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The role of exercise-induced oxidative stress in the reduced quadriceps endurance of chronic obstructive pulmonary disease (COPD) patients has never been shown. We conducted a randomized, double-blind, and crossover study in which nine severe patients performed localized dynamic quadriceps endurance tests at 40% of maximal strength after oral treatment with the antioxidant, N-acetylcysteine (NAC), and placebo. Venous blood was sampled before, immediately after exercise, and 6 hours later. Endurance time improved by 25% after NAC treatment compared with placebo (p < 0.05). Superoxide anion (oxidant) release by stimulated phagocytes decreased after treatment (p < 0.05). No change in the antioxidant system was observed. Lipid peroxidation, an index of oxidative stress, was significantly increased 6 hours after exercise in the placebo condition (p < 0.05) but not after treatment. Advanced oxidized protein products, another index of oxidative stress, were also increased 6 hours after exercise by 139 +/- 27% in the placebo condition but only by 54 +/- 19% after treatment (p < 0.05). This study shows that NAC treatment in COPD reduced basal disturbance in the prooxidant system, improved endurance time, and prevented exercise-induced oxidative stress. Oxidative stress thus seems to be implicated in the reduced quadriceps endurance of patients with COPD. [ABSTRACT FROM AUTHOR]

Unlabelled: In preliminary observations, significant amounts of free cysteine, a neurotoxic amino acid, were noted in the urine of asphyxiated or septic-shocked neonates. The present study was conducted to determine whether free urinary cysteine was elevated in these critically ill neonates compared with a control group, and to assess the clinical significance of this generation. Free cysteine was measured in the urine of newborn infants with perinatal asphyxia (n = 16) or neonatal sepsis (n = 14) and the urine of a control group (n = 10) by ion-exchange chromatography. Relationships between cysteine levels and the clinical severity, sulfite supply and neurological outcome of the patients were then studied. Urinary cysteine was 27.6 (15-49) mmol mol(-1) creatinine for the patients but was not detectable in the control group. Cysteine levels were correlated with the severity of neonatal septic shock but not with the grade of perinatal asphyxia and did not have a specific influence on the neurological outcome of these patients. The correlation between cysteine level and the severity of neonatal septic shock was indirect and probably linked to higher sulfite administration in this population.Conclusion: The mean daily supply of sulfites is high in critically ill neonates, mainly originating from dopamine and generating significant amounts of cysteine. Although a worsening effect attributable to cysteine on the neurological outcome of the patients could not be demonstrated, the appropriateness of cryptic administration of sulfites by way of drug excipients is called into question. [ABSTRACT FROM AUTHOR]

Imipenem (thienamycin formamidine), a broad-spectrum beta-lactam antibiotic, is always used in combination with cilastatin in order to avoid the premature breakdown of imipenem by renal tubular dipeptidase. As this dipeptidase also hydrolyzes the glutathione metabolite cysteinylglycine, the therapeutic association of imipenem and cilastatin might cause an accumulation of the aminothiol cysteinylglycine. We demonstrate here that when patients are treated with imipenem-cilastatin, their plasma levels of cysteinylglycine are significantly and specifically increased, while cysteine levels are decreased and homocysteine levels are unaffected. We conclude that antibiotic treatment using imipenem-cilastatin induces important metabolic changes that should not remain unrecognized.

Amino acid analysis in physiological fluids remains expensive, as it usually requires a dedicated analyzer. We modified an RP-HPLC method originally devoted to peptide and protein hydrolysate analysis in order to apply it to plasma amino acid determination. The described method uses a commercial kit based on 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate derivatization followed by reversed-phase high-performance liquid chromatography. The described method is easy to use and allows the determination of twelve amino acids frequently involved in aminoacidopathies, thus enabling the diagnosis and follow-up of affected patients. The results obtained by this method are comparable to those obtained with a classical amino acid analyzer.

Background: Moderate hyperhomocysteinaemia is a risk factor for venous thromboembolism. We do not know whether this risk depends on homocysteine itself or on components of the homocysteine remethylation pathway, such as methylfolate. We did a case-control study to analyse the relation between the major components of the homocysteine remethylation pathway and risk of venous thromboembolism., Methods: We measured concentrations of homocysteine, methionine, and folate in plasma, total folate and methylfolate in red-blood cells, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotype and other known risk factors for venous thromboembolic disease in 243 patients with deep vein thrombosis or pulmonary embolism and controls matched for sex and age., Findings: Concentrations in plasma of homocysteine differed significantly between cases and controls. We noted a strong concentration-dependent association between concentrations of methylfolate in red-blood cells and risk of venous thromboembolism. The adjusted conditional odds ratio ranged from 1.0 for methylfolate 249 microg/L or greater to 7.1 (3.2-15.8) for methylfolate 141 microg/L or less. Methionine concentrations below the median were also independently associated with raised risk of venous thromboembolic disease, as were established risk factors such as high body-mass index, history of cancer, family history of thromboembolism, oral contraceptive use, and factor V Leiden mutation. Furthermore, the association between concentrations of methylfolate in red-blood cells and risk of thromboembolism varied according to MTHFR C677T genotype., Interpretation: Measurement of methylfolate concentrations in red-blood cells might help to identify people at risk of venous thromboembolism.

Purpose: Arterial or venous thromboses are frequent in patients with homocystinuria. Because severe homocystinuria is rare, prevalence of thrombosis, especially in France, is still unknown., Methods: Review of the clinical outcome of 37 patients with homocystinuria due to cystathionine-cystathionine beta-synthase deficiency (34) and 5,10-methylenetetrahydrofolate reductase (three) lead us to describe vascular complications occurring in 12 (32%) of them., Results: Venous thromboembolism is the earlier and the most frequent one and is mainly found in untreated late-diagnosed cases. Under specific treatment of homocystinuria, thromboses are rare and always a complication of surgery associated with high thromboembolic risk. Association with factor V Leiden increased the risk of venous thrombosis.

Background: Highly active antiretroviral therapies (HAART) in HIV-infected patients are often associated with lipodystrophy syndrome and metabolic disorders. Atherogenic lipid profile could expose these patients to atheromatous cardiovascular disease. We describe carotid artery intima-media thickness (IMT), a surrogate marker of atherosclerosis, according to HIV status, antiretroviral treatment, lipodystrophy and conventional cardiovascular risk factors., Method: In a multicenter prospective cohort study we have surveyed HIV-infected subjects with a carotid IMT measurement by B-mode ultrasonography. We collected information on lipodystrophy clinical manifestations, age, gender, body mass index (BMI), smoking habits, alcohol intake, systolic blood pressure, HIV transmission category, AIDS stage, type and duration of HAART, CD4+ cell count, plasma HIV-1 RNA, glucose, insulin, total cholesterol and homocysteine., Results: Four hundred and twenty-three HIV-infected patients were studied. The median carotid IMT measurement was 0.54 mm (range: 0.50-0.60). Lipodystrophy syndrome was diagnosed in 161 HIV-infected patients (38.1%). In univariate linear regression, IMT was significantly higher (P<0.05) with older age, male gender, higher body mass index, higher waist-to-hip ratio, increased systolic blood pressure, total cholesterol, glucose disorders and homocysteine, regular smoking and alcohol consumption, lipodystrophy and HAART. In a multivariate analysis, the effect of lipodystrophy and HAART disappeared after adjustment for other cardiovascular risk factors., Conclusions: It was concluded that only conventional cardiovascular risk factors are independently associated with increased IMT in HIV-infected patients.

Hyperprolinemia type I is a deficiency of proline oxidase (McKusick 23950), leading to hyperprolinemia and iminoglycinuria, usually with renal involvement. Hyperprolinemia type I is considered a benign trait. We reported a case of hyperprolinemia type I with a severe neurologic disorder and without renal involvement. The patient had marked psychomotor delay and right hemiparesis. Epilepsy was characterized by status epilepticus or a cluster of seizures. Laboratory findings revealed elevated levels of proline in the serum, urine, and cerebrospinal fluid without delta1-pyrroline 5-carboxylate dehydrogenase in the plasma or urine. Fluorescence in situ hybridization excluded a chromosome 22q11 deletion. Vigabatrin inhibits ornithine transaminase. Thus, vigabatrin could lead to a depletion of the normal pool of pyrroline 5-carboxylate dehydrogenase and could aggravate the clinical condition of the child. In this study, vigabatrin was discontinued. In the following months, the patient had marked psychomotor improvement, without modification of the epilepsy. We suggest that vigabatrin should be avoided in hyperprolinemia type I.

Objective: To evaluate the medical relevance of hyperhomocysteinemia in women with primary recurrent miscarriages., Design: Case report and retrospective cross-sectional study., Setting: Hematology outpatient department of a university hospital., Patient(s): Case report concerning a woman with five consecutive fetal losses. One hundred consecutive women with primary recurrent unexplained miscarriages (study group) and matched healthy controls (control group) with no antecedent fetal loss., Intervention(s): Venous blood sample collection in resting individuals., Main Outcome Measure(s): Plasma total homocysteine concentrations, plasma folate concentrations, and DNA analysis for the C677T mutation of the 5,10 methylene tetrahydrofolate reductase gene. Normal threshold homocysteine concentration was obtained from values found in the control group (95th percentile)., Result(s): The case patient was hyperhomocysteinemic, was homozygous for the C677T mutation in the methylene tetrahydrofolate reductase gene, and had plasma folate deficiency. Folic acid and pyridoxine administration normalized the homocysteine concentration and favored a successful pregnancy. In the retrospective study, 12 of 100 patients were hyperhomocysteinemic. Twenty percent had the C677T methylene tetrahydrofolate reductase genotype and 15% had low plasma folate concentrations. The highest values of homocysteine concentration were found in patients with both the C677T genotype and folate deficiency., Conclusion(s): Hyperhomocysteinemia should be identified in women with recurrent miscarriages because therapeutic normalization might permit a normal birth.

Objective: to compare amino acid concentrations in healthy and malnourished elderly patients., Method: plasma amino acid concentrations were examined in 24 men and women (80-100 years of age) with protein energy malnutrition (PEM) and compared with those of 44 healthy, similarly-aged controls. Plasma samples were determined by using cation exchange columns with ninhydrin detection in an high performance liquid chromatography system., Results: essential amino acid and non-essential amino acid plasma concentrations were significantly decreased in PEM (0.01 < P < 0.0001). Branched-chain amino acids and urea cycle amino acid plasma concentrations fell significantly (P < 0.0001). Plasma concentrations of alanine and glutamic acid + glutamine were also significantly reduced (P < 0.0001)., Conclusions: in underweight elderly patients, the plasma amino acid pattern reflects the severity of the metabolic disturbance.

Context: Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear., Objective: To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors., Design: Case-control study., Setting: Nineteen centers in 9 European countries., Patients: A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years., Measurements: Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured., Results: The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of at-risk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels., Conclusions: An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.

Purpose: We describe a secondary effect of treatment with vigabatrin (VGB). A significant increase in alpha-aminoadipic acid (AAA) occurred in plasma and urine of VGB-treated children, thus mimicking a known rare metabolic disease, alpha-aminoadipic aciduria (AAAuria)., Methods: We studied eight children, aged from 3 months to 5 years, who were receiving VGB for drug-resistant partial epilepsies. Plasma and urine amino acids were assayed with ninhydrin detection on an automated Beckman 6300 analyzer., Results: In eight out of eight children, there was a significant increase of AAA in plasma and in urine. Plasma values ranged from 7 to 8 microM (control values, < 5) and urinary values from 67 to 274 mmol/mol creatinine (control values, < 25)., Conclusions: The concentrations of AAA in these VGB-treated children were as high as the concentrations found in the inherited metabolic disease, AAAuria. This could lead to incorrect diagnosis and to inappropriate genetic counseling. Thus whenever a genetic metabolic disease is suspected, amino acid chromatography testing should be performed before initiation of treatment with VGB.

Lafora disease and Unverricht-Lundborg disease are two forms of progressive myoclonus epilepsies (PME). Recently the gene for Unverricht-Lundborg disease (EPM1) was mapped to chromosome 21q22.3. Using three highly polymorphic DNA markers (D21S212, PFKL, and D21S171) which flank the EPM1 locus, we performed linkage analysis to investigate whether or not the EPM1 gene is also implicated in Lafora disease. Linkage was excluded in three North-African pedigrees each comprising at least two affected individuals. This result suggests that differential diagnosis of Lafora disease and Unverricht-Lundborg disease may be facilitated by molecular genetic analysis.

The effects of age and sex on the plasma free amino acid pattern of healthy men and women aged from 80 to 100 years were compared with those in younger adults (20 to 45 years old). Plasma amino acid concentrations were determined by ion-exchange chromatography on a 6300 Beckman analyzer. The plasma concentrations of valine, leucine, isoleucine, proline, glutamine + glutamic acid and phenylalanine were higher in males than in females. Citrulline, half-cystine, histidine, glutamine+glutamic acid, lysine, ornithine and phenylalanine plasma concentrations and the total plasma amino acids were higher in elderly than in younger subjects.

An experimental evaluation of citrulline malate (Stimol, CAS 54940-97-5), an anti-fatigue compound, was undertaken in man and in the animal in order to study the pharmacological activity of the substance at hepatic and renal level. In man, the protocol involved a double-blind randomized, placebo-controlled cross-over technique. The study in the animal was blind and placebo-controlled with two randomized parallel groups. Results showed that citrulline malate stimulates hepatic ureogenesis and favorizes the renal reabsorption of bicarbonates. These metabolic actions had a protective effect against acidosis and ammonia poisoning and explain the anti-fatigue properties of citrulline malate in man.

We have identified a Duchenne muscular dystrophy (DMD) pedigree with an unexpected pattern of inheritance. Using marker restriction fragment length polymorphisms detected by probes that lie within and outside the DMD gene, we could demonstrate that the maternal grandfather has transmitted two distinct types of X chromosomes to his offspring. This original observation may be explained by postulating that the DMD mutation must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism within this male ancestor.