Diagnosis features of pediatric Gaucher disease patients in the era of enzymatic therapy, a national-base study from the Spanish Registry of Gaucher Disease.

BACKGROUND: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. AIM: To analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. METHODS: A review of data in SpRGD from patients' diagnosed before 18 years old was performed. The cohort was split according the year of diagnosis (≤1994, cohort A; ≥1995, cohort B). RESULTS: A total of 98 pediatric patients were included, GD1: 80, GD3: 18; mean age: 7.2 (0.17-16.5) years, 58 (59.2%) males and 40 (40.8%) females. Forty-five were diagnosed ≤ 1994 and 53 ≥ 1995. Genotype: N370S/N370S: 2 (2.0%), N370S/L444P: 27 (27.5%), N370S/other: 47 (48%), L444P/L444P: 7 (7.1%), L444P/D409H: 2 (2.0%), L444P/other: 3 (6.2%), other/other: 10 (10.2%). The mean age at diagnosis was earlier in patients diagnosed after 1995 (p < 0.001) and different between the subtypes, GD1: 8.2 (0.2-16.5) years and GD3: 2.8 (0.17-10.2) years (p < 0.001). There were more severe patients in the group diagnosed before 1994 (p = 0.045) carrying L444P (2), D409H (2), G377S (1), G195W (1) or the recombinant mutation. The patients' diagnosed ≤1994 showed worse cytopenias, higher chance of bone vascular complications at diagnosis and previous spleen removal. The patients started ERT at a median time after diagnosis of 5.2 years [cohort A] and 1.6 years [cohort B] (p < 0.001). CONCLUSIONS: The early diagnosis of Gaucher disease in the era of ERT availability has permitted to reduce the incidence of severe and irreversible initial complication in pediatric patients, and this has permitted better development of these patients. This is the largest pediatric cohort from a national registry.

Effects of Maternal Ω-3 Supplementation on Fatty Acids and on Visual and Cognitive Development.

OBJECTIVES: The aim of the present study was to elucidate whether a dairy drink enriched with ω-3 long-chain polyunsaturated fatty acid (LC-PUFA) could have an impact on the lipid profile of the mother and the newborn, and also whether this intervention could affect the newborns' visual and cognitive development. METHODS: A total of 110 pregnant women were randomly assigned to one of the following intervention groups: control group (n = 54), taking 400 mL/day of the control dairy drink, and supplemented group (fish oil [FO]) (n = 56), taking 400 mL/day of the fish oil-enriched dairy drink (including ∼400 mg eicosapentaenoic acid-docosahexaenoic acid [DHA]/day). During the study, the mothers' diets were supervised by a nutritionist to encourage compliance with present recommendations of FA intake. Blood fatty acid profiles were determined in the mother's (at enrollment, at delivery, and at 2.5 and 4 months) and newborn (at delivery and at 2.5 months) placenta and breast milk (colostrum and at 1, 2, and 4 months). Pattern reversal visual evoked potentials (VEPs) (at 2.5 and 7.5 months) and Bayley test (at 12 months) were recorded. RESULTS: DHA percentage was higher in plasma, erythrocyte membranes, and breast milk samples from the FO group. The ratio of nervonic acid was also higher in plasma and erythrocyte lipids of the mother and newborn's blood samples from the FO group. No differences were observed in the Bayley test. No differences were observed in VEPs between both groups. We observed a shorter latency, however, in the lower visual angle (7.5') in the boys of the supplemented group. CONCLUSIONS: Omega-3 LC-PUFA dietary supplement during pregnancy and lactation influenced the mother and newborn's fatty acid profile and nervonic acid content but did not show effects on visual and cognitive/psychomotor development.

Arginine-guanidinoacetate-creatine pathway in preterm newborns: creatine biosynthesis in newborns.

The phosphocreatine/creatine system is fundamental for the proper development of the embryonic brain. Being born prematurely might alter the creatine biosynthesis pathway, in turn affecting creatine supply to the developing brain. We enrolled 53 preterm and very preterm infants and 55 full-term newborns. The levels of urinary guanidinoacetate, creatine, creatinine and amino acids were measured in the preterm and very preterm groups, 48 h and 9 days after birth and at discharge, and 48 h after birth in the full-term group. Guanidinoacetate concentrations of both preterm and very preterm newborns were significantly higher at discharge than the values for the full-term group at 48 h, while very preterm infants showed urinary creatine values significantly lower than those measured in the full-term group. Our results suggest an impairment of the creatine biosynthesis pathway in preterm and very preterm newborns, which could lead to creatine depletion affecting the neurological outcome in prematurely born infants.

Reliability of a visual test for the rapid detection of mucopolysaccharidoses: GAG-test(®).

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, characterized by the deficiency/absence of one of the enzymes involved in the intralysosomal degradation of glycosaminoglycans (GAGs). The quantitative determination of urinary GAGs using dimethylmethylene blue (DMB) shows high reliability. However, the logistics and staff for this method are not always available in primary care centers. Sending urine samples to reference laboratories increases the cost and delays the diagnosis. Thus, the aim of this article is to develop and evaluate a simple and low-cost visual test (GAG-test(®)) for the screening of urine samples from patients under suspicion of suffering from MPS. The purpose is to narrow down the number of samples to be assayed through the quantitative method. A measure of 50 µl urine was added to 2 ml DMB solution. A color change from dark blue to purple indicates an excess of GAGs. The quantitative analyses showed a significant difference between controls' and patients' concentrations (P<0.05). After optimization of the composition, positive and negative results obtained with the qualitative test were able to discriminate between normal urines and those from patients suffering from mucopolysaccharidosis. Therefore, GAG-test(®) has proved to be a useful tool for the prior diagnosis of patients suffering from mucopolysaccharidosis, reducing the number of individuals with whom investigations should be continued.

Methylation cycle, arginine-creatine pathway and asymmetric dimethylarginine in paediatric renal transplant.

BACKGROUND: Hyperhomocysteinaemia represents an important cause of morbidity in recipients of renal transplants, but few investigations have been carried out to evaluate the status of the methylation cycle and its relation with levels of new cardiovascular biomarkers, such as asymmetric dimethylarginine (ADMA). METHODS: Twenty-six children and adolescents aged 7-18 years (17 male, 9 female) with stable renal transplants were recruited for the study. None had received treatment with folate, vitamin B(12) or statins. Levels of ADMA in plasma and of components of the methylation cycle and arginine (Arg)-creatine pathway in plasma and urine were analysed by specific analytical methods. Results were compared to those obtained by us with identical methods in healthy children of similar age. RESULTS: Concentrations of homocysteine (Hcys), S-adenosylhomocysteine (SAH) and ADMA were significantly higher, while S-adenosylmethionine (SAM)/SAH and Arg/ADMA ratios were significantly lower than controls. Arg/ADMA ratio correlated with plasma guanidinoacetate. The components of the methylation cycle, Hcys and SAH correlated with renal function. CONCLUSIONS: Children with renal transplant showed low methylation power (SAM/SAH) mainly due to increased levels of SAH which acts as a cardiovascular biomarker. Elevated values of ADMA and low Arg/ADMA coefficients also represent a novel finding because it inhibits nitric oxide synthesis contributing to endothelial dysfunction and cardiovascular risk in such patients.

Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density.

BACKGROUND: Patients with phenylketonuria (PKU) undergo a restrictive vegan-like diet, with almost total absence of n-3 fatty acids, which have been proposed as potential contributors to bone formation in the healthy population. The PKU diet might lead these patients to bone mass loss and, consequently, to the development of osteopenia/osteoporosis. Therefore, we proposed to analyze their plasma fatty acid profile status and its relationship with bone health. METHODS: We recruited 47 PKU patients for this cross-sectional study and divided the cohort into three age groups (6-10 years, 11-18 years, 19-42 years). We measured their plasma fatty acid profile and bone mineral density (BMD) (both at the femoral neck and the lumbar spine). Seventy-seven healthy controls also participated as reference values of plasma fatty acids. RESULTS: Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and total n-3 fatty acids were significantly diminished in PKU patients compared with healthy controls. DHA, EPA, and total n-3 fatty acids were also positively associated with bone mineral density (r = 0.83, p = 0.010; r = 0.57, p = 0.006; r = 0.73, p = 0.040, respectively). There was no association between phenylalanine (Phe), Index of Dietary Control (IDC), calcium, 25-hydroxivitamin D concentrations, daily calcium intake, and BMD. CONCLUSION: Our results suggest a possible influence of essential fatty acids over BMD in PKU patients. The lack of essential n-3 fatty acids intake in the PKU diet might affect bone mineralization. Further clinical trials are needed to confirm the effect of the n-3 essential fatty acids on bone accrual in a cohort of PKU patients.

Persistence of essential fatty acid deficiency in cystic fibrosis despite nutritional therapy.

To study the evolution of plasma fatty acid composition of patients with cystic fibrosis (CF) in relation to nutritional status, pancreatic function, and development of CF-related liver disease (CFRLD) and diabetes mellitus, 24 CF pediatric patients with stable pulmonary disease were studied before and after an approximate period of 8 y. Nutritional status, pulmonary function, pancreatic function, and presence of CFRLD or diabetes mellitus were recorded. Results were compared with data obtained in 83 healthy children. Patients with CF have significantly lower linoleic acid (LA), docosahexaenoic acid (DHA), lignoceric acid, and LA x DHA product and higher oleic acid, mead acid, dihomo-gamma-linoleic acid, and docosapentaenoic acid (DPA). Comparison of samples taken at first and second studies revealed a significant decrease in LA levels and lignoceric acid associated with a significant increase in dihomo-gamma-linoleic acid levels. Patients with CFRLD showed significantly higher mead acid/arachidonic acid ratio and lower total omega6 polyunsaturated fatty acids content. There was no relation of plasma fatty acids composition with pancreatic function, pulmonary function, or diabetes mellitus. Follow-up of patients with CF shows that essential fatty acids deficiency, particularly in LA and DHA content, persisted unmodified along time despite an adequate nutritional therapy. Future studies after supplementation with omega3 polyunsaturated fatty acids should be undertaken.

Determination of creatine and guanidinoacetate by GC-MS: study of their stability in urine at different temperatures.

OBJECTIVES: Evaluation of a GC-MS method using N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA) as the silylating agent for GC-MS. Study of the stability of creatine and guanidinoacetate in urine. DESIGN AND METHODS: 22 urines were kept at RT, 4 degrees C and -30 degrees C for 15 days. RESULTS: MTBSTFA produces a single chromatographic peak in contrast with other derivatizing agents. Creatine concentration increases at room temperature (326% on average), and at 4 degrees C (75%). However, detection decreases after freezing (-37%). Guanidinoacetate is stable, but decreases after freezing (-37%). Sonication before analysis is crucial to obtain repetitive results. CONCLUSIONS: A modified GC-MS method has been validated and the conditions for preservation of the urine have been established.

The arginine-creatine pathway is disturbed in children and adolescents with renal transplants.

Cardiovascular disease is an important cause of morbidity in recipients of renal transplants. The aim of the present study was to analyze the status of the arginine-creatine pathway in such patients, given the relationship between the arginine metabolism and both renal function and the methionine-homocysteine cycle. Twenty-nine children and adolescents (median age 13, range 6-18 years), who had received a renal allograft 14.5-82.0 months before, were recruited for the study. On immunosuppressive therapy, all patients evidenced an adequate level of renal function. Plasma concentrations of homocysteine and glycine were significantly higher, whereas urinary excretions of guanidinoacetate and creatine were significantly lower than controls. Urinary excretions of guanidinoacetate and creatine correlated positively with creatinine clearance. Urinary excretion of creatine was negatively correlated with plasma concentration of homocysteine. The demonstration of disturbances in the arginine-creatine pathway in patients with well-functioning renal transplants and in absence of chronic renal failure represents a novel finding. We speculate that the low urinary excretion of guanidinoacetate and creatine is probably related to the nephrotoxic effect of immunosuppressive therapy and to defective methylation associated with the presence of hyperhomocysteinemia.

Stability of urinary glycosaminoglycans in patients with mucopolysaccharidoses.

OBJECTIVE: The aim of this work is to investigate the degradation of urinary glycosaminoglycans (GAGs) at different storage temperatures, in order to identify whether frozen transportation to reference laboratories is necessary. An improved method for the determination of total GAGs with 1,9-dimethylmethylene blue (DMB) is presented. DESIGN AND METHODS: Urine samples of 37 patients suffering from mucopolysaccharidoses (MPS) were analyzed in this study (13 Hunter, 6 Maroteaux-Lamy, 6 Morquio, 6 Sanfilippo, 5 Hurler-Scheie, and 1 Sly). Stability was assayed at room temperature, 5 degrees C and -30 degrees C, and analyses were repeated for at least 15 days. Spectrophotometric quantitation of GAGs with DMB was used for all determinations, using a variable wavelength for quantitation. RESULTS: The concentration of urinary GAGs was stable for 10 days at room temperature, but it was found to be stable for more than 15 days at 5 degrees C and -30 degrees C. CONCLUSIONS: The stability of GAGs allows urine samples to be sent for quantitation at a clinical laboratory without the need to freeze samples, as this would not affect results. This issue is important for the rapid detection of MPS at hospitals or primary health care centres, where GAGs determination is not performed.

Arachidonic acid content in adipose tissue is associated with insulin resistance in healthy children.

BACKGROUND: The fatty acid composition of membrane structural lipids, which is partly dependent on dietary intake, is associated with insulin action. AIM: To examine the association between fatty acid composition of adipose tissue and skeletal muscle phospholipids with insulin resistance markers in a healthy pediatric population. METHODS: Using a cross-sectional design, we studied 83 healthy children divided into 3 groups, ages 2 to 5, 6 to 10 and more than 10 years. MEASUREMENTS: Fatty acid composition of adipose tissue triacylglycerols and skeletal muscle phospholipids, plasma lipid profile and fasting plasma levels of glucose and insulin were measured. RESULTS: There was a linear increase of insulinemia, glycemia and homeostasis adipose tissue model assessment (HOMA) index throughout the pediatric age range. Linoleic acid proportion in skeletal muscle and arachidonic acid proportion in adipose tissue also increased significantly with age. An age-independent positive correlation between insulinemia or HOMA index and arachidonic acid content in adipose tissue triacylglycerols (r = 0.47, P < 0.001) was found. An age-dependent negative correlation was present between insulinemia or HOMA index and oleic acid content in skeletal muscle phospholipids (r = -0.30, P = 0.03 and r = -0.28, P < 0.04, respectively). Trans fatty acids content did not correlate with any marker of insulin resistance. CONCLUSION: Healthy children present a prepubertal increase of insulin resistance, which is significantly correlated with arachidonic acid content in adipose tissue.

Essential fatty acid deficiency profile in patients with nephrotic-range proteinuria.

Plasma free fatty acids are bound to albumin, filtered through the glomeruli, and reabsorbed at the proximal nephron. The aim of the present investigation was to determine if urinary loss of fatty acids results in essential fatty acid (EFA) deficiency in patients with nephrotic-range proteinuria. We studied 12 patients aged 9 months to 23 years (eight male, four female) four suffering from congenital nephrotic syndrome (NS) and eight from different renal diseases. Six patients were studied postrenal transplantation. Proteinuria ranged between 41 and 829 mg/m2/h. Results were compared with data obtained in 83 healthy children. The patients had significantly lower values for plasma arachidonic acid content and EFA index (omega3 + omega6/omega7 + omega9). Deficiency in polyunsaturated fatty acids (PUFA) was especially manifest in infants with congenital NS. Plasma content of arachidonic and docosahexaenoic acids related negatively with the degree of proteinuria. In the lineal regression model, the degree of proteinuria explained 60% of the variability of plasma values of those fatty acids. We conclude that plasma fatty acid status should be regularly monitored in patients with nephrotic-range proteinuria, especially in young infants with congenital NS, who represent a population at special risk with regard to neurological development.

Determination of free and total carnitine in plasma by an enzymatic reaction and spectrophotometric quantitation spectrophotometric determination of carnitine.

OBJECTIVES: Carnitine initiates the beta-oxidation of fatty acids and its deficiency is a problem in several metabolic diseases. This work describes a validated quick and simple enzymatic assay for the determination of free and total carnitine in plasma. METHODS: Carnitine reacts with acetyl-CoA catalized by carnitine acetyltransferase. The coenzyme A liberated combines with 5,5'-dithiobis-(2-nitrobenzoic acid) and forms thiophenolate ion, measured spectrophotometrically at 412 nm. The method requires precipitation of proteins and the alkaline hydrolysis of acylcarnitines for total carnitine. RESULTS: The detection limit is 1.7 micromol/L in plasma and inter- and intra-day imprecision is less than 5%. The recovery of spiked plasma samples is 97%. The method was tested with an inter-laboratory assay, yielding excellent correlation (r(2)=0.994), and it was applied to the determination of normal values of carnitine in plasma. CONCLUSIONS: A reliable spectrophotometric method has been validated with very good precision, with simple instrumental and easy sample preparation.

Fatty acid composition of skeletal muscle and adipose tissue in Spanish infants and children.

There is a relationship between the fatty acid profile in skeletal muscle phospholipids and peripheral resistance to insulin in adults, but similar data have not been reported in infancy and childhood. The objective of this study was to investigate the fatty acid composition of skeletal muscle and adipose tissue across the paediatric age range. The fatty acid profile of skeletal muscle phospholipids and adipose tissue triacylglycerols was analysed in ninety-three healthy Spanish infants and children distributed into four groups: group 1 (0 to <2 years, n 10); group 2 (2 to <5 years, n 41); group 3 (5 to <10 years, n 24); group 4 (10 to 15 years, n 18). In skeletal muscle phospholipids, oleic acid (18: 1n-9cis) content decreased significantly whereas that of linoleic (18: 2n-6) acid increased significantly with age (P for trend <0.01). In adipose tissue, the contents of triacylglycerol and linoleic acid increased significantly across the paediatric age range (P for trend <0.01), whereas dihomo-gamma-linolenic (20: 3n-6) and arachidonic (20: 4n-6) showed significant differences between groups. The variations in fatty acid composition observed with age indicated an imbalance in dietary n-3/n-6 long-chain PUFA.

Abnormalities in plasma fatty acid composition in human immunodeficiency virus-infected children treated with protease inhibitors.

AIM: To study plasma fatty acid composition in human immunodeficiency virus-infected children treated with protease inhibitors and its relation with other components of the metabolic syndrome observed after this therapy. DESIGN: Cross-sectional study from collected clinical database. SUBJECTS: 17 children with HIV infection treated with protease inhibitors. Nine patients received ritonavir (20-30 mg/kg/d) and the remaining eight received nelfinavir (60-90 mg/kg/d). Duration of protease inhibitors treatment was 711+/-208 d. As controls, we used 112 matched blood samples from apparently healthy children admitted for minor surgical procedures. METHODS: Plasma fatty acids were determined using a Hewlett Packard GC 5890 gas chromatograph. RESULTS: Plasma levels of cholesterol and triglycerides and insulin-like growth factor 1 (IGF-1) tended to be high in protease inhibitor-treated patients. Plasma content of omega6 long-chain polyunsaturated fatty acids and, in particular, of the highly unsaturated 22ratio4omega6 and 22ratio5omega6, was significantly increased. Also, infected children had increased Delta6 and Delta4 desaturase activities and decreased Delta5 desaturase activity. Significant correlations were present between plasma IGF-1 level and plasma triglycerides, plasminogen activator inhibitor-1 activity and Delta6 desaturase activity. CONCLUSION: HIV-infected, protease inhibitor-treated children exhibit a metabolic syndrome which is associated with significant changes in plasma fatty acid composition. These changes are similar to those observed in situations of insulin resistance and are linked to variations in plasma IGF-1 concentration.

Brain docosahexaenoic acid status and learning in young rats submitted to dietary long-chain polyunsaturated fatty acid deficiency and supplementation limited to lactation.

N-3 fatty acid deficiency has been related to decreased docosahexaenoic acid (DHA) and increased docosapentaenoic acid (DPA) levels in brain and to learning disadvantages. The influence of n-3 deficiency and supplementation on brain fatty acids and learning were investigated in young rats. Newborn Wistar rats were assigned to three groups of cross-foster mothers. The control group (C) was nursed by mothers that received essential fatty acids during pregnancy and lactation, and the deficient group (D) was nursed by mothers that did not receive those fatty acids. The supplemental group (S) had the same conditions as D, receiving an additional DHA and arachidonic acid supplement during lactation. Cerebral cortex and hippocampus fatty acid composition was examined using thin-layer and capillary column gas chromatography, and learning was measured by passive-avoidance procedure. D brains showed low DHA and high DPA levels, but S brain composition was similar to C. Learning in the S group was unaffected, but in the D group, it was poorer than C. Learning was directly correlated with DHA levels and inversely with DPA levels in brain. Low DHA and high DPA brain levels both were correlated with poor learning. DPA seems not to be a suitable brain functional analogue of DHA, and DHA supplementation reversed both biochemical and learning adverse effects observed in n-3 deficiency.

Influence of diet on atherogenic risk in children with renal transplants.

Cardiovascular disease is one of the main causes of morbidity and mortality in recipients of renal transplants. Although the risk for cardiovascular disease is in part genetically determined, it may also be influenced by diet. The aim of the present study was to analyze the cross-sectional association of dietary intake of nutrients with biochemical markers of atherogenic risk. The influence of diet on the plasma profile of fatty acids was specifically investigated. Twenty-nine children and adolescents (mean age 14 years, range 6-18 years) with stable renal transplants and on a normal diet recorded their food intake for a period of 3 days. The mean calorie intake was 40.6 kcal/kg per day (protein provided 16% of total calories, carbohydrates 45%, and fat 39%). Plasma levels of total cholesterol and low-density lipoprotein-cholesterol were significantly and positively related to intake of monounsaturated fatty acids ( r=0.66, P =0.007 and r =0.62, P =0.02, respectively) and to plasma levels of elaidic acid, a trans fatty acid ( r=0.43, P =0.02 and r =0.54, P =0.01, respectively). Insulin resistance, estimated from values of plasma glucose ( r=0.70, P =0.03), plasma insulin ( r=0.59, P =0.02), and HOMA index ( r=0.62, P =0.01), was also directly related to the intake of monounsaturated fatty acids. Plasma plasminogen activator inhibitor-1 activity correlated positively with total fat intake ( r=0.59, P =0.04). Plasma levels of homocysteine were negatively related to the intake of carbohydrates ( r=-0.62, P =0.02). We conclude that reasonable dietary recommendations to minimize the atherogenic risk in children with stable renal transplants should include a protein intake adjusted to the requirements for age, a large intake of carbohydrates leading to a low glycemic load, and a fat intake of less than 30% of the total calorie intake. The amount of monounsaturated and trans fatty acids in the diet should be especially limited. A sufficient intake of polyunsaturated fatty acids, with an adequate ratio between omega 6 and omega 3 components, should also be provided.

Supplementation with docosahexaenoic acid in the last trimester of pregnancy: maternal-fetal biochemical findings.

The nutritional significance of long-chain polyunsaturated fatty acids (LCPS) during the perinatal period is becoming increasingly important. There are currently very few studies on dietary intervention during gestation. The aim of the study was to analyze the effect of docosahexaenoic acid (DHA) supplementation during pregnancy on levels in both the newborn and the mother. A randomized placebo controlled study was carried out on 20 pregnant women in study group receiving 200 mg/day of docosahexaenoic acid-(DHA) during the last trimester of pregnancy. Results in both groups (A supplemented, B non-supplemented) highlighted a decrease in plasma arachidonic acid (5.99 +/- 0.91 vs. 4.51 +/- 0.71 p<0.001 for group A and 5.84 +/- 0.71 vs. 4.80 +/- 0.51 p<0.01 for group B) in the baseline-final intra-group comparison. The intergroup comparison revealed a significant difference in plasma DHA at delivery: it was found to be higher in the population of supplemented pregnant women (3.17 +/- 0.26 vs. 2.77 +/- 0.31). The neonate population displayed no significant differences between the two groups. The results show that LCPS are consumed during the final stages of pregnancy and that oral supplementation with 200 mg/day of DHA is reflected in an increase in the plasma level of this fatty acid in the mother. One could speculate that there would be a corresponding increase in DHA bioavailability for the fetus.

Genetic and metabolic determinants of increased plasma plasminogen activator inhibitor-1 activity in children with renal transplants.

Recent studies have shown that activity of plasminogen activator inhibitor-1 (PAI-1), a prothrombotic protein, may be increased in transplanted patients. The aim of the present investigation was to determine PAI-1 activity in pediatric recipients of renal transplants and to establish the relative contribution of both genetic and metabolic factors. In 29 children and adolescents with stable renal transplants, we related plasma PAI-1 activity to an indicator of inflammatory status [plasma concentration of C-reactive protein (CRP)] and to elements of the insulin resistance syndrome [body mass index (BMI), fasting insulinemia, HOMA index and plasma triglyceride, HDL-cholesterol, apolipoproteins A-1 and B concentrations]. Polymorphisms of PAI-1, apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genes were also investigated. In all patients the study was repeated 1 year later. PAI-1 activity remained constantly elevated (23.4+/-22.8 and 18.6+/-7.8 U/ml in the first and second study, respectively, P=NS). Plasma PAI-1 activity correlated positively with CRP ( P=0.001), BMI z score ( P=0.02), fasting insulinemia ( P=0.009), and HOMA index ( P=0.006). No significant correlations were found in this population between plasma PAI-1 activity and age, gender, time elapsed after transplantation and plasma homocysteine, total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein B, and apolipoprotein A-1. Plasma PAI-1 activity was not related to the cumulative dose of prednisone, cyclosporin A, or tacrolimus. Plasma PAI-1 activity was significantly higher in 5 children with apoE3/apoE4 genotype. No apparent influences of the PAI-1 4G/4G and ACE I/D genotypes were observed. In a multiple stepwise regression model, fasting insulinemia and apoE3/apoE4 genotype accounted for 45% of the observed plasma PAI-1 variability. We conclude that increased PAI-1 activity in children with stable renal transplants is determined both by genetic factors and by metabolic factors, the latter mainly linked to the insulin resistance syndrome.