A patient with neurological symptoms and abnormal leukotriene metabolism: a new defect in leukotriene biosynthesis.

A 15-year-old male patient presented with mental retardation, mild motor impairment, and partial deafness. Biochemical investigations showed an abnormal urinary profile of leukotrienes. Concentration of leukotriene D(4) (LTD(4)), which is usually not detectable, was highly increased, whereas LTE(4), the major urinary metabolite in humans, was completely absent. These data suggest membrane-bound dipeptidase deficiency, a new defect in leukotriene biosynthesis on the step of LTE(4) synthesis, as underlying defect.

Elevated plasma cysteinylglycine levels caused by cilastatin-associated antibiotic treatment.

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.

Determination of plasma amino acids by fluorescent derivatization and reversed-phase liquid chromatographic separation.

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.

Does oxidative stress alter quadriceps endurance in chronic obstructive pulmonary disease?

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.

Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement.

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.

Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study.

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.