RESUMEN
Metabolomics studies of disease conditions related to chronic alcohol consumption provide compelling evidence of several perturbed metabolic pathways underlying the pathophysiology of alcoholism. The objective of the present study was to utilize proton nuclear magnetic resonance (1H-NMR) spectroscopy metabolomics to study the holistic metabolic consequences of acute alcohol consumption in humans. The experimental design was a cross-over intervention study which included a number of substances to be consumed-alcohol, a nicotinamide adenine dinucleotide (NAD) supplement, and a benzoic acid-containing flavoured water vehicle. The experimental subjects-24 healthy, moderate-drinking young men-each provided six hourly-collected urine samples for analysis. Complete data sets were obtained from 20 of the subjects and used for data generation, analysis and interpretation. The results from the NMR approach produced complex spectral data, which could be resolved sufficiently through the application of a combination of univariate and multivariate methods of statistical analysis. The metabolite profiles resulting from acute alcohol consumption indicated that alcohol-induced NAD+ depletion, and the production of an excessive amount of reducing equivalents, greatly perturbed the hepatocyte redox homeostasis, resulting in essentially three major metabolic disturbances-up-regulated lactic acid metabolism, down-regulated purine catabolism and osmoregulation. Of these, the urinary excretion of the osmolyte sorbitol proved to be novel, and suggests hepatocyte swelling due to ethanol influx following acute alcohol consumption. Time-dependent metabolomics investigations, using designed interventions, provide a way of interpreting the variation induced by the different factors of a designed experiment, thereby also giving methodological significance to this study. The outcomes of this approach have the potential to significantly advance our understanding of the serious impact of the pathophysiological perturbations which arise from the consumption of a single, large dose of alcohol-a simulation of a widespread, and mostly naive, social practice.
Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Etanol/administración & dosificación , Redes y Vías Metabólicas/fisiología , Adulto , Ácido Benzoico/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Humanos , Masculino , Redes y Vías Metabólicas/efectos de los fármacos , Metabolómica/métodos , Espectroscopía de Protones por Resonancia Magnética/métodos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Adulto JovenRESUMEN
Metabolomics studies of diseases associated with chronic alcohol consumption provide compelling evidence of several perturbed metabolic pathways. Moreover, the holistic approach of such studies gives insights into the pathophysiological risk factors associated with chronic alcohol-induced disability, morbidity and mortality. Here, we report on a GC-MS-based organic acid profiling study on acute alcohol consumption. Our investigation - involving 12 healthy, moderate-drinking young men - simulated a single binge drinking event, and indicated its metabolic consequences. We generated time-dependent data that predicted the metabolic pathophysiology of the alcohol intervention. Multivariate statistical modelling was applied to the longitudinal data of 120 biologically relevant organic acids, of which 13 provided statistical evidence of the alcohol effect. The known alcohol-induced increased NADH:NAD+ ratio in the cytosol of hepatocytes contributed to the global dysregulation of several metabolic reactions of glycolysis, ketogenesis, the Krebs cycle and gluconeogenesis. The significant presence of 2-hydroxyisobutyric acid supports the emerging paradigm that this compound is an important endogenous metabolite. Its metabolic origin remains elusive, but recent evidence indicated 2-hydroxyisobutyrylation as a novel regulatory modifier of histones. Metabolomics has thus opened an avenue for further research on the reprogramming of metabolic pathways and epigenetic networks in relation to the severe effects of alcohol consumption.
Asunto(s)
Consumo de Bebidas Alcohólicas/orina , Ácidos Carboxílicos/orina , Etanol/metabolismo , Redes y Vías Metabólicas , Metabolómica , Biomarcadores/metabolismo , Biomarcadores/orina , Ácidos Carboxílicos/metabolismo , Ciclo del Ácido Cítrico , Etanol/toxicidad , Cromatografía de Gases y Espectrometría de Masas , Glucólisis , Humanos , Cinética , Masculino , Factores de Tiempo , Adulto JovenRESUMEN
Benzoic acid is widely used as a preservative in food products and is detoxified in humans through glycine conjugation. Different viewpoints prevail on the physiological significance of the glycine conjugation reaction and concerns have been raised on potential public health consequences following uncontrolled benzoic acid ingestion. We performed a metabolomics study which used commercial benzoic acid containing flavored water as vehicle for designed interventions, and report here on the controlled consumption of the benzoic acid by 21 cases across 6 time points for a total of 126 time points. Metabolomics data from urinary samples analyzed by nuclear magnetic resonance spectroscopy were generated in a time-dependent cross-over study. We used ANOVA-simultaneous component analysis (ASCA), repeated measures analysis of variance (RM-ANOVA) and unfolded principal component analysis (unfolded PCA) to supplement conventional statistical methods to uncover fully the metabolic perturbations due to the xenobiotic intervention, encapsulated in the metabolomics tensor (three-dimensional matrices having cases, spectral areas and time as axes). Identification of the biologically important metabolites by the novel combination of statistical methods proved the power of this approach for metabolomics studies having complex data structures in general. The study disclosed a high degree of inter-individual variation in detoxification of the xenobiotic and revealed metabolic information, indicating that detoxification of benzoic acid through glycine conjugation to hippuric acid does not indicate glycine depletion, but is supplemented by ample glycine regeneration. The observations lend support to the view of maintenance of glycine homeostasis during detoxification. The study indicates also that time-dependent metabolomics investigations, using designed interventions, provide a way of interpreting the variation induced by the different factors of a designed experiment-an approach with potential to advance significantly our understanding of normal and pathophysiological perturbations of endogenous or exogenous origin.
Asunto(s)
Ácido Benzoico/metabolismo , Glicina/metabolismo , Inactivación Metabólica , Metaboloma , Metabolómica , Adulto , Análisis por Conglomerados , Voluntarios Sanos , Humanos , Masculino , Redes y Vías Metabólicas , Metabolómica/métodos , Espectroscopía de Protones por Resonancia Magnética , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Identifying the etiologies of real or perceived adverse clinical events and undesired outcomes is an important step in improving patient safety and reducing malpractice risks. Systematic analysis of obstetrics and gynecology-related risk management files allows a more complete examination of ways that human and systems factors may contribute to adverse events. OBJECTIVE: To learn the medical complaints of patients who experienced apparent adverse events, the general causes of those adverse events, and the significant specific causal factors involved in obstetrics and gynecology-related risk management cases. METHODS: This was a retrospective analysis of 90 consecutive obstetrics and gynecology-related internal review files opened by a medical center's risk managers between 1995 and 2001. Each file was analyzed to identify factors that may have contributed to or caused unanticipated adverse events. The main outcome was the pattern of contributing factors when they were aggregated into categories. RESULTS: Fifty percent of cases were associated with inpatient obstetrics. Factors that may have contributed to adverse events were identified in 78% of cases, and most had more than one contributing factor. Thirty-one percent of adverse events were associated with apparent communication problems. Clinical performance issues were identified in 31% of cases, diagnostic issues in 18% of cases, and patient behavior contributed to 14% of adverse events. CONCLUSION: Diagnostic, therapeutic, and communication issues were the most common factors identified. Although the generalizability of these data are unknown, all obstetrics and gynecology departments face multiple challenges in assuring consistent quality care. Analysis of claims files may help identify opportunities for improvement.
Asunto(s)
Ginecología/normas , Enfermedad Iatrogénica/epidemiología , Auditoría Médica , Errores Médicos/estadística & datos numéricos , Obstetricia/normas , Gestión de Riesgos , Estudios de Cohortes , Medicina Defensiva/métodos , Femenino , Ginecología/estadística & datos numéricos , Hospitales Universitarios/estadística & datos numéricos , Humanos , Mala Praxis/estadística & datos numéricos , Errores Médicos/clasificación , Obstetricia/estadística & datos numéricos , Relaciones Médico-Paciente , Embarazo , Estudios Retrospectivos , Análisis de Sistemas , Tennessee/epidemiologíaRESUMEN
OBJECTIVES: Identifying the etiologies of adverse outcomes is an important first step in improving patient safety and reducing malpractice risks. However, relatively little is known about the causes of emergency department-related adverse outcomes. The objective was to describe a method for identification of common causes of adverse outcomes in an emergency department. This methodology potentially can suggest ways to improve care and might provide a model for identification of factors associated with adverse outcomes. METHODS: This was a retrospective analysis of 74 consecutive files opened by a malpractice insurer between 1995 and 2000. Each risk-management file was analyzed to identify potential causes of adverse outcomes. The main outcomes were rater-assigned codes for alleged problems with care (e.g., failures of communication or problems related to diagnosis). RESULTS: About 50% of cases were related to injuries or abdominal complaints. A contributing cause was found in 92% of cases, and most had more than one contributing cause. The most frequent contributing categories included failure to diagnose (45%), supervision problems (31%), communication problems (30%), patient behavior (24%), administrative problems (20%), and documentation (20%). Specific relating factors within these categories, such as lack of timely resident supervision and failure to follow policies and procedures, were identified. CONCLUSIONS: This project documented that an aggregate analysis of risk-management files has the potential to identify shared causes related to real or perceived adverse outcomes. Several potentially correctable systems problems were identified using this methodology. These simple, descriptive management tools may be useful in identifying issues for problem solving and can be easily learned by physicians and managers.