Factors influencing endothelial function in healthy pre- and post-menopausal women of the EU-RISC study.

BACKGROUND: We studied the impact of lifestyle, body composition, different insulin sensitivity indices and the first insulin response in healthy pre- and post-menopausal women with a low cardiovascular risk profile (the EU-RISC study, 'Relationship between Insulin Sensitivity and Cardiovascular Disease' (n = 51, 47 ± 4 years, body mass index 23.6 ± 3.7 kg/m(2), waist girth 79.2 ± 10.3 cm) on endothelial function (flow mediated arterial dilatation (FMD)), an early marker for atherosclerosis. RESULTS: Waist circumference (p = 0.06), tobacco consumption (p = 0.02) and leucocyte count (p = 0.09) were inversely related with FMD in both pre- and post-menopausal women. Neither insulin sensitivity nor first insulin response indices were correlated with FMD. In pre-menopausal women (n = 24), waist (p < 0.02), waist-to-hip ratio (p < 0.02), HDL cholesterol (p < 0.01) and smoking habits (p < 0.03) were significantly correlated with endothelial function. In postmenopausal women (n = 27) age (r = -0.17, p = 0.04) was related with FMD. CONCLUSION: Smoking and waist circumference, a simple marker of visceral adiposity, were related with endothelial function in healthy pre- and post-menopausal women.

Comparison of two different radioimmunoassays to measure 17-hydroxyprogesterone during treatment monitoring of children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Accurate measurement of 17-hydroxyprogesterone (17-OHP) concentrations is essential for the correct diagnosis and treatment management of children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21 OHD). METHODS: We analysed 102 serum samples from 15 children with known 21 OHD twice using two different 17-OHP assays. 17-OHP concentrations were measured by an in-house radioimmunoassay (RIA) after recovery-corrected extraction and chromatographic purification and by a commercially available RIA without extraction (Immunotech). RESULTS: The correlation coefficient for results of pairs of 17-OHP concentrations was 0.974. The median ratio (17-OHP concentration measured with the commercial assay/17-OHP concentration measured with the in-house assay) was 0.593 with a 95% confidence interval ranging from 0.258 to 1.370. The ratio was constant throughout the average 17-OHP concentrations ranging from 0.24 to 149.2 nmol/L, as well as throughout the age range from 0.3 to 16.4 years. CONCLUSIONS: Despite good overall correlation, absolute 17-OHP concentrations differed dramatically. This could lead to misclassification of patients suspected for 21 OHD on the basis of the hormonal profile and to a reduced quality during treatment monitoring of patients with 21 OHD with the risk of under- and overtreatment.

Dystonia with secondary contractures: a psychogenic movement disorder mimicking its neurological counterpart.

We report the case of an 11-year-old girl presenting with a 1.5-year history of swan neck-like deformed joint contractures of both hands. A possible diagnosis was sought in a wide range of rheumatological, metabolic, and neurological disorders. After detailed diagnostic procedures to exclude an organic pathology, steps were taken to establish a psychogenic origin. She showed symptoms that were incongruent with an organic neurological disorder, for example, a paroxysmal fluctuating course, reaction to placebo, and complete remission with psychotherapy and physiotherapy. The psychosomatic evaluation revealed a highly emotional conflict. This bizarre case demonstrates that secondary contractures are by no means an exclusion criterion for a psychogenic dystonia.

The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations.

This paper reviews current knowledge on the role of the long-chain polyunsaturated fatty acids (LC-PUFA), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, 20:4n-6), in maternal and term infant nutrition as well as infant development. Consensus recommendations and practice guidelines for health-care providers supported by the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation are provided. The fetus and neonate should receive LC-PUFA in amounts sufficient to support optimal visual and cognitive development. Moreover, the consumption of oils rich in n-3 LC-PUFA during pregnancy reduces the risk for early premature birth. Pregnant and lactating women should aim to achieve an average daily intake of at least 200 mg DHA. For healthy term infants, we recommend and fully endorse breastfeeding, which supplies preformed LC-PUFA, as the preferred method of feeding. When breastfeeding is not possible, we recommend use of an infant formula providing DHA at levels between 0.2 and 0.5 weight percent of total fat, and with the minimum amount of AA equivalent to the contents of DHA. Dietary LC-PUFA supply should continue after the first six months of life, but currently there is not sufficient information for quantitative recommendations.

Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation.

The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.

Cardiomyopathy in congenital disorders of glycosylation.

Congenital disorders of glycosylation are a group of inherited metabolic multisystem disorders characterized by defects in the glycosylation of proteins and lipids. In most cases, neuromuscular disease is present. The purpose of this study was to characterize the cardiological aspects in this disorder. From the literature, we identified six children with congenital disorders of glycosylation associated with cardiac disease. We then screened for cardiovascular manifestations 20 patients diagnosed with congenital disorders of glycosylation at our own institution. Of the 6 patients identified in the literature, 4 had hypertrophic cardiomyopathy, while in the other 2 the cardiac diagnosis was unclear. The mean age at cardiac diagnosis was 5 months, with a range from 34 weeks to 24 months. Of the patients, five had died at a mean age of 3.5 months, with a range from 1.5 to 6 months, with one documented cardiac death. Three of our 20 patients (15%) had coexistent cardiomyopathy, and in three additional patients presenting with cardiomyopathy we made the diagnosis of a congenital disorder of glycosylation. In our cohort, dilated cardiomyopathy was found in two-thirds of the patients, with hypertrophic cardiomyopathy in the other third. The mean age at cardiac diagnosis was 19 months, with a range from 0.5 to 84 months. Of these patients, two died in infancy at a mean age of 4 months, specifically at 1.5 and 7 months, due to cardiac disease, with one dying suddenly. The remaining four patients are alive with minor to severe cardiac dysfunction. We conclude that congenital disorders of glycosylation have to be considered in the differential diagnosis of children presenting with cardiomyopathy, and that all patients with congenital disorders of glycosylation should be screened for an associated cardiomyopathy. Cardiac involvement contributes significantly to morbidity and mortality, and probably to sudden cardiac death in this disorder.

Fatty acid profiles, antioxidant status, and growth of preterm infants fed diets without or with long-chain polyunsaturated fatty acids. A randomized clinical trial.

Long-chain polyunsaturated fatty acids (LCP) are considered conditionally essential nutrients for the infant born prematurely, and attempts are being made to match fatty acid profiles of formula and breast fed infants. In this double-blind, randomized study we investigated the effects of a formula enriched with both n-6 and n-3 LCP on plasma fatty acid profiles, antioxidant status and growth of premature infants. 29 infants received either a formula devoid of LCP or a LCP supplemented formula (0.5 g/100 g fat linoleic acid metabolites, 0.8 g/100 g fat alpha-linolenic acid metabolites). 17 breast fed infants served as a control group. At study entry as well as two and four weeks later, plasma and urine samples were collected, growth data obtained and food tolerance was documented. At the end of the four week study period, plasma docosahexaenoic acid (DHA) levels of supplemented infants were significantly higher than those of unsupplemented infants and similar to those of infants fed human milk. Plasma n-6 LCP concentrations including arachidonic acid (AA) were similar between groups. The plasma alpha-tocopherol levels of breast fed and supplemented infants were similar and tended to be lower than in infants fed the formula devoid of LCP. Urinary malondialdehyde (MDA) excretion of formula fed infants was significantly higher compared to infants fed human milk, but did not differ between the two formula groups. Parameters of growth and milk tolerance did not differ between groups. Our results demonstrate that plasma LCP levels similar to those of breast fed infants can be achieved with the LCP supplemented formula used in this trial, without evidence of adverse effects of the LCP enrichment.

N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria.

In patients with methylmalonic aciduria (MMA), the accumulating metabolite propiony-CoA results in an inhibition of the urea circle via the decreased synthesis of N-acetylglutamate, an essential activator of carbamylphosphat synthetase (CPS). This results in one of the major clinical problems which is hyperammonaemia. In a patient with decompensated MMA, the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA-induced hyperammonaemia. Oral carbamylgutamate administration resulted in an impressive increase in ammonia detoxification compared to peritoneal dialysis. Safe, fast and easy to administer, carbamylglutamate improves the acute therapy of decompensated MMA by increasing ammonia detoxification and avoiding hyperammonaemia.

Parenteral fat emulsions based on olive and soybean oils: a randomized clinical trial in preterm infants.

OBJECTIVE: To evaluate in premature infants a new parenteral lipid emulsion based on olive and soybean oils (ratio 4:1), with less polyunsaturated fatty acids (PUFA) and more alpha-tocopherol than standard soybean oil emulsion. STUDY DESIGN: Premature infants (gestational age, 28-<37 weeks) were randomized to receive one of the two emulsions within the first 72 hours of life. The triglyceride dose was increased to 2 g/kg/day within 3 days. Plasma phospholipid fatty acids, alpha-tocopherol/lipid ratio, and urinary malondialdehyde (MDA) excretion were determined at baseline and after 7 days. RESULTS: Of 45 recruited infants, 33 completed the study per protocol (15 soybean oil, 18 olive oil emulsion). At study end, groups did not differ in plasma phospholipid arachidonic acid, total n-6 and n-3 metabolites, but the olive oil group showed higher values of the PUFA intermediates C18:3n-6 (0.19% +/- 0.01% vs. 0.13% +/- 0.02%, P < 0.05) and C20:3n-6 (2.92% +/- 0.12% vs. 2.21% +/- 0.17%, P = 0.005). The plasma alpha-tocopherol/total lipd ratio was higher in the olive oil group (2.45 +/- 0.27 micromol/mmol vs. 1.90 +/- 0.08 micromol/mmol, P = 0.001), whereas urinary MDA excretion did not differ. CONCLUSION: The lower PUFA supply with the olive/soybean oil emulsion appears to enhance linoleic acid conversion. The reduced PUFA content, combined with a higher antioxidant intake in the olive oil group, results in an improved vitamin E status. The olive oil-based emulsion is a valuable alternative for parenteral feeding of preterm infants who are often exposed to oxidative stress, while their antioxidative defense is weak.

Cerebrovascular complications of L-asparaginase in the therapy of acute lymphoblastic leukemia.

L-asparaginase is frequently used in combination therapy for the treatment of lymphoid malignancies. We report 5 children aged between 8 and 14 years with neurologic complications presenting with headache and seizures during the first three weeks of L-asparaginase treatment. Three patients had venous thrombosis, one presented a parenchymal hemorrhage, and one showed a peculiar encephalopathy with extended cortical and subcortical lesions suggesting a neurotoxic reaction. Decreased fibrinogen and antithrombin III levels were found. Early MRI is critical even in cases with mild neurologic symptoms. Diagnosis should be followed by early cessation of l-asparaginase application.

Elevated oxidative stress in patients with ataxia telangiectasia.

Ataxia telangiectasia (AT) is a pleiotropic genetic disorder characterized by progressive neurodegeneration, especially of cerebellar Purkinje cells, immunodeficiency, increased incidence of cancer, and premature aging. The disease is caused by functional inactivation of the ATM (AT-mutated) gene product, which is thought to act as a sensor of reactive oxygen species and oxidative damage of cellular macromolecules and DNA. The compound phenotype of AT might thus be linked to a continuous state of oxidative stress leading to an increase of programmed cell death (apoptosis). To assess this hypothesis, we analyzed lipid peroxidation products and the oxidative stress associated DNA base damage 8-hydroxy-2-deoxyguanosine in patients with AT. Oxidative damage to lipids and DNA was found to be markedly increased in AT patients. These results indicate that ATM might play an important role in the maintenance of cell homeostasis in response to oxidative damage. In this context, a better control of levels of reactive oxygen species could be a rational foundation of therapeutic intervention to help alleviate some of the symptoms associated with AT.

Antibiotic treatment-induced tubular dysfunction as a risk factor for renal stone formation in cystic fibrosis.

OBJECTIVES: Our purpose was to characterize the decisive pathophysiologic factors that lead to renal stone formation (nephrolithiasis) in patients with cystic fibrosis (CF). METHODS: Patients with CF (n = 96) were investigated with respect to lithogenic and inhibitory factors of urolithiasis and compared with 30 healthy control patients. They were subdivided into 2 groups, 86 without renal stones and 10 with renal stones. RESULTS: All stones were exclusively composed of calcium oxalate. As a major pathogenic factor, a urinary disequilibrium between promoting and inhibitory components of stone formation, characterized mainly by hypercalciuria, hyperoxaluria, and hypocitraturia, was found in the patients with nephrolithiasis. They tended to have lower plasma phosphate concentrations and an increased urinary phosphate excretion. The citrate/calcium ratio proved to be a valuable means to discriminate patients with renal stones from control patients. Patients with stones had ingested more cotrimoxazole and ceftazidim, cumulatively, than patients without stones. There was an inverse correlation between the amounts of antibiotics ingested and the percentage of tubular phosphate reabsorption (r = -0.91, P <.0046). CONCLUSION: Renal stone formation in patients with CF is caused by a disequilibrium between promoting and inhibitory components of stone formation, which is dominated by hypercalciuria, hyperoxaluria, and hypocitraturia. Treatment with cotrimoxazole and ceftazidim, primarily, may lead to renal proximal tubular damage with an ensuing sequence of phosphate loss, increase of parathyroid hormone secretion, increased 1,25-dihydroxyvitamin D3 formation, and absorptive hypercalciuria.