Neural mechanisms of response inhibition and impulsivity in 22q11.2 deletion carriers and idiopathic attention deficit hyperactivity disorder.

•22q11DS offers a compelling model to understand the neural substrates of attentional dysfunction.•First study directly comparing neural function in 22q11DS vs. ADHD patients•22q11DS and ADHD patients show a shared deficit in RI-related activation.•ADHD patients showed greater activity in the middle frontal gyrus than 22q11DS during RI.•Neural activity is inversely correlated with self-reported Cognitive Impulsivity in 22q11DS.

Neural substrates of inhibitory control deficits in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is associated with elevated levels of impulsivity, inattention, and distractibility, which may be related to underlying neurobiological dysfunction due to haploinsufficiency for genes involved in dopaminergic neurotransmission (i.e. catechol-O-methyltransferase). The Stop-signal task has been employed to probe the neural circuitry involved in response inhibition (RI); findings in healthy individuals indicate that a fronto-basal ganglia network underlies successful inhibition of a prepotent motor response. However, little is known about the neurobiological substrates of RI difficulties in 22q11DS. Here, we investigated this using functional magnetic resonance imaging while 45 adult participants (15 22q11DS patients, 30 matched controls) performed the Stop-signal task. Healthy controls showed significantly greater activation than 22q11DS patients within frontal cortical and basal ganglia regions during successful RI, whereas 22q11DS patients did not show increased neural activity relative to controls in any regions. Using the Barratt Impulsivity Scale, we also investigated whether neural dysfunction during RI was associated with cognitive impulsivity in 22q11DS patients. RI-related activity within left middle frontal gyrus and basal ganglia was associated with severity of self-reported cognitive impulsivity. These results suggest reduced engagement of RI-related brain regions in 22q11DS patients, which may be relevant to characteristic behavioral manifestations of the disorder.

Disrupted working memory circuitry and psychotic symptoms in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research suggests that 22q11DS patients exhibit a characteristic neurocognitive phenotype that includes differential impairment in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder, yet little is known about the neurobiological substrates of WM in 22q11DS. In order to investigate the neural systems engaged during spatial WM in 22q11DS patients, we collected functional magnetic resonance imaging (fMRI) data while 41 participants (16 22q11DS patients, 25 demographically matched controls) performed a spatial capacity WM task that included manipulations of delay length and load level. Relative to controls, 22q11DS patients showed reduced neural activation during task performance in the intraparietal sulcus (IPS) and superior frontal sulcus (SFS). In addition, the typical increases in neural activity within spatial WM-relevant regions with greater memory load were not observed in 22q11DS. We further investigated whether neural dysfunction during WM was associated with behavioral WM performance, assessed via the University of Maryland letter-number sequencing (LNS) task, and positive psychotic symptoms, assessed via the Structured Interview for Prodromal Syndromes (SIPS), in 22q11DS patients. WM load activity within IPS and SFS was positively correlated with LNS task performance; moreover, WM load activity within IPS was inversely correlated with the severity of unusual thought content and delusional ideas, indicating that decreased recruitment of working memory-associated neural circuitry is associated with more severe positive symptoms. These results suggest that 22q11DS patients show reduced neural recruitment of brain regions critical for spatial WM function, which may be related to characteristic behavioral manifestations of the disorder.

Three-day intravenous triple therapy is not effective for the eradication of Helicobacter pylori infection in patients with bleeding gastro-duodenal ulcer.

AIM: To test the efficacy of an ultra-short intravenous triple therapy against Helicobacter pylori infection in patients with bleeding peptic ulcer against standard oral 1-week triple therapy in a randomised, double-blind prospective trial. PATIENTS: (n = 75) with haemorrhagic peptic ulcer and H. pylori infection were randomised into: an Intravenous Group to receive omeprazole, clarithromycin and amoxicillin-clavulanic acid intravenously b.d. for 3 days followed by 7 days of oral omeprazole plus placebo of clarithromycin and amoxicillin; an Oral Group to receive intravenous omeprazole plus placebo of clarithromycin and amoxicillin-clavulanic acid followed by 7 days of oral omeprazole, clarithromycin and amoxicillin b.d. Gastric biopsies were obtained for urease test. A 13C-urea breath test was performed to check for H. pylori eradication. RESULTS: Intention-to-treat eradication was 50% (19/38) in the Intravenous Group and 78% (29/37) in the Oral Group (odds ratio 3.63; 95% confidence interval 1.32-9.94; P < 0.01; number needed to treat (NNT) = 4). Per protocol eradication was 50% (14/28) in the Intravenous Group and 86% (24/28) in the Oral Group (P < 0.005). There were no statistically significant differences in adverse events between the two treatment groups. CONCLUSIONS: An ultra-short, 3-day, intravenous, triple therapy containing omeprazole, clarithromycin and amoxicillin-clavulanic acid cannot be recommended as an effective eradication regimen for H. pylori infection related to haemorrhagic gastro-duodenal ulcer.

Analytical evaluation of TDx cyclosporine and metabolites fluorescence polarization immunoassay and comparison with the Cyclo-Trac RIA kit.

The fluorescence polarization immunoassay (FPIA) developed by Abbott Laboratories (TDx system) for the determination of cyclosporine in plasma was evaluated using whole blood as the analytical sample. The coefficients of variation for the within-run and between-run precision ranged from 3.7 to 5.7% and from 5.5 to 7.3%, respectively, for cyclosporine controls ranging in concentration from 200 to 1500 ng/ml. The detection limit was seen to be 26 ng/ml. We used specimens from renal transplant patients who received cyclosporine to compare the TDx assay with the RIA method (Incstar Cyclo-Trac). There was a good correlation between FPIA and RA results (r = 0.91; TDx = 1.29 RIA + 39.13; n = 88). It was concluded that the FPIA is an acceptable and rapid method for patient cyclosporine analysis in whole blood samples. In therapeutic drug monitoring this method offers advantages over the RIA procedure.

Predictive techniques applied to imipramine therapeutic drug monitoring.

The aim of this study was to establish the performance of pharmacokinetic methods employing little data on serum drug concentrations obtained in routine therapeutic drug monitoring of imipramine. Forty-three and 123 serum levels were obtained in 8 adult depressive patients (aged 57-80 y) and 34 enuretic children (aged 5-13 y), respectively. Forecasting of the serum concentrations was performed based on mean population pharmacokinetic parameters (method A), with knowledge of one steady-state serum concentration (method B), and from two or more steady-state serum concentrations (method C). The accuracy and precision of each method were evaluated from the mean prediction error (ME) and from the root mean squared prediction error (RMSE), respectively. The values of ME and RMSE of methods B and C proved to be significantly lower than those found using method A. Method C was the most precise and accurate in both populations. Method A underestimates the serum concentrations observed in adults (ME greater than 0) but overestimates them in children (ME less than 0), although to a lesser extent. The study shows that it is possible to obtain a good estimation of individual dosage needs from one or more serum concentrations obtained at steady state. Clinical application of these methods (B and C) yields an increase in the efficiency and safety of the treatment, particularly in special populations such as geriatric and pediatric patients.