Function of striatum beyond inhibition and execution of motor responses

We used functional magnetic resonance imaging (fMRI) to study the role of the striatum in inhibitory motor control. Subjects had to refrain from responding to designated items (STOP trials) within a similar series of motor stimuli. Striatal activation was increased significantly compared to that when responding to all targets within a series of motor stimuli, indicating that the striatum is more active when inhibitory motor control over responses is required. The likelihood of a STOP trial was varied parametrically by varying the number of GO trials before a STOP trial. We could thus measure the effect of expecting a STOP trial on the fMRI response in the striatum. We show for the first time in humans that the striatum becomes more active when the likelihood of inhibiting a planned motor response increases. Our findings suggest that the striatum is critically involved in inhibitory motor control, most likely by controlling the execution of planned motor responses.     

The predictive validity of subjective adherence measures in patients with schizophrenia

Despite frequent use of subjective adherence measures in patients with schizophrenia as well as other chronic conditions, there are several reports that question the validity of these instruments. Three well known, representative subjective measures are the Medication Adherence Questionnaire (MAQ), the Drug Attitude Inventory (DAI), and the Compliance Rating Scale (CRS). In this study we explored the predictive validity of these instruments in a European sample of 119 stabilized outpatients with schizophrenia. Clinical outcome variables were relapse and admission to a psychiatric hospital during a follow‐up period of 12 months. Results indicate that the predictive validity of all three measures was poor. The MAQ was the least problematic predictor for relapse (Nagelkerke R² = 0.09), and time to relapse (R² = 0.07) and had the best sensitivity for relapse (63.6%) as well as admission (87.5%). The MAQ and CRS were both moderate predictive for admission (Nagelkerke R² = 0.21, and R² = 0.29). We conclude that the validity of the instruments studied here is questionable and have limited clinical relevance. Given the feasibility and ease of most subjective instruments, researchers may be tempted to use them but should be aware of the serious drawbacks of these instruments. Copyright © 2011 John Wiley & Sons, Ltd.     

Task-evoked reconfiguration of the fronto-parietal network is associated with cognitive performance in brain tumor patients

Brain Imaging and Behavior - In healthy participants, the strength of task-evoked network reconfigurations is associated with cognitive performance across several cognitive domains. It is, however,...     

Haemodynamic effects of patent foramen ovale and atrial septal defect closure: a comparison during percutaneous shunt closure

Objectives: We investigated the haemodynamic effect of percutaneous closure of an intra‐atrial shunt, using non‐invasive finger pressure measurements. Background: Percutaneous closure of both patent foramen ovale (PFO) and atrial septal defect (ASD) is widely practised. Currently no data are available on short‐term haemodynamic changes induced by closure. Methods: Twenty‐five consecutive patients (mean age 49 ± 17 years, 10 men) who underwent a percutaneous closure of a PFO (n = 15) or ASD (n = 10) were included in this study. During the procedure blood pressure and heart rate (HR) were monitored continuously with a Finometer^®. Changes in systolic, mean, and diastolic pressure, stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) were computed from the pressure registrations using Modelflow^® methodology. Results: Baseline characteristics were similar for the PFO and ASD patients. After PFO closure none of the haemodynamic parameters changed significantly. After ASD closure the systolic, mean, and diastolic pressures increased 7·1 ± 5·4 (P = 0·003), 3·8 ± 3·5 (P = 0·007) and 2·0 ± 3·0 mmHg (P = ns) respectively. HR decreased 5·1 ± 5·3 beats per minute (P = 0·01). SV, CO and TPR increased 8·5 ± 6·4 ml (13·5%; P = 0·002), 0·21 ± 0·45 l min^?1 (5·6%; P = ns) and 0·02 ± 0·14 dynes (4·1%; P = ns) respectively. The changes in SV differ between the PFO and ASD patients (P = 0·009). Conclusions: Using non‐invasive finger pressure measurements, we found that SV, mean and systolic blood pressure increased immediately after percutaneous closure of an ASD in adults, whereas the percutaneous PFO closure had no effect on haemodynamic characteristics.     

Evidence for genetic heterogeneity in D‐2‐hydroxyglutaric aciduria

We performed molecular, enzyme, and metabolic studies in 50 patients with D ‐2‐hydroxyglutaric aciduria (D ‐2‐HGA) who accumulated D ‐2‐hydroxyglutarate (D ‐2‐HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D ‐2‐hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D ‐2‐hydroxyglutarate dehydrogenase (D ‐2‐HGDH). Enzyme assay of D ‐2‐HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D ‐2‐HGA whose enzyme activity was normal did not have mutations. Significantly lower D ‐2‐HG concentrations in body fluids were observed in mutation‐positive D ‐2‐HGA patients than in mutation‐negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D ‐2‐HG. Accordingly, we suggest a new classification: D ‐2‐HGA Type I associates with D ‐2‐HGDH deficiency, whereas idiopathic D ‐2‐HGA manifests with normal D ‐2‐HGDH activity and higher D ‐2‐HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D ‐2‐HGA patients with diverse genetic loci will be revealed in future studies. Hum Mutat 31:1–5, 2010. © 2009 Wiley‐Liss, Inc.     

Influence of the TP53 codon 72 polymorphism on the cellular responses to X-irradiation in fibroblasts from nonagenarians

In mice, genetic modification of the gene encoding p53 affects both cancer incidence and longevity. In humans, we recently found that a TP53 codon 72 Arginine (Arg) to Proline (Pro) polymorphism affected both cancer incidence and longevity as well. The TP53 codon 72 polymorphism has previously been shown to influence the apoptotic potential of human cells in response to oxidative stress. Here, we studied the influence of this polymorphism on the cellular responses to X-irradiation of fibroblasts obtained from nonagenarians. We found that the average clonogenic survival after X-irradiation was similar for the three TP53 codon 72 genotype groups. As described before, X-irradiation did not induce an appreciable degree of apoptosis in human fibroblasts. However, percentages of senescence-associated (SA)-β-galactosidase positive cells (p < 0.001), micronucleated cells (p < 0.001) and cells displaying abnormal nuclear morphologies (p < 0.001) significantly increased with the radiation dose. Compared to Arg/Arg fibroblasts, Pro/Pro fibroblasts exhibited higher irradiation dose-dependent increases in SA-β-galactosidase positive cells (p_interaction = 0.018), micronucleated cells (p_interaction = 0.005) and cells displaying abnormal nuclear morphologies (p_interaction = 0.029) at 3 days after irradiation. Possibly, these differences in cellular responses to stress between the TP53 codon 72 genotypes contribute to the differences in cancer incidence and longevity observed earlier for these genotypes.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.