures were somatic symptoms (SCL-90) and health-related quality of life (EuroQol 5-Dimensional [EQ-5D]). These measures were assessed four times before treatment (on intake, twice during an observation period, at start of treatment) and four times after treatment (during follow-up for 2 years). Multilevel analysis was used to separate effects of time (maturation) and treatment. Results revealed significant improvements in SCL-90 somatic symptoms (d = 0.51), EQ-5D index (d = 0.27), and EQ visual analogue scale (d = 0.56). Significant reductions were also observed in SCL-90 anxiety, depression, and overall psychopathology as well as in medical consumption associated with psychiatric illness (Trimbos/iMTA Questionnaire for Costs Associated With Psychiatric Illness). Large interindividual differences were found in treatment outcome. The long-term improvement seen in many patients suggests that intensive multidisciplinary tertiary care treatment is a useful approach to chronic severe SFD

Prospective Analysis in GIST Patients on the Role of Alpha-1 Acid Glycoprotein in Imatinib Exposure

Background: For imatinib, a relationship between systemic exposure and clinical outcome has been suggested. Importantly, imatinib concentrations are not stable and decrease over time, for which several mechanisms have been suggested. In this study, we investigated if a decrease in alpha-1 acid glycoprotein (AGP) is the main cause of the lowering in imatinib exposure over time. Methods: We prospectively measured imatinib trough concentration (Cmin) values in 28 patients with gastrointestinal stromal tumours, at 1, 3 and 12 months after the start of imatinib treatment. At the same time points, AGP levels were measured. Results: Overall, imatinib Cmin and AGP levels were correlated (r2 = 0.656; P < 0.001). However, AGP levels did not fluctuate significantly over time, nor did the change in AGP levels correlate with the change in the imatinib Cmin. Conclusion: We showed that systemic AGP levels are not likely to be a key player in the decrease in systemic imatinib exposure over time. As long as intra-individual changes in imatinib exposure remain unexplained, researchers should standardize the sampling times for imatinib in order to be able to assess the clinical applicability of therapeutic drug monitoring

Fremdheitskonstruktion durch politische Entscheidungsprozesse - wer zugewandert ist, bleibt fremd!

Fremdheitskonstruktionen durch politische Entscheidungsprozesse – wer zugewandert ist, bleibt fremd! Ziele der Dissertation sind anhand der politischen Entscheidungsprozesse Green Card, Kopftuchdebatte, Zuwanderungsgesetz, Deutsche Islamkonferenz und dem Nationalen Integrationsgipfel in den Jahren 1998-2009, die Entscheidungsprozesse im politischen Zentrum und in der medialen Betrachtung inhaltlich zu analysieren. Eine zentrale These der Arbeit lautet, das nur über die konstante Behandlung und Sichtung der Diskurse in den Kontrollmedien Bild, FAZ, SZ, Taz und in den politischen Programmen, die Tragweite der Konstruktionen, ein Demokratiedefizit und die Schieflage im Diskurs zu Tage treten, die zu diesen Fremdheitskonstruktionen führen. Das theoretische Fundament bilden die Luhmannschen Überlegungen zum Mediendiskurs und eine Erweiterung des Schleusenmodells von Habermas/Peters hin zu einem Öffentlichkeitsmodell, um die komplexen Prozesse erfassen zu können, die politische Entscheidungsprozesse und den öffentlichen Diskurs darüber bestimmen

Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination

Background and purpose Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels

Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients

The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen Cmax and area under the curve (AUC)0–8 h were 20 % higher (P max was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0–24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen

How well do computer-generated faces tap face expertise?

The use of computer-generated (CG) stimuli in face processing research is proliferating due to the ease with which faces can be generated, standardised and manipulated. However there has been surprisingly little research into whether CG faces are processed in the same way as photographs of real faces. The present study assessed how well CG faces tap face identity expertise by investigating whether two indicators of face expertise are reduced for CG faces when compared to face photographs. These indicators were accuracy for identification of own-race faces and the other-race effect (ORE)-the well-established finding that own-race faces are recognised more accurately than other-race faces. In Experiment 1 Caucasian and Asian participants completed a recognition memory task for own- and other-race real and CG faces. Overall accuracy for own-race faces was dramatically reduced for CG compared to real faces and the ORE was significantly and substantially attenuated for CG faces. Experiment 2 investigated perceptual discrimination for own- and other-race real and CG faces with Caucasian and Asian participants. Here again, accuracy for own-race faces was significantly reduced for CG compared to real faces. However the ORE was not affected by format. Together these results signal that CG faces of the type tested here do not fully tap face expertise. Technological advancement may, in the future, produce CG faces that are equivalent to real photographs. Until then caution is advised when interpreting results obtained using CG faces

Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex genetic alterations in cervical cancer

BACKGROUND: Cervical carcinoma develops as a result of multiple genetic alterations. Different studies investigated genomic alterations in cervical cancer mainly by means of metaphase comparative genomic hybridization (mCGH) and microsatellite marker analysis for the detection of loss of heterozygosity (LOH). Currently, high throughput methods such as array comparative genomic hybridization (array CGH), single nucleotide polymorphism array (SNP array) and gene expression arrays are available to study genome-wide alterations. Integration of these 3 platforms allows detection of genomic alterations at high resolution and investigation of an association between copy number changes and expression. RESULTS: Genome-wide copy number and genotype analysis of 10 cervical cancer cell lines by array CGH and SNP array showed highly complex large-scale alterations. A comparison between array CGH and SNP array revealed that the overall concordance in detection of the same areas with copy number alterations (CNA) was above 90%. The use of SNP arrays demonstrated that about 75% of LOH events would not have been found by methods which screen for copy number changes, such as array CGH, since these were LOH events without CNA. Regions frequently targeted by CNA, as determined by array CGH, such as amplification of 5p and 20q, and loss of 8p were confirmed by fluorescent in situ hybridization (FISH). Genome-wide, we did not find a correlation between copy-number and gene expression. At chromosome arm 5p however, 22% of the genes were significantly upregulated in cell lines with amplifications as compared to cell lines without amplifications, as measured by gene expression arrays. For 3 genes, SKP2, ANKH and TRIO, expression differences were confirmed by quantitative real-time PCR (qRT-PCR). CONCLUSION: This study showed that copy number data retrieved from either array CGH or SNP array are comparable and that the integration of genome-wide LOH, copy number and gene expression is useful for the identification of gene specific targets that could be relevant for the development and progression in cervical cancer