Metabolomics reveals the metabolic map of procainamide in humans and mice

Procainamide, a type I antiarrhythmic agent, is used to treat a variety of atrial and ventricular dysrhythmias. It was reported that long-term therapy with procainamide may cause lupus erythematosus in 25-30% of patients. Interestingly, procainamide does not induce lupus erythematosus in mouse models. To explore the differences in this side-effect of procainamide between humans and mouse models, metabolomic analysis using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) was conducted on urine samples from procainamide-treated humans, CYP2D6-humanized mice, and wild-type mice. Thirteen urinary procainamide metabolites, including nine novel metabolites, derived from P450-dependent, FMO-dependent oxidations and acylation reactions, were identified and structurally elucidated. In vivo metabolism of procainamide in CYP2D6-humanized mice as well as in vitro incubations with microsomes and recombinant P450s suggested that human CYP2D6 plays a major role in procainamide metabolism. Significant differences in N-acylation and N-oxidation of the drug between humans and mice largely account for the interspecies differences in procainamide metabolism. Significant levels of the novel N-oxide metabolites produced by FMO1 and FMO3 in humans might be associated with the development of procainamide-induced systemic lupus erythematosus. Observations based on this metabolomic study offer clues to understanding procainamide-induced lupus in humans and the effect of P450s and FMOs on procainamide N-oxidation.

A second generation radiation hybrid map to aid the assembly of the bovine genome sequence

BACKGROUND: Several approaches can be used to determine the order of loci on chromosomes and hence develop maps of the genome. However, all mapping approaches are prone to errors either arising from technical deficiencies or lack of statistical support to distinguish between alternative orders of loci. The accuracy of the genome maps could be improved, in principle, if information from different sources was combined to produce integrated maps. The publicly available bovine genomic sequence assembly with 6x coverage (Btau_2.0) is based on whole genome shotgun sequence data and limited mapping data however, it is recognised that this assembly is a draft that contains errors. Correcting the sequence assembly requires extensive additional mapping information to improve the reliability of the ordering of sequence scaffolds on chromosomes. The radiation hybrid (RH) map described here has been contributed to the international sequencing project to aid this process. RESULTS: An RH map for the 30 bovine chromosomes is presented. The map was built using the Roslin 3000-rad RH panel (BovGen RH map) and contains 3966 markers including 2473 new loci in addition to 262 amplified fragment-length polymorphisms (AFLP) and 1231 markers previously published with the first generation RH map. Sequences of the mapped loci were aligned with published bovine genome maps to identify inconsistencies. In addition to differences in the order of loci, several cases were observed where the chromosomal assignment of loci differed between maps. All the chromosome maps were aligned with the current 6x bovine assembly (Btau_2.0) and 2898 loci were unambiguously located in the bovine sequence. The order of loci on the RH map for BTA 5, 7, 16, 22, 25 and 29 differed substantially from the assembled bovine sequence. From the 2898 loci unambiguously identified in the bovine sequence assembly, 131 mapped to different chromosomes in the BovGen RH map. CONCLUSION: Alignment of the BovGen RH map with other published RH and genetic maps showed higher consistency in marker order and chromosome assignment than with the current 6x sequence assembly. This suggests that the bovine sequence assembly could be significantly improved by incorporating additional independent mapping information.

Human intervertebral disc stiffness correlates better with the Otsu threshold computed from axial T2 map of its posterior annulus fibrosus than with clinical classifications

Degeneration of the intervertebral disc, sometimes associated with low back pain and abnormal spinal motions, represents a major health issue with high costs. A non-invasive degeneration assessment via qualitative or quantitative MRI (magnetic resonance imaging) is possible, yet, no relation between mechanical properties and T2 maps of the intervertebral disc (IVD) has been considered, albeit T2 relaxation time values quantify the degree of degeneration. Therefore, MRI scans and mechanical tests were performed on 14 human lumbar intervertebral segments freed from posterior elements and all soft tissues excluding the IVD. Degeneration was evaluated in each specimen using morphological criteria, qualitative T2 weighted images and quantitative axial T2 map data and stiffness was calculated from the load-deflection curves of in vitro compression, torsion, lateral bending and flexion/extension tests. In addition to mean T2, the OTSU threshold of T2 (TOTSU), a robust and automatic histogram-based method that computes the optimal threshold maximizing the distinction of two classes of values, was calculated for anterior, posterior, left and right regions of each annulus fibrosus (AF). While mean T2 and degeneration schemes were not related to the IVDs' mechanical properties, TOTSU computed in the posterior AF correlated significantly with those classifications as well as with all stiffness values. TOTSU should therefore be included in future degeneration grading schemes.

Psychomotor symptoms of schizophrenia map on the cerebral motor circuit

Schizophrenia is a devastating disorder thought to result mainly from cerebral pathology. Neuroimaging studies have provided a wealth of findings of brain dysfunction in schizophrenia. However, we are still far from understanding how particular symptoms can result from aberrant brain function. In this context, the high prevalence of motor symptoms in schizophrenia such as catatonia, neurological soft signs, parkinsonism, and abnormal involuntary movements is of particular interest. Here, the neuroimaging correlates of these motor symptoms are reviewed. For all investigated motor symptoms, neural correlates were found within the cerebral motor system. However, only a limited set of results exists for hypokinesia and neurological soft signs, while catatonia, abnormal involuntary movements and parkinsonian signs still remain understudied with neuroimaging methods. Soft signs have been associated with altered brain structure and function in cortical premotor and motor areas as well as cerebellum and thalamus. Hypokinesia is suggested to result from insufficient interaction of thalamocortical loops within the motor system. Future studies are needed to address the neural correlates of motor abnormalities in prodromal states, changes during the course of the illness, and the specific pathophysiology of catatonia, dyskinesia and parkinsonism in schizophrenia.