Rapid and Bifunctional Chemoselective Metabolome Analysis of Liver Disease Plasma Using the Reagent 4-Nitrophenyl-2H-azirine.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that has been associated with diverse metabolic carboxylic acids. Mass spectrometric techniques are the method of choice for their analysis. However, the broad investigation of this metabolite class remains challenging. Derivatization of carboxylic acids represents a strategy to overcome these limitations but available methods suffer from diverse analytical challenges. Herein, we have designed a novel strategy introducing 4-nitrophenyl-2H-azirine as a new chemoselective moiety for the first time for carboxylic acid metabolites. This moiety was selected as it rapidly forms a stable amide bond and also generates a new ketone, which can be analyzed by our recently developed quant-SCHEMA method specific for carbonyl metabolites. Optimization of this new method revealed a high reproducibility and robustness, which was utilized to validate 102 metabolic carboxylic acids using authentic synthetic standard conjugates in human plasma samples including nine metabolites that were newly detected. Using this sequential analysis of the carbonyl- and carboxylic acid-metabolomes revealed alterations of the ketogenesis pathway, which demonstrates the vast benefit of our unique methodology. We anticipate that the developed azirine moiety with rapid functional group transformation will find broad application in diverse chemical biology research fields.

Design Fluency in Children with ADHD and Comorbid Disorders.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is often associated with frontal executive impairment in children. Oppositional defiant disorder (ODD) and anxiety disorders (AD) frequently accompany ADHD, but the impact of these comorbid disorders on cognition remains elusive. The five-point test (FPT), a design fluency task, has been shown to be sensitive to neurological damage, specifically to frontal lobe lesions in patients with brain injuries. The purpose of this study was to compare the performances of neurotypical children with that of children with ADHD, ADHD-ODD, and ADHD-AD on the FPT in order to examine whether these groups could be distinguished from one another based on their cognitive profile. METHODS: A total of 111 children aged 8 to 11 years old participated in the study. Six measures from the FPT were used to characterize their performance. RESULTS: Statistically significant differences between groups were observed for five of the six FPT measures. Essentially, children with ADHD-ODD made more repeated designs than the three other groups (control p > 0.001, ADHD p = 0.008, ADHD-AD p = 0.008), while children with ADHD-AD produced fewer total and correct designs than the control and ADHD groups (p = 0.009). CONCLUSIONS: This suggests that comorbidities have an additive impact on the cognitive profile of children with ADHD. Design fluency may be a sensitive measure for capturing the subtle cognitive deficits that are likely to be involved in these disorders.