The Experts below are selected from a list of 359904 Experts worldwide ranked by ideXlab platform
Damian J. Tyler - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial krebs Cycle Activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Julian L Griffin, Helen J. Atherton, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle Activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle Activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle Activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial krebs Cycle Activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Julian L Griffin, Helen J. Atherton, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle Activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle Activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle Activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle Activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
Richard A. Yost - One of the best experts on this subject based on the ideXlab platform.
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lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid Cycle Activity
American Journal of Physiology-endocrinology and Metabolism, 2016Co-Authors: Rainey E. Patterson, Srilaxmi Kalavalapalli, Caroline M. Williams, Manisha Nautiyal, Justin T. Mathew, Janie Martinez, Mary K. Reinhard, Danielle J. Mcdougall, James R. Rocca, Richard A. YostAbstract:The hepatic tricarboxylic acid (TCA) Cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative fl...
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Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid Cycle Activity
American journal of physiology. Endocrinology and metabolism, 2016Co-Authors: Rainey E. Patterson, Srilaxmi Kalavalapalli, Caroline M. Williams, Manisha Nautiyal, Justin T. Mathew, Janie Martinez, Mary K. Reinhard, Danielle J. Mcdougall, James R. Rocca, Richard A. YostAbstract:The hepatic tricarboxylic acid (TCA) Cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux through the TCA Cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA Cycle. Mice (C57/BL6) were fed a high-trans-fat high-fructose diet (TFD) for 8 wk to induce simple steatosis and NASH by 24 wk. In vivo fasting hepatic mitochondrial fluxes were determined by(13)C-nuclear magnetic resonance (NMR)-based isotopomer analysis. Hepatic metabolic intermediates were quantified using mass spectrometry-based targeted metabolomics. Hepatic triglyceride accumulation and insulin resistance preceded alterations in mitochondrial metabolism, since TCA Cycle fluxes remained normal during simple steatosis. However, mice with NASH had a twofold induction (P< 0.05) of mitochondrial fluxes (μmol/min) through the TCA Cycle (2.6 ± 0.5 vs. 5.4 ± 0.6), anaplerosis (9.1 ± 1.2 vs. 16.9 ± 2.2), and pyruvate cycling (4.9 ± 1.0 vs. 11.1 ± 1.9) compared with their age-matched controls. Induction of the TCA Cycle Activity during NASH was concurrent with blunted ketogenesis and accumulation of hepatic diacylglycerols (DAGs), ceramides (Cer), and long-chain acylcarnitines, suggesting inefficient oxidation and disposal of excess free fatty acids (FFA). Sustained induction of mitochondrial TCA Cycle failed to prevent accretion of "lipotoxic" metabolites in the liver and could hasten inflammation and the metabolic transition to NASH.
Michael Boshart - One of the best experts on this subject based on the ideXlab platform.
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Procyclic Trypanosoma brucei do not use Krebs Cycle Activity for energy generation.
Journal of Biological Chemistry, 2003Co-Authors: Susanne W. H. Van Weelden, Beate Fast, Achim M. Vogt, Pieter Van Der Meer, Joachim Saas, Jaap J. Van Hellemond, Aloysius G.m. Tielens, Michael BoshartAbstract:Abstract The importance of a functional Krebs Cycle for energy generation in the procyclic stage of Trypanosoma brucei was investigated under physiological conditions during logarithmic phase growth of a pleomorphic parasite strain. Wild type procyclic cells and mutants with targeted deletion of the gene coding for aconitase were derived by synchronous in vitrodifferentiation from wild type and mutant (Δaco::NEO/Δaco::HYG) bloodstream stage parasites, respectively, where aconitase is not expressed and is dispensable. No differences in intracellular levels of glycolytic and Krebs Cycle intermediates were found in procyclic wild type and mutant cells, except for citrate that accumulated up to 90-fold in the mutants, confirming the absence of aconitase Activity. Surprisingly, deletion of aconitase did not change differentiation nor the growth rate or the intracellular ATP/ADP ratio in those cells. Metabolic studies using radioactively labeled substrates and NMR analysis demonstrated that glucose and proline were not degraded via the Krebs Cycle to CO2. Instead, glucose was degraded to acetate, succinate, and alanine, whereas proline was degraded to succinate. Importantly, there was absolutely no difference in the metabolic products released by wild type and aconitase knockout parasites, and both were for survival strictly dependent on respiration via the mitochondrial electron transport chain. Hence, although the Krebs Cycle enzymes are present, procyclic T. brucei do not use Krebs Cycle Activity for energy generation, but the mitochondrial respiratory chain is essential for survival and growth. We therefore propose a revised model of the energy metabolism of procyclic T. brucei.
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Procyclic Trypanosoma brucei do not use Krebs Cycle Activity for energy generation.
The Journal of biological chemistry, 2003Co-Authors: Susanne W. H. Van Weelden, Beate Fast, Achim M. Vogt, Pieter Van Der Meer, Joachim Saas, Jaap J. Van Hellemond, Aloysius G.m. Tielens, Michael BoshartAbstract:The importance of a functional Krebs Cycle for energy generation in the procyclic stage of Trypanosoma brucei was investigated under physiological conditions during logarithmic phase growth of a pleomorphic parasite strain. Wild type procyclic cells and mutants with targeted deletion of the gene coding for aconitase were derived by synchronous in vitro differentiation from wild type and mutant (Delta aco::NEO/Delta aco::HYG) bloodstream stage parasites, respectively, where aconitase is not expressed and is dispensable. No differences in intracellular levels of glycolytic and Krebs Cycle intermediates were found in procyclic wild type and mutant cells, except for citrate that accumulated up to 90-fold in the mutants, confirming the absence of aconitase Activity. Surprisingly, deletion of aconitase did not change differentiation nor the growth rate or the intracellular ATP/ADP ratio in those cells. Metabolic studies using radioactively labeled substrates and NMR analysis demonstrated that glucose and proline were not degraded via the Krebs Cycle to CO(2). Instead, glucose was degraded to acetate, succinate, and alanine, whereas proline was degraded to succinate. Importantly, there was absolutely no difference in the metabolic products released by wild type and aconitase knockout parasites, and both were for survival strictly dependent on respiration via the mitochondrial electron transport chain. Hence, although the Krebs Cycle enzymes are present, procyclic T. brucei do not use Krebs Cycle Activity for energy generation, but the mitochondrial respiratory chain is essential for survival and growth. We therefore propose a revised model of the energy metabolism of procyclic T. brucei.
Michael S. Dodd - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial krebs Cycle Activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Julian L Griffin, Helen J. Atherton, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle Activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle Activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle Activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial krebs Cycle Activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Julian L Griffin, Helen J. Atherton, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle Activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle Activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle Activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle Activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
Julian L Griffin - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial krebs Cycle Activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Julian L Griffin, Helen J. Atherton, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle Activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle Activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle Activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial krebs Cycle Activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Julian L Griffin, Helen J. Atherton, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle Activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle Activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle Activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle Activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
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Group I and II metabotropic glutamate receptors alter brain cortical metabolic and glutamate/glutamine Cycle Activity: a 13C NMR spectroscopy and metabolomic study
Journal of Neurochemistry, 2005Co-Authors: Charbel El-hajj Moussa, Trent Wallis, William A Bubb, Julian L Griffin, Vladimir J BalcarAbstract:Metabotropic glutamate receptors (mGluR) modulate neuronal function. Here, we tested the effect on metabolism of a range of Group I and II mGluR ligands in Guinea pig brain cortical tissue slices, applying 13C NMR spectroscopy and metabolomic analysis using multivariate statistics. The effects of Group I agonists (S)-3,5-dihydroxyphenylglycine (DHPG) and (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) depended upon concentration and were mostly stimulatory, increasing both net metabolic flux through the Krebs Cycle and glutamate/glutamine Cycle Activity. Only the higher (50 µm) concentrations of CHPG had the opposite effect. The Group I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), consistent with its neuroprotective role, caused significant decreases in metabolism. With principal components analysis of the metabolic profiles generated by these ligands, the effects could be separated by two principal components. Agonists at Group II mGluR [(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG IV) and 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC)] generally stimulated metabolism, including glutamate/glutamine cycling, although this varied with concentration. The antagonist (2S)-α-ethylglutamic acid (EGLU) stimulated astrocyte metabolism with minimal impact on glutamate/glutamine cycling. (RS)-1-Aminophosphoindan-1-carboxylic acid (APICA) decreased metabolism at 5 µm but had a stimulatory effect at 50 µm. All ligand effects were separated from control and from each other using two principal components. The ramifications of these findings are discussed.
