Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy

Background An early objective biomarker to predict the severity of hypoxic-ischaemic encephalopathy (HIE) and identify infants suitable for intervention remains elusive. This thesis aims to progress metabolomic markers of HIE through a pipeline of biomarker discovery and validation by employing a novel untargeted mass spectrometry metabolomic method. Methodology Term infants with perinatal asphyxia were recruited, all having umbilical cord blood (UCB) drawn and biobanked within three hours of birth. HIE was defined by Sarnat score at 24hours and continuous multichannel-EEG. Infant neurodevelopment was assessed at 36-42 months using the Bayley Scales of Infant and Toddler Development Ed. III (BSID-III). Untargeted metabolomic analysis of UCB was performed using direct injection FT-ICR mass spectrometry (DI FT-ICR MS). Putative metabolite annotations and lipid classes were assigned and pathway analysis was performed. Results Untargeted metabolomic analysis: Thirty enrolled infants were diagnosed with HIE, including 17 mild, 8 moderate, and 5 severe cases. Pathway analysis revealed that ΔHIE was associated with a 50% and 75% perturbation of tryptophan and pyrimidine metabolism respectively, alongside alterations in amino acid pathways. Significant metabolite alterations were detected from six putatively identified lipid classes including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids and prenol lipids. Outcome prediction: Metabolite model scores significantly correlated with outcome R=0.429 (model A) and R=0.549 (model B) respectively. Model B demonstrates the potential to predict both severe outcome (AUROC of 0.915) and intact survival (AUROC of 0.800). The effect of haemolysis: On average 5% of polar and 1.5% of non-polar features were altered between paired haemolysed and clean samples. However unsupervised multivariate analysis concluded that the preanalytical variability introduced by haemolysis was negligible compared with the inherent biological inter-individual variability. Conclusion This research has employed untargeted metabolomics to identify potential early cord blood biomarkers of HIE and has performed the technical validation of previously proposed markers.

Oral glutamate intake reduces acute and chronic effects of ethanol in rodents

Purpose: To assess the effects of oral glutamate intake on acute motor effects and chronic intake of ethanol in rodents. Methods: The acute effects of ethanol on motor function were studied in ICR mice by giving 2 or 6 g/kg of ethanol 2 h after distilled water or 2.5 g/kg glutamate per os. Thirty minutes after ethanol treatment, behavioral assays, including rotarod tests and foot print analysis were monitored. In chronic ethanol treatment, male Wistar rats were trained to consume ethanol-sucrose solution during a 2-h period daily, starting with 2 % ethanol/10 % sucrose and gradually increasing to 10 % ethanol/5 % sucrose solution over 56 days. After training session, the drug treatment phase was done for 10 days. The animals were force-fed 50 mg/kg/day topiramate or 2.5 g/kg/day glutamate 2 h before ethanol treatment sessions. Each day, ethanol intake, water intake, food intake and body weight were recorded. Results: Mice that received 2 or 6 g/kg of ethanol orally, showed a significant reduction in time on the rod in the rotarod test and a significant increase in both forelimb and hindlimb stride lengths when compared to control. Oral treatment with 2.5 g/kg of glutamate reversed the acute motor effects of ethanol. In chronic ethanol treatment, the intake of 10 % ethanol/5 % sucrose, accessible for 2 h, was significantly decreased in rats treated with either topiramate or glutamate. Conclusion: These results provide evidence that oral glutamate administration help to reduce the acute motor effects of ethanol in mice and ethanol intake in the chronic ethanol drinking rats.

Performance determinants For Swedish Financial Monetary Institutions: Panel Data evidence between 2010-2014.

Due to the rapid changes that governs the Swedish financial sector such as financial deregulations and technological innovations, it is imperative to examine the extent to which the Swedish Financial institutions had performed amid these changes. For this to be accomplish, the work investigates what are the determinants of performance for Swedish Financial Monetary Institutions? Assumptions were derived from theoretical and empirical literatures to investigate the authenticity of this research question using seven explanatory variables. Two models were specified using Returns on Asset (ROA) and Return on Equity (ROE) as the main performance indicators and for the sake of reliability and validity, three different estimators such as Ordinary Least Square (OLS), Generalized Least Square (GLS) and Feasible Generalized Least Square (FGLS) were employed. The Akaike Information Criterion (AIC) was also used to verify which specification explains performance better while performing robustness check of parameter estimates was done by correcting for standard errors. Based on the findings, ROA specification proves to have the lowest Akaike Information Criterion (AIC) and Standard errors compared to ROE specification. Under ROA, two variables; the profit margins and the Interest coverage ratio proves to be statistically significant while under ROE just the interest coverage ratio (ICR) for all the estimators proves significant. The result also shows that the FGLS is the most efficient estimator, then follows the GLS and the last OLS. when corrected for SE robust, the gearing ratio which measures the capital structure becomes significant under ROA and its estimate become positive under ROE robust. Conclusions were drawn that, within the period of study three variables (ICR, profit margins and gearing) shows significant and four variables were insignificant. The overall findings show that the institutions strive to their best to maximize returns but these returns were just normal to cover their costs of operation. Much should be done as per the ASC theory to avoid liquidity and credit risks problems. Again, estimated values of ICR and profit margins shows that a considerable amount of efforts with sound financial policies are required to increase performance by one percentage point. Areas of further research could be how the individual stochastic factors such as the Dupont model, repo rates, inflation, GDP etc. can influence performance.