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At least 109 records · Page 6Linked to original sources
PubMed1998

Increased vulnerability to 3-nitropropionic acid in an animal model of Huntington's disease.

There is substantial evidence for both metabolic dysfunction and oxidative damage in Huntington's disease (HD). In the present study, we used in vivo microdialysis to measure the conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of hydroxyl radical production in a transgenic mouse model of HD, as well as in littermate controls. The conversion of 4-hydroxybenzoic acid to 3,4-DHBA was unchanged in the striatum of transgenic HD mice at baseline. Following administration of the mitochondrial toxin 3-nitropropionic acid (3-NP), there were significant increases in 3,4-DHBA generation in both control and transgenic HD mice, and the increases in the transgenic HD mice were significantly greater than those in controls. Furthermore, administration of 3-NP produced significantly larger striatal lesions in transgenic HD mice than in littermate controls. The present results show increased sensitivity to the mitochondrial toxin 3-NP in transgenic HD mice, which suggests metabolic dysfunction in this mouse model of HD.

Animals↗
PubMed1981

Disorders of glutamate metabolism and neurological dysfunction.

Disorders of glutamate metabolism are associated with profound alteration of CNS function. Although the precise biochemical mechanisms responsible for nervous system dysfunction in most of these disorders are unknown, it can be concluded that biochemical aberrations in the metabolism of glutamate usually result in malfunction of the CNS. As with most disorders of amino acid metabolism that are associated with brain dysfunction, the molecular mechanisms underlying pathogenesis of these disorders remain obscure. Why do some biochemically affected individuals remain free of significant neurological involvement? The explanation that the accumulation of a specific metabolite is responsible for the pathogenesis of a disease process does not answer this and may frequently prove to be incorrect. More complete descriptions of these disorders of glutamate metabolism and their attendant neurological dysfunction will be required before any firm linkage between the biochemical defects and the clinical manifestations of the disease processes can be established. In addition, a much greater knowledge of the control mechanisms regulating glutamate metabolism in the CNS will be needed before the complexities of these disorders can be fully understood. Finally, the dual role of glutamate metabolites as intermediates in crucial pathways of metabolism and as neurotransmitters modulating electrical signals stresses the complexity and importance of glutamate metabolism in CNS function.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis.

OBJECTIVE: To ascertain the effect of delayed tumor necrosis factor alpha (TNF-alpha) on the evolution of systemic and pulmonary injury after the onset of sepsis. DESIGN: Prospective controlled trial. INTERVENTION: Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti-TNF-alpha monoclonal antibody (5 mg/kg). Control animals received 0.9% saline. RESULTS: Delayed anti-TNF-alpha treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P < .05 by t test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (+/- SEM) plasma lactate levels at 5 hours compared with baseline values (3.8 +/- 0.7 vs 2 +/- 0.4, P < .05), but remained unchanged from baseline following anti-TNF-alpha treatment (1.5 +/- 0.1 vs 1.6 +/- 0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti-TNF-alpha treatment and was associated with downregulation (P < .05 by t test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P < .05 by t test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (+/- SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti-TNF-alpha animals (septic animals at 5 hours compared with baseline value, 1044 +/- 270 vs 149 +/- 28 micrograms/mL; control animals at 5 hours compared with baseline value, 217 +/- 83 vs 129 +/- 19 micrograms/mL; P < .05 by t test and analysis of variance). CONCLUSIONS: These data show that delayed anti-TNF-alpha treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti-TNF-alpha treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti-TNF-alpha treatment in clinical practice.

Acidosis, Lactic↗
PubMed1993

Effects of K+ channel openers on ischemic dysfunction and metabolic disturbance in isolated perfused rat heart.

The effects of two structurally different K+ channel openers, KRN2391 and cromakalim, on cardiac mechanisms during ischemia and reperfusion were studied in isolated perfused rat hearts. Isolated buffer-perfused rat hearts pretreated with KRN2391, cromakalim and vehicle were subjected to 25 min of ischemia followed by 30 min of reperfusion. Before ischemia, KRN2391 (1-10 microM) and cromakalim (1-10 microM) increased coronary flow, but did not modify cardiac function or biochemical parameters (adenine nucleotides, energy charge potential: ECP, lactate). During ischemia, KRN2391 (3, 10 microM) and cromakalim (10 microM) significantly accelerated the reduction in cardiac function and attenuated the decreased levels of ATP and ECP, but did not change the lactate content. After 30 min of reperfusion, pretreatment with KRN2391 and cromakalim resulted in a significant improvement in cardiac function, ischemic contracture and biochemical parameters. Thus, both KRN2391 and cromakalim have beneficial effects on biochemical parameters during ischemia and reperfusion, effects which may be related to cardiodepression during ischemia.

Animals↗
PubMed2001

Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation.

BACKGROUND/AIMS: Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large overdoses or intravenous misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3A. METHODS: We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and its toxicity in isolated rat hepatocytes and treated mice. RESULTS: Whereas norbuprenorphine had few mitochondrial effects, buprenorphine (25-200 microM) concentrated in mitochondria, collapsed the membrane potential, inhibited beta-oxidation, and both uncoupled and inhibited respiration in rat liver mitochondria. Both buprenorphine and norbuprenorphine (200 microM) underwent CYP3A-mediated covalent binding to rat liver microsomal proteins and both caused moderate glutathione depletion and increased cell calcium in isolated rat hepatocytes, but only buprenorphine also depleted cell adenosine triphosphate (ATP) and caused necrotic cell death. Four hours after buprenorphine administration to mice (100 nmol/g body weight), hepatic glutathione was unchanged, while ATP was decreased and serum transaminase increased. This transaminase increase was attenuated by a CYP3A inducer and aggravated by a CYP3A inhibitor. CONCLUSIONS: Both buprenorphine and norbuprenorphine undergo metabolic activation, but only buprenorphine impairs mitochondrial respiration and ATP formation. The hepatotoxicity of high concentrations or doses of buprenorphine is mainly related to its mitochondrial effects.

Adenosine Triphosphate↗
PubMed1998

The highly structured climate in families of adolescents with diabetes: functional or dysfunctional for metabolic control?

OBJECTIVE: Compare changes in perceived family climate over time in families with healthy adolescents and families with adolescents with diabetes and analyze the links to metabolic control. METHOD: In a total of four annually conducted surveys, 89 German adolescents with diabetes and 106 healthy adolescents as well as their parents completed the Family Environment Scale (FES). Metabolic control was determined by physicians' reports of adolescents' hemoglobin (HbA1) levels. RESULTS: Compared to families with healthy adolescents, families caring for an adolescent with diabetes portrayed their family interactions as considerably more structured and less cohesive and stimulating. Family climate was not associated with metabolic control and varied little with time, illness duration, and adolescents' gender. CONCLUSIONS: The findings suggest that continued parental monitoring is necessary for good metabolic control. However, a balance must be found between medical adaptation to illness and the adolescent's developmental needs.

Adaptation, Psychological↗
PubMed1998

Perioperative determinants of morbidity and mortality in elderly patients undergoing cardiac surgery.

OBJECTIVE: To determine perioperative predictors of morbidity and mortality in patients > or =75 yrs of age after cardiac surgery. DESIGN: Inception cohort study. SETTING: A tertiary care, 54-bed cardiothoracic intensive care unit (ICU). PATIENTS: All patients aged > or =75 yrs admitted over a 30-month period for cardiac surgery. INTERVENTION: Collection of data on preoperative factors, operative factors, postoperative hemodynamics, and laboratory data obtained on admission and during the ICU stay. MEASUREMENTS AND MAIN RESULTS: Postoperative death, frequency rate of organ dysfunction, nosocomial infections, length of mechanical ventilation, and ICU stay were recorded. During the study period, 1,157 (14%) of 8,501 patients > or =75 yrs of age had a morbidity rate of 54% (625 of 1,157 patients) and a mortality rate of 8% (90 of 1,157 patients) after cardiac surgery. Predictors of postoperative morbidity included preoperative intraaortic balloon counterpulsation, preoperative serum bilirubin of >1.0 mg/dL, blood transfusion requirement of >10 units of red blood cells, cardiopulmonary bypass time of >120 mins (aortic cross-clamp time of >80 mins), return to operating room for surgical exploration, heart rate of >120 beats/min, requirement for inotropes and vasopressors after surgery and on admission to the ICU, and anemia beyond the second postoperative day. Predictors of postoperative mortality included preoperative cardiac shock, serum albumin of <4.0 g/dL, systemic oxygen delivery of <320 mL/ min/m2 before surgery, blood transfusion requirement of >10 units of red blood cells, cardiopulmonary bypass time of >140 mins (aortic cross-clamp time of >120 mins), subsequent return to the operating room for surgical exploration, mean arterial pressure of <60 mm Hg, heart rate of >120 beats/min, central venous pressure of >15 mm Hg, stroke volume index of <30 mL/min/m2, requirement for inotropes, arterial bicarbonate of <20 mmol/L, plasma glucose of >300 mg/dL after surgery, and anemia beyond the second postoperative day. During the study period, the study cohort used 6,859 (21.5%) ICU patient-days out of a total 31,867 ICU patient-days. Nonsurvivors used 2,023 (30%) ICU patient-days and patients with morbidity used 5,903 (86%) ICU patient-days. CONCLUSIONS: Severe underlying cardiac disease (including shock, requirement for mechanical circulatory support, hypoalbuminemia, and hepatic dysfunction), intraoperative blood loss, surgical reexploration, long ischemic times, immediate postoperative cardiovascular dysfunction, global ischemia and metabolic dysfunction, and anemia beyond the second postoperative day predicted poor outcome in the elderly after cardiac surgery. Postoperative morbidity and mortality disproportionately increased the utilization of intensive care resources in elderly patients. Future efforts should focus on preoperative selection criteria, improvement in surgical techniques, perioperative therapy to ameliorate splanchnic and global ischemia, and avoidance of anemia to improve the outcome in the elderly after cardiac surgery.

Aged↗
PubMed1991

Contractile dysfunction during metabolic acidosis: role of impaired energy metabolism.

To investigate the mechanisms by which acidosis depresses cardiac function, a Langendorff isolated perfused rat heart preparation was studied using 31P magnetic resonance spectroscopy. Isolated hearts were subjected to normal perfusion conditions or experimental manipulations simulating severe metabolic acidosis, substrate depletion, impairment of oxidative metabolism, or low perfusate calcium concentrations. All maneuvers resulted in marked reductions in oxygen consumption and the force of myocardial contraction (dP/dt). Metabolic acidosis had bioenergetic changes suggestive of impaired energy production, specifically, increases in Pi and decreases in phosphocreatine concentrations, which did not occur in hearts subjected to low perfusate calcium concentrations. In acidotic perfusions as well as substrate depletion and impairment of oxidative metabolism, the change in dP/dt correlated best with the change in the intracellular concentration of monovalent Pi (P(im)) (r = 0.70, P less than 0.01), whereas in hearts subjected to a low perfusate calcium concentration, there was no relationship between dP/dt and the change in Pim concentrations. More detailed analysis of the time course of the metabolic and physiological changes with metabolic acidosis revealed a discordance between changes in Pim and the decreases in dP/dt during the first 20 min of the induction of acidosis and the first 10 min of recovery from acidosis. These data suggest that metabolic acidosis has a major direct effect on energy metabolism in this model. Moreover, impairment of oxidative metabolism in concert with decreases in intracellular pH may be important in the contractile failure associated with prolonged metabolic acidosis.

Acidosis↗
PubMed1992

[Autonomic dysfunction in metabolic diseases].

Among many metabolic disorders, porphyrias and Fabry disease are known to affect autonomic nervous system. In patients with acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, autonomic symptoms such as abdominal pain, vomiting, hypertension and tachycardia are among the most prominent clinical manifestations. Fabry disease is clinically characterized by severe limb pain, hypohidrosis, angiokeratomas and various autonomic symptoms. In both porphyrias and Fabry disease, pathological changes in the central and peripheral autonomic nervous system have been documented. In porphyrias, a loss of myelinated fibers, axonal degeneration, and segmental demyelination in peripheral autonomic nerves as well as chromatolysis of several brain stem nuclei have been found. In Fabry disease, abnormal amount of the substrates of alpha-galactosidase, i.e. ceramide di- and trihexoside, are found to be accumulated in the central and peripheral autonomic nerves.

Autonomic Nervous System Diseases↗
PubMed1997

Pathogenesis of cardiac dysfunction during metabolic acidosis: therapeutic implications.

Based on work performed in many laboratories including our own, we suggest the following schematic shown in Figure 4 to explain metabolic acidosis and the effects of alkalinization therapy. Metabolic acidosis induces prompt and substantial decreases in cardiac functional performance. This is mediated by an intracellular acidosis which impairs cardiac function directly as well as leads to an impairment of cardiac energy metabolism which further impairs cardiac function. Attempts to alkalinize the cell with sodium bicarbonate therapy lead to a paradoxical intracellular acidosis and further impairment of cardiac function, whereas Carbicarb may correct the intracellular acidosis and improve physiological function. However, at the time which this paper was written, Carbicarb was not available for clinical use in the United States.

Acidosis↗
PubMed1992

[Diabetic cardiopathy. Pathophysiologic concepts and therapeutic approaches].

Epidemiological data reviewed suggest that diabetes itself increases the cardiac risk of diabetics (types I and II), independently from the development of coronary heart disease and in addition to other risk factors (hypertension, hypercholesterolemia, hypertriglyceridemia, smoking and others), presumably by a specific myocardial disease called "diabetic cardiopathy", or according to the recommendations of the WHO, "diabetic heart muscle disease." Disturbances of the left and right ventricular function as well as the autonomic function of the heart can be understood as signs of this specific cardiopathy. The pathophysiological mechanisms underlying this disease are not yet fully known; however, recent evidence is presented that diabetes leads to a facet of metabolic dysfunctions regarding glucose and energy metabolism, calcium homeostasis and the expression of specific proteins that diminish the ability of the heart to respond to increased workload and increase the vulnerability of the heart in diabetes. Since preliminary experimental data indicate that inhibitors of the angiotensin-converting enzyme can protect the heart in diabetes, it is intriguing to suggest that increased release of angiotensin II plays a significant role in the change from reduced adaptability to irreversible damage of the heart in diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Magnetic resonance spectroscopic imaging in temporal lobe epilepsy: neuronal dysfunction or cell loss?

BACKGROUND: Magnetic resonance spectroscopy (MRS) has demonstrated consistent metabolic abnormalities in temporal lobe epilepsy. The reason for decreases in N-acetylated compounds are thought to be related to neuronal hippocampal cell loss as observed in hippocampal sclerosis. However, mounting evidence suggest that the N-acetylated compound decreases may be functional and reversible. OBJECTIVE: To establish whether the metabolic changes measured by MRS correlate to hippocampal cell loss in temporal lobe epilepsy. SUBJECTS AND METHODS: We prospectively performed quantitative hippocampal MR imaging volumetry and MRS imaging in 33 patients with intractable mesial temporal lobe epilepsy who were undergoing surgery. A neuronal-glial ratio of cornu ammonis and fascia dentata was obtained and correlated while validating the pathologic analysis by comparisons with specimens of age-matched autopsy control-case hippocampus (n = 14). RESULTS: The neuronal-glial ratio of the patient group was statistically significantly lower than in the control group for the cornu ammonis region (P<.001). Correlations of hippocampal volumes with cornu ammonis and neuronal-glial ratios revealed a significant interdependence (P<.01). However, correlations of the resected hippocampal creatine-N-acetylated compound ratio with the cornu ammonis or fascia dentata neuronal-glial ratios showed no significant interdependence (P>.8). CONCLUSIONS: Our findings support the concept that the metabolic dysfunction measured by MRS imaging and the hippocampal volume loss detected by MR imaging volumetry do not have the same neuropathologic basis. These findings suggest that the MRS imaging metabolic measures reflect neuronal and glial dysfunction rather than neuronal cell loss as previously assumed.

Adolescent↗
PubMed1990

Pathophysiology of shock.

Shock is an acute widespread reduction in effective tissue perfusion that invokes an imbalance of oxygen supply and demand, anaerobic metabolism, lactic acidosis, cellular and organ dysfunction, metabolic abnormalities, and, if prolonged, irreversible damage and death. The pathophysiologic events in the various types of shock are different and complex with hemodynamic and oxygenation changes, alterations in the composition of the fluid compartments, and various mediators. Shock results from a change in one or a combination of the following: intravascular volume, myocardial function, systemic vascular resistance, or distribution of blood flow. The clinical types of shock include hypovolemic, cardiogenic, distributive (septic), and obstructive. An understanding of the pathophysiologic changes, rapid diagnosis, appropriate monitoring, and appropriate therapy can reduce the high morbidity and mortality in shock states.

Humans↗
PubMedDate not supplied

The effects of ischemia and reperfusion on mucosal respiratory function, adenosine triphosphate, electrolyte, and water content in the ascending colon of ponies.

OBJECTIVE: The purpose of this study was to examine the effects of ischemia and reperfusion on the biochemical integrity of equine colonic mucosa to assess the relative roles of ischemic- and reperfusion-induced damage. STUDY DESIGN: Two hours of no-flow ischemia experimentally induced by 720 degrees counterclockwise ascending colon volvulus followed by 2 hours reperfusion after derotation. ANIMALS: Ten ponies. METHODS: Ascending colon biopsies were obtained every hour for measurement of mucosal adenosine triphosphate (ATP), water, sodium, and potassium content. Additional samples were homogenized for assay of mitochondrial respiratory function. RESULTS: ATP content diminished 92% after ischemia and recovered to only 44% of control levels (P < .001 versus controls) after 2 hours reperfusion. Reperfusion increased mucosal water and decreased sodium and potassium content for the duration of the experiment. Both NADH-(pyruvate) and FADH-linked (succinate) respiration decreased after ischemia and did not recover during reperfusion indicating electron transport chain dysfunction. CONCLUSIONS: Two hours ischemia induced severe metabolic dysfunction in equine colon mucosa which persisted throughout reperfusion. Unequivocal evidence of injury specific to reperfusion was not observed in this study suggesting that much of the damage observed during reperfusion may be a continuation of injury induced during the ischemic period and not specific to reperfusion per se. CLINICAL RELEVANCE: This study suggests that greater efforts to metabolically support ischemically injured mucosa may be an important aspect of obtaining improved survival of horses affected by ascending colon volvulus (ACV).

Adenosine Triphosphate↗