Untargeted analysis of plasma samples from pre-eclamptic women reveals polar and apolar changes in the metabolome

Introduction Pre-eclampsia is a hypertensive gestational disorder that affects approximately 5% of all pregnancies. Objectives As the pathophysiological processes of pre-eclampsia are still uncertain, the present case–control study explored underlying metabolic processes characterising this disease. Methods Maternal peripheral plasma samples were collected from pre-eclamptic (n = 32) and healthy pregnant women (n = 35) in the third trimester. After extraction, high-resolution mass spectrometry-based untargeted metabolomics was used to profile polar and apolar metabolites and the resulting data were analysed via uni- and multivariate statistical approaches. Results The study demonstrated that the metabolome undergoes substantial changes in pre-eclamptic women. Amongst the most discriminative metabolites were hydroxyhexacosanoic acid, diacylglycerols, glycerophosphoinositols, nicotinamide adenine dinucleotide metabolites, bile acids and products of amino acid metabolism. Conclusions The putatively identified compounds provide sources for novel hypotheses to help understanding of the underlying biochemical pathology of pre-eclampsia.

Postmortem studies in schizophrenia

For over a century, postmortem studies have played a central part in the search for the structural and biochemical pathology of schizophrenia. However, for most of this time, little progress has been made. Recently, the situation has begun to change, helped by the emergence of more powerful methodologies and research designs, and by the availability of brain imaging to provide complementary information. As a result, it can now be clearly concluded that there are structural cerebral abnormalities in schizophrenia that are intrinsic to the disorder. The neuropathological process is not primarily degenerative, but involves a change in the normal cytoarchitecture of the brain, probably originating in development. Neurochemically, there is postmortem evidence for alterations in several transmitter systems including dopamine, glutamate, serotonin, and γ-aminobutyric acid (GABA). The cardinal findings are reviewed here, together with a consideration of the conceptual and methodological issues that face postmortem studies of schizophrenia.

Effect of l-alanine infusion on 31P nuclear magnetic resonance spectra of normal human liver: towards biochemical pathology in vivo

1. 31P n.m.r. spectroscopy in vivo was used to study the effect of l-alanine infusion on the concentrations of gluconeogenic intermediates in normal human liver. Studies were performed in six healthy male subjects (34–44 years, fasted overnight) using a chemical shift imaging pulse sequence on a whole-body n.m.r. system operating at 1.6T. Hepatic 31P n.m.r. spectra were obtained from 10 min before to 70 min after intravenous administration of 0.70 (n = 2), 1.40 (n = 3) or 2.80 (n = 5) nmol of l-alanine/kg body weight over 4.5 min. Concentrations of phosphomonoesters, Pi and phosphodiesters relative to ATP were calculated from peak areas in the n.m.r. spectra, using the β-ATP peak as a reference. 2. Dose-dependent spectral changes were observed for [phosphomonoesters]/[ATP] and [Pi]/[ATP]. At the highest dose given, maximal changes in [phosphomonoesters]/[ATP] (mean ± sem: 98 ± 12%, P<0.005) and [Pi]/[ATP] (−33 ± 3%, P<0.001) were observed approximately 45 min after the l-alanine infusion. [Phosphodiesters]/[ATP] showed a maximal increase of 24 ± 6% (P<0.05), which was independent of the l-alanine dose. Hepatic ATP levels and pH did not change. 3. To identify the metabolites responsible for the changes observed in vivo, male Wistar rats were infused with 11.2 mmol of l-alanine/kg body weight. After 15 min, livers were freeze-clamped and were extracted according to standard procedures. In vitro, 31P n.m.r. spectra obtained at 8.4 or 11.7 T revealed sharp increases in the concentrations of 3-phosphoglycerate and phosphoenolpyruvate after l-alanine infusion. No significant increases in other metabolites contributing to the phosphomonoester or phosphodiester resonances in vivo were observed, suggesting that the rise in [phosphomonoesters] observed in vivo was caused by increasing concentrations of 3-phosphoglycerate, and that phosphoenolpyruvate contributed to the rise in [phosphodiesters]. 5. These results show that l-alanine infusion leads to consistent changes in the 31P n.m.r. spectra of the human liver owing to increased concentrations of gluconeogenic intermediates. The ‘n.m.r.-alanine test’ may constitute a useful tool for studies of gluconeogenesis and hepatic biochemical pathology in vivo.