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PubMed2005

Fatty acid methyl esters are detectable in the plasma and their presence correlates with liver dysfunction.

BACKGROUND: Methanol is a component of certain alcoholic beverages and is also an endogenously formed product. On this basis, we have proposed that methanol may promote synthesis of fatty acid methyl esters (FAMEs) in the same way that ethanol promotes fatty acid ethyl ester (FAEE) synthesis. We tested the hypothesis that FAMEs appear in the blood after ethanol intake. METHODS: Patient plasma samples obtained from our laboratory (n=78) were grouped according to blood ethanol concentrations (intoxicated, blood ethanol >800 mg/l) and non-intoxicated. These samples were further subdivided into groups based on whether the patient had normal or abnormal liver function tests (abnormal, defined as > or =1 abnormality of plasma alanine and aspartate aminotransferase, albumin, total bilirubin, and alkaline phosphatase). A separate set of plasma samples were also divided into normal and abnormal groups based on pancreatic function tests (amylase and lipase). There were no patients with detectable ethanol in this group. Patients with abnormalities in pancreatic function tests were included upon recognition of endogenously produced FAMEs by patients with liver function test abnormalities. FAMEs were extracted from plasma and individual species of FAMEs quantified by gas chromatography-mass spectrometry (GC/MS). RESULTS: Increased concentrations of FAME were found in patient samples with evidence of liver dysfunction, regardless of whether or not they were intoxicated (n=21, p=0.01). No significant differences in plasma FAME concentrations were found between patients with normal (n=15) versus abnormal pancreatic function tests (n=22, p=0.72). CONCLUSIONS: The presence of FAMEs in human plasma may be related to the existence of liver disease, and not to blood ethanol concentrations or pancreatic dysfunction. The metabolic pathways associated with FAME production in patients with impaired liver function remain to be identified.

Esters↗
PubMed2005

Neuroprotective effects of the aqueous extract of the Chinese medicine Danggui-Shaoyao-san on aged mice.

Danggui-Shaoyao-san (DSS), a famous Chinese complex prescription, has been widely used for gynecological and obstetrical purposes for a long time, and recently it has gained much attention due to its therapeutic efficacy for senile dementia. In the present study, the effects of aqueous extract of Danggui-Shaoyao-san on naturally aged mice were examined to investigate the pharmacological basis for its therapeutic efficacy on senile dementia. The results showed that DSS significantly prolonged latency in a step-through test and increased brain index so as to improve impaired cognitive function of aged mice after oral administration at doses of 250 and 500 mg/kg for 3 months. Using high-performance liquid chromatography technique with electrochemical detection (HPLC-ECD), it was found that DSS increased the content of monoamine neurotransmitters such as norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in brains of aged mice. Using transmission electron microscope, it was found that DSS dose-dependently protected the ultrastructure of brain cortex in aged mice. These results indicate that DSS ameliorates memory dysfunction, modulates metabolism of monoamine neurotransmitters and protects the ultrastructure of cortex changed by aging. These findings suggest that DSS may be a useful therapeutic agent for senile dementia, especially Alzheimer's disease (AD).

Aging↗
PubMed2003

A model to predict the development of mental status changes of unclear cause after liver transplantation.

Postoperative mental status changes are common after liver transplantation (LT). A clear cause of these mental status changes cannot be identified in a significant proportion of patients. In adult liver transplant recipients, our goals are to: (1) identify independent predictors for the development of post-LT mental status changes of unclear cause and (2) derive a practical formula to predict the risk for developing this complication by using simple clinical parameters. Eligible patients had documented mental status changes of at least 3 days' duration, occurring within 1 month of LT. Exclusion criteria were known structural brain disorders, major organ dysfunction, or metabolic causes of altered mentation. Age- and sex-matched controls were liver transplant recipients without post-LT neurological sequelae. Data were collected on preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were performed to detect factors predictive of the development of post-LT mental status of unclear cause. There were 40 cases and 40 controls. Independent predictors of mental status changes of unclear cause included alcoholic and metabolic liver diseases; pre-LT mechanical ventilation; Model for End-Stage Liver Disease (MELD) score greater than 15; and nonelective LT. Using these four preoperative factors, a simple predictive rule was developed. Risk for developing altered mental status of unclear cause after LT was 78% to 89% if all four predictors were present versus 0.8% to 2.4% if no predictors were present. In conclusion, alcoholic and metabolic liver diseases, pre-LT mechanical ventilation, MELD score greater than 15, and nonelective LT are independent predictive factors for post-LT altered mental status changes of unclear cause. A simple model can be used to calculate the risk for developing altered mental status post-LT.

Case-Control Studies↗
PubMed2004

Correlation between some metabolic markers of vascular risk and carotid artery intima-media thickness in postmenopausal women.

UNLABELLED: AIM AND SETTING: This study investigated correlations between insulinemia, insulin sensitivity, body mass index, lipids and lipoproteins with intima-media thickness in a group of 25 (age range 40-55 years) postmenopausal women (minimum duration of menopause 2 years) not on hormone replacement treatment. METHODOLOGY: Uni and multivariate correlations showed a direct relationship between insulin pattern, insulin sensitivity, body mass index, low density lipoproteins and increased intima-media thickness. RESULTS: Our multivariate correlation results revealed that intima-media thickness is influenced by the associations of the different metabolic functions investigated. Therefore, carotid wall intima-media thickness represents a dependent variable in postmenopausal women for some metabolisms whose dysfunction leads to atherosclerosis. CONCLUSION: This multielement synergy is able to detect cardiovascular risk and may underlie cardiovascular mortality in postmenopausal women.

Adult↗
PubMedDate not supplied

Sensitivity of zebrafish to environmental toxins implicated in Parkinson's disease.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra and movement defects, including bradykinesia, tremor, and postural imbalance. Whereas the etiology and pathogenesis of PD is still poorly understood, studies in animal models are providing important insights. One valuable type of animal model for PD is established by treating animals with PD-inducing neurotoxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. These neurotoxins are thought to inhibit mitochondrial complex I activity leading to oxidative stress, impaired energy metabolism, proteasomal dysfunction, and, eventually, dopamine neuronal loss. However, the genes and pathways that underlie the neurotoxicity of these agents are not known. In this study, we explored the effect of MPTP, rotenone, and paraquat in both adult and larval zebrafish, which are highly amenable to genetic analysis that can lead to the identification of the underlying genes and pathways. Here, we report that adult zebrafish display behavioral alterations, including decreased locomotor activity in response to MPTP, whereas larval zebrafish exhibited developmental, behavioral, and DA sensitivity to these agents. Taken together, these findings suggest that zebrafish could be a valuable model for genetically dissecting the molecular mechanisms underlying the neurotoxicity of PD-inducing agents.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Decreased serum semicarbazide sensitive aminooxidase (SSAO) activity in patients with major depression.

Semicarbazide sensitive aminooxidase (SSAO) is known to interplay with monoamine oxidases (MAO) and several antidepressants. Taking into account the monoamine hypothesis concerning the pathophysiology of depression, the aim of the present pilot study was to evaluate serum SSAO activity in depressed patients. A total of 21 inpatients with major depression and 41 healthy controls were studied. Serum SSAO activity was determined by HPLC on days 1, 5 and 10 of inpatient treatment. At baseline without medication including antidepressants, highly depressed patients (MADRS score>or=30) had significantly decreased serum SSAO activity (mean 385+/-161 mU/l) when compared to healthy controls (mean 526+/-141 mU/l; p=0.003). This SSAO decrease was less pronounced at day 5 and day 10 under an antidepressive drug regime. Decreased serum SSAO activity was observed in patients with major depression, especially in those with high MADRS scores. The present results support the hypothesis of dysfunctional monoaminergic metabolism in the pathogenesis of depressive disorders. The disputable association between depression and monoamine metabolism requires further investigation, particularly with regard to SSAO activity and medication status.

Amine Oxidase (Copper-Containing)↗
PubMed2003

Beneficial effects of L-carnitine in myoblastic C2C12 cells. Interaction with zidovudine.

L-Carnitine is a key molecule in the transfer of fatty acid across mitochondrial membranes. Bioavailable L-carnitine is either provided by an endogeneous biosynthesis or after intestinal absorption of dietary items containing L-carnitine. After intestinal absorption or hepatic biosynthesis, L-carnitine is transferred to organs whose metabolism is dependent upon fatty acid oxidation, such as skeletal muscle. To cross the muscle plasma membrane, there are several transporters involved. Among those transporters, OCTN2 is actually the only one to have been clearly characterized. Zidovudine is a commonly used inhibitor of human immunodeficiency virus (HIV) replication. Zidovudine has many side effects, including induction of myopathy characterized by a metabolic mitochondria dysfunction and a diminution of the muscle L-carnitine content. In this study, we described the characteristics of L-carnitine transport in C2C12 cells. We also demonstrated that zidovudine inhibited the L-carnitine transporter. This inhibition led to a significant reduction of the muscle cell growth. In C2C12 cells, the supplementation of L-carnitine prevented the effects of zidovudine and restored the normal cell growth.

Animals↗
PubMed1995

pH heterogeneity in aged hypertensive rat hearts distinguishes reperfused from persistently ischemic myocardium.

Myocardium reperfused following ischemia may contain regions that are adequately perfused but temporarily dysfunctional or metabolically abnormal, and regions that are persistently ischemic. By examining heterogeneity in the inorganic phosphate (Pi) resonance in 31P NMR spectra obtained for isolated perfused young v old hypertensive rat hearts made globally ischemic and then reperfused, areas of persistent intracellular acidosis (pHi about 6) were distinguished from recovering tissue (pHi about 7). The extent of persistent regional acidosis reported by Pi heterogeneity in the 31P NMR spectrum of the reperfused heart correlates well with (1) whole heart flow deficit measured as coronary flow, (2) the decrease in extracellular (primarily vascular) 23Na NMR resonance area measured using 23Na NMR and shift reagent, and (3) regional flow deficits identified using perfusate-borne dye markers. Persistent intracellular acidosis during reperfusion was observed only in the hearts of aged hypertensive rats, confirming that the vasculature of these animals is more susceptible to ischemic injury than both younger hypertensive rats and age-matched controls. The portion of the heart that is reperfused following only 16 min of global ischemia is metabolically abnormal, showing incomplete recovery of ATP and pH.

Adenosine Triphosphate↗
PubMed1995

Leber hereditary optic neuropathy. Electron microscopy and molecular genetic analysis of a case.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder characterized by bilateral central visual loss typically in early adulthood. Few histopathologic studies, including ultrastructural and molecular genetic analysis, have been reported. METHODS: Ocular tissue was obtained postmortem from an 81-year-old woman with LHON from the Queensland 1 pedigree characterized by mutations at nucleotide positions 4160 and 14484. Routine histopathologic studies, electron microscopy, electron-probe analysis, and molecular genetic analysis were performed. RESULTS: Marked atrophy of the nerve fiber and retinal ganglion cell layers and optic nerves was present. Results of electron microscopic examination demonstrated 1.2 microns electron-dense, double-membrane-bound inclusions, consisting of calcium by electron-probe analysis, in retinal ganglion cells. The optic nerve was homoplasmic for mutations 4160 and 14484. CONCLUSION: Optic nerve and inner retinal atrophy in LHON may be a result of metabolic mitochondrial dysfunction leading to intramitochondrial calcification. Homoplasmy for mitochondrial mutations 4160 and 14484 in the leukocyte/platelet fraction of whole blood may correlate with homoplasmy in the optic nerve.

Aged↗
PubMed2001

An evaluation of thiram toxicity on cultured human skin fibroblasts.

Thiram is widely used in agriculture as a fungicide and, to a lesser extent, as a vulcanizing agent in the rubber industry. In spite of the extensive use of thiram, knowledge on its toxicity and health risk remains limited, and few investigations have been performed to assess specific damage at the cellular and subcellular level. We report here the cytotoxic effects of thiram on cultured human skin fibroblasts. Our results demonstrated that thiram exposure induced a dose- and time-dependent decrease in the viable cell recovery with 100% cell death observed with a concentration of 5.0 mg/l. As judged by morphological changes and biochemical criteria, thiram-mediated cell death was not of the apoptotic but seemed to be of the necrotic type. This cell death was not associated with a modification of gene expression of different constituents of the extracellular matrix. A late increase of lactate production was evident after thiram treatment, suggesting a mitochondrial metabolic pathway dysfunction as reported by other authors using similar compounds. However, this phenomenon appeared as a secondary response to the toxic action of thiram. The cytotoxic effect of thiram is possibly due to an oxidant effect inherent to the structure of thiram and the interaction between thiram and vital cellular molecules.

Adult↗
PubMedDate not supplied

Impact of delayed reperfusion of myocardial hibernation on myocardial ultrastructure and function and their recoveries after reperfusion in a pig model of myocardial hibernation.

UNLABELLED: This study examined the effect of delayed reperfusion of myocardial hibernation from 24 hours to 7 days on myocardial ultrastructural and functional changes and their recoveries after reperfusion. BACKGROUND: We have previously shown in pigs that after reperfusion the functional and structural alterations in short-term myocardial hibernation which was reperfused in 24 hours can recover in 7 days. The effect of delayed reperfusion of hibernating myocardium on the extent and severity of cellular and extracellular structural changes of hibernating myocardium, and their recoveries after reperfusion is not known. METHODS AND RESULTS: A severe LAD stenosis was created in 27 pigs, reducing resting flow by 30-40% immediately after placement of the stenosis and producing acute ischemia as evidenced by regional lactate production, a decrease in regional coronary venous pH, reduced regional wall thickening (from 38.5 +/- 5.1% to 10.4 +/- 8.0%) and a 33% reduction of regional oxygen consumption. The stenosis was maintained either for 24 hours in 9 pigs (group 1) with LAD flow of 0.65 +/- 0.13 ml/min/g (38% reduction), or for 7 days in 17 pigs (group 2) with LAD flow of 0.67 +/- 0.14 ml/min/g (36% reduction). There were no differences (p = NS) in the reduction of wall thickening, rate-pressure product, lactate production, or regional oxygen consumption between group 1 and group 2. Quantitative morphometric evaluation of the ultrastructure on electromicrographs revealed a greater decrease in sarcomere volume and a higher incidence of myocytes with reduced sarcomere volume in 7-day than in 24-hour hibernating regions (53 +/- 19% versus 33 +/- 14%, p < 0.05). Patchy myocardial necrosis with replacement fibrosis was common, but 6 of the 18 pigs had no myocardial necrosis or replacement fibrosis in the 7-day hibernating group, and 4 of 9 pigs had no patchy myocyte necrosis in the 24 hour hibernating group. In 6 pigs in group 1 in which the stenosis was then released and hibernating myocardium reperfused in 24 hours, regional wall thickening recovered to 30 +/- 6% (p = NS compared to baseline) after one week of reperfusion. In 12 pigs in group 2 in which the stenosis was released and hibernating myocardium reperfused in 7 days, regional wall thickening recovered slowly, from 10.1 +/- 7.2% to 18.1 +/- 8.3% at one week (n = 5) and to 28.0 +/- 3.6% at 3-4 weeks of reperfusion (n = 7, p < 0.05 compared to baseline). Similarly, the sarcomere volume or myofilament recovered significantly (p < 0.01) and was not different compared to the normal region (p = NS) in the 24-hour hibernating region of group 1, but the recovery was much slower and was incomplete at 4 weeks (p < 0.01) compared to baseline in the 7-day hibernating region of group 2. Recovery of regional wall thickening correlated with ultrstructural recovery (p < 0.01). By multivariate stepwise regression analysis, the degree of LAD flow reduction, the extent of fibrosis, and myofilament loss were independent predictors of the extent of functional recovery. CONCLUSIONS: In a porcine model of myocardial hibernation with myocardial hypoperfusion, systolic dysfunction, and metabolic adaptations, a longer period of myocardial hibernation with delayed reperfusion was associated with more severe abnormalities of myocytes. an increasing interstitial fibrosis, and more protracted myofibrillar and functional recoveries after reperfusion. The extent of functional recovery is related to the degree of coronary flow reduction, the severity of the ultrastructural changes, and the extent of interstitial fibrosis.

Animals↗
PubMed1998

Genetic dissection of familial Parkinson's disease.

In the past few years, the genetic contribution to Parkinson's disease (PD) has gained major attention and has resulted in the identification of the first mutant gene, called alpha-synuclein, involved in the pathogenesis of autosomal-dominant PD. alpha-Synuclein is a major component of Lewy bodies, which are a neuropathological feature of PD. Furthermore, deletions in the parkin gene have been identified as the primary cause in rare forms of autosomal-recessive juvenile PD. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and metabolism of xenobiotics is now technically possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of PD at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.

Amino Acid Sequence↗
PubMed2002

Lactic acidosis following heart transplantation: a common phenomenon?

BACKGROUND: Lactic acidosis (LAc) is a common form of metabolic acidosis early after heart transplantation (HTX). The mechanism remains unclear. This study analyzed 13 patients who developed severe LAc after HTX. METHODS: From a series of 60 consecutive heart transplant patients, we identified 13 patients with LAc in the first hours following HTX. Nine patients with normal or mildly elevated lactate levels (<5.0 mmol/l) were investigated as controls. RESULTS: Thirteen patients developed a moderate or severe LAc (up to 14.6 mmol/l) after HTX. Serum lactate levels increased immediately following surgery with a peak after 6.3+/-1.4 h, spontaneously returning to normal values within 24 h. In contrast to the control group, a significant correlation was found between the maximal serum lactate level and the maximal dosage of inotropic drugs (r=0.93, P<0.02), administered during the reperfusion phase and continued for 12-24 h postoperatively. No correlation was found between LAc and blood gas analysis during extracorporeal perfusion period. CONCLUSION: LAc can occur after HTX and seems to be related to the inotropic support of the graft. In contrast to other forms, LAc after HTX has an excellent prognosis and resolves rapidly and spontaneously without treatment. The fact that inotropic support during and immediately after cardiac transplantation can enhance preexisting severe peripheral metabolic cellular dysfunction remains hypothetical.

Acidosis, Lactic↗
PubMed2006

Restless legs syndrome: a review.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an irresistible urge to move the limbs accompanied by uncomfortable sensations, leading to sleep disturbances. It is associated with psychiatric comorbidities and a decreased quality of life. RLS is common and most severe among females and the elderly. It may be primary or secondary to other conditions and may be familial. Linkage to several chromosomal loci have been demonstrated. The pathogenesis of RLS involves dopaminergic dysfunction, iron metabolism, and abnormalities in supraspinal inhibition. The mainstay of RLS therapy are dopamine agonists or levodopa. This article reviews the clinical characteristics, epidemiology, diagnosis, pathogenesis, and treatment of RLS.

Dopamine Agonists↗
PubMed2005

Accumulation of long-chain acylcarnitine and 3-hydroxy acylcarnitine molecular species in diabetic myocardium: identification of alterations in mitochondrial fatty acid processing in diabetic myocardium by shotgun lipidomics.

Diabetic cardiomyopathy is the result of maladaptive changes in energy homeostasis. However, the biochemical mechanisms underlying dysfunctional lipid metabolism in diabetic myocardium are incompletely understood. Herein, we exploit shotgun lipidomics to demonstrate a 4-fold increase in acylcarnitines in diabetic myocardium, which was reversible upon insulin treatment. Analysis of acylcarnitine molecular species in myocardium unexpectedly identified acylcarnitine molecular species containing a mass shift of 16 amu in comparison to the anticipated molecular species. Synthesis of 3-hydroxy acylcarnitine identified the natural products as the 3-hydroxylated acylcarnitines through comparisons of diagnostic fragmentation patterns of synthetic and naturally occurring constituents using tandem mass spectrometry. Diabetes induced an increase of both calcium-independent phospholipase A(2) (iPLA(2)) mRNA and iPLA(2) activity in rat myocardium. Cardiac ischemia in myocardium genetically engineered to overexpress iPLA(2) dramatically increased the amount of acylcarnitine present in myocardium. Moreover, mechanism-based inactivation of iPLA(2) in either wild-type or transgenic myocardium ablated a substantial portion of the acylcarnitine increase. Collectively, these results identify discrete insulin remediable abnormalities in mitochondrial fatty acid processing in diabetic myocardium and identify iPLA(2) as an important enzymatic contributor to the pool of fatty acids that can be used for acylcarnitine synthesis and energy production in myocardium.

Animals↗
PubMed2004

[Serum uric acid--a cardiovasular risk factor?].

Serum uric acid represents an important, independent risk factor for cardiovascular and renal disease in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Although the mechanism(s) by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemrheology, and aggregation. Whether a reduction in uric acid impacts CV and renal disease remains to be determined. However, recent findings from LIFE in hypertensive patients with LVH suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. Almost one third of the treatment benefit of a losartan-based versus atenolol-based therapy on the composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Clearly, randomized clinical trials are needed to investigate further the long-term cardioprotective benefits issue of reducing hyperuricemia in hypertensive patients.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

[The comatose patient].

Consciousness and wakefulness require normal functioning of the cerebral cortex, as well as of the midbrain reticular formation and its ascending projections. Bilateral structural lesions or functional disturbances of these brain areas can impair consciousness and can produce coma. The bodily posture and brainstem reflexes of the comatose patient provide clues as to whether the lesion lies in the brainstem or in the cerebral hemispheres. Brainstem reflexes are usually preserved in coma due to bilateral hemispheric dysfunction, including metabolic, anoxic, and toxic coma. Ancillary tests are used to answer specific diagnostic questions. The treatment of coma depends on its etiology.

Brain Injuries↗