Maternal urinary metabolic signatures of fetal growth and associated clinical and environmental factors in the INMA study

Background Maternal metabolism during pregnancy is a major determinant of the intra-uterine environment and fetal outcomes. Herein, we characterize the maternal urinary metabolome throughout pregnancy to identify maternal metabolic signatures of fetal growth in two subcohorts and explain potential sources of variation in metabolic profiles based on lifestyle and clinical data. Methods We used 1H nuclear magnetic resonance (NMR) spectroscopy to characterize maternal urine samples collected in the INMA birth cohort at the first (n = 412 and n = 394, respectively, in Gipuzkoa and Sabadell cohorts) and third trimesters of gestation (n = 417 and 469). Metabolic phenotypes that reflected longitudinal intra- and inter-individual variation were used to predict measures of fetal growth and birth weight. Results A metabolic shift between the first and third trimesters of gestation was characterized by 1H NMR signals arising predominantly from steroid by-products. We identified 10 significant and reproducible metabolic associations in the third trimester with estimated fetal, birth, and placental weight in two independent subcohorts. These included branched-chain amino acids; isoleucine, valine, leucine, alanine and 3 hydroxyisobutyrate (metabolite of valine), which were associated with a significant fetal weight increase at week 34 of up to 2.4 % in Gipuzkoa (P < 0.005) and 1 % in Sabadell (P < 0.05). Other metabolites included pregnancy-related hormone by-products of estrogens and progesterone, and the methyl donor choline. We could explain a total of 48–53 % of the total variance in birth weight of which urine metabolites had an independent predictive power of 12 % adjusting for all other lifestyle/clinical factors. First trimester metabolic phenotypes could not predict reproducibly weight at later stages of development. Physical activity, as well as other modifiable lifestyle/clinical factors, such as coffee consumption, vitamin D intake, and smoking, were identified as potential sources of metabolic variation during pregnancy. Conclusions Significant reproducible maternal urinary metabolic signatures of fetal growth and birth weight are identified for the first time and linked to modifiable lifestyle factors. This novel approach to prenatal screening, combining multiple risk factors, present a great opportunity to personalize pregnancy management and reduce newborn disease risk in later life

Fundamental noise limitations to supercontinuum generation in microstructure fiber

Broadband noise on supercontinuum spectra generated in microstructure fiber is shown to lead to amplitude fluctuations as large as 50 % for certain input laser pulse parameters. We study this noise using both experimental measurements and numerical simulations with a generalized stochastic nonlinear Schroedinger equation, finding good quantitative agreement over a range of input pulse energies and chirp values. This noise is shown to arise from nonlinear amplification of two quantum noise inputs: the input pulse shot noise and the spontaneous Raman scattering down the fiber.Comment: 16 pages with 6 figure

Application of multidisciplinary optimization methods to the design of a supersonic transport

An optimization design method is discussed. This method is based on integrating existing disciplinary analysis and sensitivity analysis techniques by means of generalized sensitivity equations. A generic design system implementing this method is described. The system is being used to design the configuration and internal structure of a supersonic transport wing for optimum performance. This problem combines the disciplines of linear aerodynamics, structures, and performance. Initial results which include the disciplines of aerodynamics and structures in a conventional minimum weight design under static aeroelastic constraints are presented

Oyster Reef Restoration: Convergence Of Harvest And Conservation Strategies

Oyster reef restoration, protection, and construction are important to meeting harvest, water quality, and fish habitat goals. However, the strategies needed to achieve harvest and conservation goals have often been considered to be at odds. We argue that these goals are. in fact, compatible and that the same strategies will promote a sustainable harvest of the resource, increased filtration of estuarine waters, and increased provision of structured habitat for finfish, crabs, and other organisms that utilize oyster reefs or receive benefit indirectly from them. Creation or designations of unharvested sites (refuge sites) are key components of these strategies. Unharvested reefs have the potential to provide vertical relief, which is typically destroyed by harvest practices, to act as a source of larvae, which potentially increases the supply of harvestable oysters, and to protect those individuals most likely to have some resistance to disease. Furthermore. proper monitoring and design of refuge and restoration efforts are critical to providing information needed to improve the success of future restoration efforts, and will simultaneously enhance the basic information needed to understand the ecology of oysters and their role in estuarine and coastal systems

Economic Interests and the European Union: A Catalyst for European Integration or a Hindrance?

The influence of economic interest groups on national policy-making on European Union-level policy and European integration seems to be case specific and circumstantial. Certain economic interests (for example, pension funds) are so influential that some of them become almost inseparable from the state. However, economic interests are less likely to become influential when broad institutional questions are negotiated, rather than specific rules with a clear cost-benefit balance. And it is especially when they feel challenged by the state that they turn their efforts to EU-level lobbying. The record of economic interest groups in EU policy-making appears also to be mixed. They are influential when they enjoy privileged institutionalised interactions with a policy-making node, such as European Parliament (EP) committees. However, access to the EP has recently become less privileged and institutional advocacy has become more contested, to the disadvantage of interest groups. Many economic interest groups actually obstruct the legislative process with seemingly inconsistent behaviour: they are in favour of European integration in general, but end up lobbying against concrete pieces of legislation if they are costly to them

Unraveling the Effects of Acute Inflammation on Pharmacokinetics: A Model-Based Analysis Focusing on Renal Glomerular Filtration Rate and Cytochrome P450 3A4-Mediated Metabolism

Background and Objectives Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. Methods A physiologically based model incorporating renal and hepatic drug clearance was implemented. Functions correlating IL-6 levels with GFR and in vitro CYP3A4 activity were derived and incorporated into the modeling framework. We then simulated treatment scenarios for hypothetical drugs by varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the concentration-time curve (AUC) was computed for these scenarios. Results Inflammation showed opposite effects on drug exposure for drugs eliminated via the liver and kidney, with the effect of inflammation being inversely proportional to the extraction ratio (ER). For renally cleared drugs, the relative decrease in AUC was close to 30% during severe inflammation. For CYP3A4 substrates, the relative increase in AUC could exceed 50% for low-ER drugs. Finally, the impact of inflammation-induced changes in drug clearance is smaller for drugs with a larger unbound fraction. Conclusion This analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on pharmacokinetics may explain the inter-individual variability in pharmacokinetics in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., by incorporating the effect of inflammation on other drug-metabolizing enzymes or physiological processes

Quantification of Urinary Mevalonic Acid as a Biomarker of HMG-CoA Reductase Activity by a Novel Translational LC-MS/MS Method

Background: Mevalonic acid (MVA), as a product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, represents a potential multipurpose biomarker in health and disease. A translational urinary MVA quantification method was developed, validated and used to demonstrate the diurnal variation of urinary MVA excretion in rats and healthy children. Methods: Urinary MVA was converted to mevalonolactone at pH 2, extracted with ethyl acetate and quantified by reversed-phase liquid chromatography-tandem mass spectrometry. Results: The assay had a dynamic range of 0.0156-10 µg/ml with precision <15% CV, accuracy 85-115% and was transferred between laboratories. Urinary MVA excretion in rats and healthy children displayed a diurnal variation consistent with the known diurnal variation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Conclusion: Urinary MVA can be quantified accurately over a wide dynamic range by a validated translational and transferable method with biomarker capability