The effect of liver warm ischaemia reperfusion injury and modulation on bile composition evaluated by magnetic resonance spectroscopy

Orthotopic liver transplantation has become the preferred treatment for a variety of end-stage liver disease. As competency and survival rates increase, so does increasing demand, which puts greater strain on a static donor pool. This increases pressure to accept more marginal grafts, e.g. non-heart-beating and steatotic donors. However, graft dysfunction post-transplantation contributes considerably to postoperative morbidity and mortality. Proton nuclear magnetic resonance (1HNMR) spectroscopy is a powerful technique to explore the biochemical composition of biological fluids; it is rapid, non-invasive, nondestructive and it can detect metabolites at millimolar concentrations. In this study, 1HNMR assessed the changes in bile composition during liver ischaemia/reperfusion. The primary hypothesis was that bile composition changes during liver ischaemia reperfusion injury (IRI). The aims were to document these changes, identify biliary markers for liver IRI using 1HNMR, validate these markers using known modulators, determine if the same was true for steatotic livers and attempt to understand the mechanisms by which these changes happen in relation to the redox state of the liver. Materials and methods: A rabbit model of hepatic lobar IRI was used. In most experiments 3 groups were used (n=6): Sham group (laparotomy alone), I/R group (1hr ischaemia and 6hrs reperfusion), and a modulation group similar to I/R with the addition of N-acetylcysteine (I/R+NAC: 150mg/kg of NAC) and glycine (I/R+glycine: 5mg/kg glycine). Steatosis was induced by feeding with a 2% cholesterol diet for 8 weeks. Experiments were repeated on steatotic animals with Sham, I/R, I/R+NAC and IPC+I/R (5min ischaemia followed by 10min of reperfusion before prolonged ischaemia was induced) groups. The following parameters were measured: portal blood flow, bile flow (BF) and bile 1HNMR spectroscopy, hepatic microcirculation, intracellular tissue oxygenation, serum ALT, AST and ICG clearance were measured at 1, 2, 5 and 7 hours following reperfusion. Results: Bile spectroscopy demonstrated significant changes in bile composition following I/R and alterations with NAC, glycine and IPC. These changes are evident despite a constant post-reperfusion rate of BF. They were also present in steatotic livers, and were modulated by NAC and IPC. In experiment 1: BF, COX and biliary acetate decreased following I/R while AST, ALT, biliary PC and lactate increased along with PMN accumulation in sinusoids, KC hypertrophy, necrosis and apoptosis in normal livers. In experiment 2: BF, COX and biliary acetate decreased following I/R while ALT, PC, conjugated bile acids and lactate increased in the I/R group in normal livers. NAC administration attenuated the increase in ALT and lactate following I/R in the NAC+I/R group compared to the I/R group. Changes in conjugated bile acids seem to reflect changes in BF. In experiment 3: I/R+glycine was associated with increased BF, bile acid, acetate, pyruvate, glucose, acetoacetate, and decreased bile lactate and PC levels in normal livers. In experiment 4: NAC administration in steatotic livers reduced the extent of IRI, increased portal blood flow and liver parenchymal perfusion. NAC increased BF, biliary acetate and pyruvate and reduced acute liver injury, ALT and biliary PC. In experiment 5: IPC protected the steatotic liver from IRI and maintained hepatic oxygenation, tissue perfusion and mitochondrial redox state. COX activity was decreased by IRI in the fatty liver, but can was protected by IPC. Conclusions: This thesis has demonstrated changes in bile composition during warm normal liver I/R and its modulation with NAC and glycine. It has also demonstrated changes in bile composition during warm steatotic liver I/R and its modulation with NAC and IPC. It has noted several metabolites that are consistently changed, as well as the bile redox ratio of metabolites that provides a clearer indication of liver redox state than individual metabolites

V2O5/SiO2 as an efficient catalyst in the synthesis of 5-amino- pyrazole derivatives under solvent free condition

An efficient and facile approach for the synthesis of 5-aminopyrazoles from ketene S,N-acetal and hydrazine hydrate via catalytic reaction under solvent free condition has been described. V2O5/SiO2 as a heterogeneous catalyst was prepared and characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM).               KEY WORDS: One-pot synthesis, 5-Amino-1H-pyrazole, Hydrazine hydrate, Vanadium oxide, Silica Bull. Chem. Soc. Ethiop. 2019, 33(1), 135-142DOI: https://dx.doi.org/10.4314/bcse.v33i1.13

A modified least squares formulation for a system of first order equations

Second order equations in terms of auxiliary variables similar to potential and stream functions are obtained by applying a weighted least squares formulation to a first order system. The additional boundary conditions which are necessary to solve the higher order equations are determined and numerical results are presented for the Cauchy-Riemann equations

Analysis of the convergence history of fluid flow through nozzles with shocks

Convergence of iterative methods for the solution of the steady quasi-one-dimensional nozzle problem with shocks is considered. The finite-difference algorithms obtained from implicit schemes are used to approximate both the Euler and Navier-Stokes Equations. These algorithms are investigated for stability and convergence characteristics. The numerical methods are broken down into their matrix-vector components and then analyzed by examining a subset of the eigensystem using a method based on the Arnoldi process. The eigenvalues obtained by this method are accurate to within 5 digits for the largest ones and to within 2 digits for the ones smaller in magnitude compared the elgenvalues obtained using the full Jacobian. In the analysis we examine the functional relationship between the numerical parameters and the rate of convergence of the iterative scheme. Acceleration techniques for iterative methods like Wynn\u27s e-algorithm are also applied to these systems of difference equations in order to accelerate their convergence. This acceleration translates into savings in the total number of iterations and thus the total amount of computer time required to obtain a converged solution. The rate of convergence of the accelerated system is found to agree with the prediction based on the eigenvalues of the original iteration matrix. The ultimate goal of this study is to extend this elgenvalue analysis to multi-dimensional problems and to quantitatively estimate the effects of different parameters on the rate of convergence

Lafora Disease Masquerading as Hepatic Dysfunction

Lafora disease is fatal intractable progressive myoclonic epilepsy. It is frequently characterized by epileptic seizures, difficulty walking, muscle spasms, and dementia in late childhood or adolescence. We chronicle here an unusual case of an asymptomatic young male soccer player who presented with elevated liver enzymes. Neurological examination was unremarkable. The diagnostic workup for hepatitis, infectious etiologies, autoimmune disorders, hemochromatosis, Wilson\u27s disease, alpha-1 antitrypsin deficiency, and other related diseases was inconclusive. He subsequently underwent an uneventful percutaneous liver biopsy. Based on the pathognomonic histopathological findings, Lafora disease was considered the likely etiology. The present study is a unique illustration of this rare disorder initially manifesting with abnormal liver enzymes. It underscores the importance of clinical suspicion of Lafora disease in cases with unexplained hepatic dysfunction. Prompt liver biopsy and genetic testing should be performed to antedate the onset of symptoms in these patients

From Gapped Excitons to Gapless Triplons in One Dimension

Often, exotic phases appear in the phase diagrams between conventional phases. Their elementary excitations are of particular interest. Here, we consider the example of the ionic Hubbard model in one dimension. This model is a band insulator (BI) for weak interaction and a Mott insulator (MI) for strong interaction. Inbetween, a spontaneously dimerized insulator (SDI) occurs which is governed by energetically low-lying charge and spin degrees of freedom. Applying a systematically controlled version of the continuous unitary transformations (CUTs) we are able to determine the dispersions of the elementary charge and spin excitations and of their most relevant bound states on equal footing. The key idea is to start from an externally dimerized system using the relative weak interdimer coupling as small expansion parameter which finally is set to unity to recover the original model.Comment: 18 pages, 10 figure

Detecting Heart Attacks Using Learning Classifiers

Cardiovascular diseases (CVDs) have emerged as a critical global threat to human life. The diagnosis of these diseases presents a complex challenge, particularly for inexperienced doctors, as their symptoms can be mistaken for signs of aging or similar conditions. Early detection of heart disease can help prevent heart failure, making it crucial to develop effective diagnostic techniques. Machine Learning (ML) techniques have gained popularity among researchers for identifying new patients based on past data. While various forecasting techniques have been applied to different medical datasets, accurate detection of heart attacks in a timely manner remains elusive. This article presents a comprehensive comparative analysis of various ML techniques, including Decision Tree, Support Vector Machines, Random Forest, Extreme Gradient Boosting (XGBoost), Adaptive Boosting, Multilayer Perceptron, Gradient Boosting, K-Nearest Neighbor, and Logistic Regression. These classifiers are implemented and evaluated in Python using data from over 300 patients obtained from the Kaggle cardiovascular repository in CSV format. The classifiers categorize patients into two groups: those with a heart attack and those without. Performance evaluation metrics such as recall, precision, accuracy, and the F1-measure are employed to assess the classifiers’ effectiveness. The results of this study highlight XGBoost classifier as a promising tool in the medical domain for accurate diagnosis, demonstrating the highest predictive accuracy (95.082%) with a calculation time of (0.07995 sec) on the dataset compared to other classifiers

Genome-wide identification and predictive modeling of tissue-specific alternative polyadenylation

MOTIVATION: Pre-mRNA cleavage and polyadenylation are essential steps for 3'-end maturation and subsequent stability and degradation of mRNAs. This process is highly controlled by cis-regulatory elements surrounding the cleavage/polyadenylation sites (polyA sites), which are frequently constrained by sequence content and position. More than 50% of human transcripts have multiple functional polyA sites, and the specific use of alternative polyA sites (APA) results in isoforms with variable 3'-untranslated regions, thus potentially affecting gene regulation. Elucidating the regulatory mechanisms underlying differential polyA preferences in multiple cell types has been hindered both by the lack of suitable data on the precise location of cleavage sites, as well as of appropriate tests for determining APAs with significant differences across multiple libraries. RESULTS: We applied a tailored paired-end RNA-seq protocol to specifically probe the position of polyA sites in three human adult tissue types. We specified a linear-effects regression model to identify tissue-specific biases indicating regulated APA; the significance of differences between tissue types was assessed by an appropriately designed permutation test. This combination allowed to identify highly specific subsets of APA events in the individual tissue types. Predictive models successfully classified constitutive polyA sites from a biologically relevant background (auROC = 99.6%), as well as tissue-specific regulated sets from each other. We found that the main cis-regulatory elements described for polyadenylation are a strong, and highly informative, hallmark for constitutive sites only. Tissue-specific regulated sites were found to contain other regulatory motifs, with the canonical polyadenylation signal being nearly absent at brain-specific polyA sites. Together, our results contribute to the understanding of the diversity of post-transcriptional gene regulation. AVAILABILITY: Raw data are deposited on SRA, accession numbers: brain SRX208132, kidney SRX208087 and liver SRX208134. Processed datasets as well as model code are published on our website: http://www.genome.duke.edu/labs/ohler/research/UTR/