Energy expenditure in infants with congenital heart disease, including a meta-analysis.

AIM: To assess energy requirements and body composition in preoperative children with congenital heart disease (CHD). METHODS: In 11 infants with CHD (2-8 mo), total daily energy expenditure (TDEE) and total body water (TBW) were measured with doubly labelled water and compared with historic data from healthy controls. Within the patient group, energy expenditure of infants with versus those without congestive heart failure was compared. Subsequently, the data were pooled with literature data in meta-analyses. RESULTS: CHD patients showed increased TBW (mean +/- SD 66 +/- 3 vs 58 +/- 5% of body weight, p < 0.05) and energy expenditure (381 +/- 42 vs 298 +/- 36 kJ kg(-1) d(-1), p < 0.001). Meta-analyses showed that CHD infants have 35% increased TDEE (376 vs 278 kJ kg(-1) d(-1) , p < 0.00001) and 7% higher TBW (p < 0.0001). Coexistent congestive heart failure (treated with diuretics) had no influence on TDEE (mean difference 14 kJ kg(-1) d(-1) , not significant). In patients with heart failure and growth retardation, an energy balance study showed an average 12% loss of initially ingested energy due to vomiting, increased TDEE and low faecal energy loss, resulting in low energy available for growth, compared with controls (42 +/- 30 vs 96 +/- 61 kJ kg(-1) d(-1) , p < 0.05). CONCLUSION: Many infants with CHD require substantially higher energy intake (at least 100 kJ kg(-1) d(-1) extra) owing to increased TDEE, which is not explained by a higher percentage of body water. Coexistent heart failure does not appear to have an additional influence on TDEE. In infants with CHD and growth failure factors other than elevated TDEE, including vomiting, may explain the disturbed energy balance.

Effects of therapy with lansoprazole on intestinal permeability and inflammation in young cystic fibrosis patients.

BACKGROUND: Defective pancreatic bicarbonate secretion with low intestinal pH or intestinal inflammation of any origin increase intestinal permeability in cystic fibrosis (CF). METHODS: In this open study, the authors evaluated the effect of a proton-pump inhibitor on intestinal permeability and inflammation in 14 young, pancreatic-insufficient CF patients. Permeability was measured by a three-sugar permeability test before and after 1 year of lansoprazole use, and urinary nitric oxide (NO) oxidation products were assessed before and during that year as a marker of inflammation. RESULTS: After 1 year of lansoprazole use, median urinary recovery percentages changed from 2.5% to 1.7% (P = 0.064), from 24.9% to 24.5% (no significance), and from 10.5% to 11.1% (no significance) for lactulose, mannitol, and L-rhamnose, respectively. Despite the fact that the median urinary excretion ratios decreased from 0.108 to 0.083 (P = 0.03) and from 0.246 to 0.176 (P = 0.016) for lactulose and mannitol and for lactulose and rhamnose, respectively, they both remained increased. Median urinary NO products-to-creatinine ratios were 0.287 for CF patients before lansoprazole and 0.130 for healthy control participants (P = 0.002). Although there was a tendency toward a decrease in the NO products-to-creatinine ratio during treatment, this was not significant at the end point. CONCLUSIONS: Intestinal permeability is considerably increased in CF patients and is partly corrected after the use of a proton-pump inhibitor for 1 year, which may point to a harmful effect of the acid luminal contents on the tight junctional related paracellular permeability pathway. The start and end values for the NO products-to-creatinine ratio in CF patients were not significantly different, but were considerably increased when compared with control participants (P = 0.002).

Are children with cystic fibrosis who are treated with a proton-pump inhibitor at risk for vitamin B(12) deficiency?

BACKGROUND: In a recent study, the authors demonstrated the beneficial effect of proton-pump inhibitors (PPI) on fat malabsorption and bone mineral content in children with cystic fibrosis (CF). Prolonged use of PPI could result in vitamin B(12) deficiency as a consequence of impaired release of vitamin B(12) from food in a nonacid environment. The aim of this study was to evaluate the vitamin B 12 status of CF patients either treated with a PPI or not by measuring vitamin B(12) and homocysteine blood levels, the latter being a sensitive indicator of vitamin B(12) deficiency. METHODS: The study population consisted of 20 CF patients, 11 patients treated with a PPI for at least 2 years and 9 patients not treated with a PPI, and 10 healthy, age-matched control participants. Homocysteine blood levels were measured by high-performance liquid chromatography, and vitamin B(12) levels were measured by a competitive protein-binding assay. RESULTS: Vitamin B(12) levels were significantly higher in both CF groups compared with the control participants (PPI+, P = 0.02; PPI-, P = 0.009). There was no significant difference in vitamin B(12) levels between both CF groups. Homocysteine levels were normal and similar in all groups. CONCLUSIONS: Cystic fibrosis patients treated with a PPI for at least 2 years show no signs of vitamin B(12) deficiency.

Acid steatocrit: a reliable screening tool for steatorrhoea.

UNLABELLED: This study compared the acid steatocrit (AS) results of healthy children with those of sick children with and without gastrointestinal involvement. Stool samples of 166 children were investigated, comprising 50 healthy children, 26 asthma patients, and 90 patients with gastrointestinal problems divided into 34 treated cystic fibrosis (CF) patients with exocrine pancreatic insufficiency, 16 untreated coeliac disease (CD) patients and 40 patients with various gastrointestinal problems. The median values (5th-95th percentile) of AS results were 3.3% (0.0-21%) for healthy children, 4.5% (1.8-22.5%) for asthma patients, 24.7% (2.6-68.2%) for treated CF patients with exocrine pancreatic insufficiency, 19.8% (3-77.7%) for untreated CD patients and 5.5% (1.8-29%) for patients with various gastrointestinal diseases. CONCLUSION: The AS results of treated CF patients with exocrine pancreatic insufficiency and untreated CD patients were similar and significantly higher than those of healthy children and asthma patients. AS can be considered to be a reliable tool in screening for steatorrhoea in paediatric patients.

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates.

Four neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 micromol/L) were investigated further to differentiate between phenylalanine hydroxylase (PAH) deficiency and variant hyperphenylalaninaemia (HPA) forms. In patients 1 and 2 a tetrahydrobiopterin (BH4) load caused a significant decrease of the plasma Phe levels. A combined phenylalanine/BH4 loading test was performed in patients 2, 3 and 4. In the latter two patients, plasma Phe concentrations completely normalized within 8 h after the BH4 load (20 mg/kg). Basal urinary pterins were normal in all four patients. The activity of dihydropteridine reductase (DHPR) was normal in patients 1, 2 and 3 and 50% of control values in patient 4 (not in the range of DHPR-deficient patients). In patient 3 a subsequent phenylalanine loading test with concomitant analysis of plasma biopterins revealed a normal increase of biopterin, excluding a BH4 biosynthesis defect. Pterins and neurotransmitter metabolites in CSF of patients 1, 3 and 4 were normal. DNA mutations detected in the PAH gene of patients 1-4 were A313T, and L367fsinsC; V190A and R243X; A300S and A403V; R241C and A403V. The results are suggestive for mutant PAH enzymes with decreased affinity for the cofactor BH4.

Changes in pulmonary hyperinflation and bronchial hyperresponsiveness following treatment with lansoprazole in children with cystic fibrosis.

SUMMARY. In this prospective open study of 14 children with cystic fibrosis (CF), we evaluated the effect of 1 year adjuvant therapy with lansoprazole, a proton pump inhibitor (PPI), on growth, fecal fat loss, body composition and lung function. Only stable patients with pancreatic insufficiency were included, and their data were compared to those of a large Dutch pediatric normal reference population. During the use of the PPI, mean weight and height did not change significantly, while body mass index improved (P < 0.05). An immediate significant and persistent reduction of fecal acid steatocrit (P < 0.05) was demonstrated. Compared to normal Dutch children, the CF patients showed significantly decreased standard deviation scores (SDS) for total body fat (TBF, -0.966) and fat-free mass (FFM, -1.826). Under lansoprazole, TBF improved significantly (P < 0.05), while mean FFM remained unchanged. A significant improvement in total lung capacity (P < 0.05), residual volume (P = 0.055), and maximal inspiratory mouth pressure (P = 0.002) was also demonstrated. Hyperinflation tended to decrease during the use of a PPI. Daily recordings of peak expiratory flow (PEF) showed a maximal diurnal variability of 28% of recent best PEF and minimal morning PEF of 72% of recent best PEF, confirming that bronchial hyperresponsiveness is increased in CF. We conclude that adjuvant therapy with lansoprazole in young CF patients with persistent fat malabsorption, decreased fat losses and improved total body fat. Lung hyperinflation decreased, which may partly explain the improvement in inspiratory muscle performance. The simultaneous improvements in body composition and lung hyperinflation suggest a relationship between these two parameters. Further research is necessary to confirm such a relationship and to elucidate the mechanisms involved.

Neuroleptic malignant syndrome during zuclopenthixol therapy in X-linked cerebral adrenoleukodystrophy.

An 8 year-old boy with X-ALD under treatment with simvastatin developed a severe adverse reaction when the dose of his other medication, zuclopenthixol was increased. Both drugs were withdrawn after a diagnosis of neuroleptic malignant syndrome was made.

Measurement of total body water in children using bioelectrical impedance: a comparison of several prediction equations.

BACKGROUND: Body composition evaluation by bioelectrical impedance analysis in children makes use of different group-specific population-derived equations. The present study was conducted to attempt to validate the use of population-independent physical model-derived equations in children. METHODS: The validity of bioelectrical impedance analysis for the measurement of total body water in children was evaluated by comparing results of two physical model-derived and two population-derived equations with those of deuterium dilution as reference method in a group of 38 heterogeneous children. RESULTS: Means +/- standard deviation (in liters) for total body water measured with deuterium dilution and the physical model 1-derived equation were 18.4 +/- 4.7 L and 18.1 +/- 4.4 L, respectively. This difference is not significant, whereas significant differences were found for all other tested equations. Significant smaller absolute differences between the model 1 equation and deuterium reference results were found when compared with the results of the other three tested equations. CONCLUSION: When compared with results of the reference deuterium method the physical model 1-derived equation was the only one that provided reliable total body water results by bioelectrical impedance analysis in children.

Regulation of lipopolysaccharide-induced NO synthase expression in the major organs in a mouse model. The roles of endogenous interferon-gamma, tumor necrosis factor-alpha and interleukin-10.

Elevated NO production mediated by activation of the enzyme iNOS is thought to play a central role in the development of tissue damage observed during septic shock. IFN-gamma, TNF-alpha and IL-10 have been shown to be involved in the regulation of LPS-induced serum levels of the NO-oxidation products nitrate and nitrite. Therefore, in the present study, we investigated the role of endogenous IFN-gamma, TNF-alpha and IL-10 in the regulation of LPS-induced tissue iNOS expression in the major organs. To this end, mice were pre-treated with anti-IFN-gamma, anti-TNF-alpha, anti-IL-10 monoclonal antibodies, or combinations of these, two hours before intraperitoneal LPS-challenge. Immunohistochemical staining for iNOS and determination of iNOS activity indicated that iNOS expression was mainly upregulated in the small intestine, lung and heart, and that IFN-gamma, TNF-alpha as well as IL-10 are involved in the regulation of iNOS expression and enzyme activity. Whereas blocking either IFN-gamma or TNF-alpha did not affect iNOS expression, iNOS enzymatic activity seems to be inhibited. In contrast, blocking both mediators nearly completely prevents iNOS expression after LPS challenge, suggesting that the presence of either IFN-gamma or TNF-alpha is essential for LPS-induced iNOS expression in these organs. Combined treatment of these monoclonal antibodies revealed that whereas on the one hand IL-10 inhibits LPS-induced iNOS expression, on the other hand IL-10 or an IL-10 inducible factor is also involved in the upregulation of iNOS expression after LPS challenge.

Increased urinary nitric oxide oxidation products in children with active coeliac disease.

BACKGROUND: Nitric oxide (NO) production catalyzed by iNOS (inducible NO synthase) is thought to take place mainly in macrophages after activation by inflammatory mediators. NO is subsequently oxidized to nitrite and nitrate, which are excreted in urine. The concentration of inflammatory mediators in small bowel biopsy specimens from patients with coeliac disease is increased. The latter could induce increased NO production by stimulation of intestinal macrophage iNOS, resulting in high levels of urinary NO oxidation products, nitrite and nitrate (NOx). AIM: In the present study we evaluated the urinary NOx/creatinine ratios in children with active coeliac disease (n = 22), coeliac disease patients on a gluten-free diet (n = 9), healthy (n = 11) and sick control children (n = 18). METHODS: The Griess reagent method was used for measuring urinary NOx. RESULTS: Median NOx/creatinine ratios of active coeliac disease patients, coeliac disease patients on a gluten-free diet, healthy and sick control patients were 1.21, 0.19, 0.10 and 0.13 mmol/mmol, respectively. All active coeliac disease patients showed increased NOx/ creatinine ratios. Urinary NOx/creatinine ratios of the active coeliac disease patients were significantly higher than those of healthy controls (p < 0.0001), sick controls (p < 0.0001) and coeliac disease patients on a gluten-free diet (p < 0.0001). CONCLUSION: The urinary NOx/creatinine ratio is increased in patients with active coeliac disease and reverts to normal on a gluten-free diet.

Oral spermine administration inhibits nitric oxide-mediated intestinal damage and levels of systemic inflammatory mediators in a mouse endotoxin model.

Enhanced intestinal nitric oxide production observed during sepsis is thought to play a central role in lipopolysaccharide-induced intestinal damage. In contrast intestinal polyamines, both from endogenous and exogenous origin, are essential for the maintenance of mucosal integrity. Polyamines have been shown to inhibit lipopolysaccharide-induced nitric oxide release in vitro and have been claimed to exert additional antiinflammatory actions. In this study, the effect of the polyamine spermine on the release of the proinflammatory mediators nitric oxide and tumor necrosis factor-alpha by a murine macrophage cell line was investigated. Furthermore, we investigated whether oral spermine administration inhibits lipopolysaccharide-induced intestinal inducible nitric oxide synthase and nitrotyrosine expression and modulates the release of inflammatory mediators. Our results show that although spermine inhibited lipopolysaccharide-induced nitric oxide release in a murine macrophage cell line, no effect on tumor necrosis factor-alpha release was observed. In addition, oral spermine administration inhibited intestinal inducible nitric oxide synthase and nitrotyrosine expression suggesting a protective effect of spermine on lipopolysaccharide-induced intestinal damage. In parallel a decrease in serum levels of the proinflammatory mediators nitrate, nitrite, and interferon-gamma and an increase in the antiinflammatory cytokine interleukin-10 was observed, although tumor necrosis factor-alpha levels were unaffected. These results indicate that spermine inhibits lipopolysaccharide-induced nitric oxide release in vitro as well as in vivo. Further, intraluminally derived polyamines modulate the systemic immune response. It is concluded that oral spermine administration might have therapeutic perspectives for several disorders characterized by systemic inflammation and intestinal damage.

Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA.

Inflammation is characterized by increased nitric oxide production. Nitrotyrosine has recently been suggested to be useful as a marker for NO-mediated tissue damage. In context of the development of an ELISA for detection of nitrotyrosine in plasma, monoclonal anti-nitrotyrosine antibodies were developed by injecting mice with nitrated keyhole limpet hemocyanin. The specificity of the antibodies was determined by binding to nitrated BSA, lack of binding to unmodified BSA, tyrosine, 3-chlorotyrosine or phenylalanine and inhibition of binding by nitrotyrosine. The antibodies developed are useful for Western blot analysis and immunohistochemical staining. Using these antibodies a nitrotyrosine sandwich ELISA was developed with a lower detection limit of approximately 0.2 nM. The intra- and interassay variance were 2.4% and 11.9%, respectively. Using this newly developed ELISA, 1.27 +/- 1.03 microM nitrotyrosine was detected in plasma samples of celiac disease patients whereas nitrotyrosine was undetectable in control samples. Elevated nitrotyrosine levels were paralleled by an increase in plasma concentrations of NO-oxidation products (NOx), nitrite and nitrate from 15.1 +/- 6.1 microM in controls to 61.0 +/- 28.2 microM in celiac disease patients. Both nitrotyrosine and NOx levels declined when the patients were on a gluten-free diet, suggesting a relation between intestinal inflammation and plasma nitrotyrosine and NOx levels.

Effects of a proton-pump inhibitor in cystic fibrosis.

Most children with cystic fibrosis (CF) show persisting steatorrhoea even when treated with pancreatic enzyme. As a low duodenal pH could be responsible for this persisting fat loss, we evaluated the effects of a proton-pump inhibitor (lansoprazole) on both steatorrhoea and growth parameters in 15 CF patients, aged 3.1-22.6 y. Acid steatocrit, anthropometry and dual-energy X-ray absorptiometry were used to evaluate steatorrhoea and the nutritional status before, during and 3 months after stopping lansoprazole treatment (15 mg/d for 3 months). Mean +/- SD acid steatocrit values decreased from 37.1 +/- 8.8% to 28.5 +/- 10.6% (p = 0.02). Significant mean Z-score improvements were found for weight (+0.14; p = 0.02), height (+0.15; p = 0.03), subscapular (+0.61; p = 0.003), supra-iliac (+0.8; p = 0.002) and the sum of the four measured skinfolds (+0.61; p = 0.002). Z-scores deteriorated again after stopping lansoprazole. Fat mass and bone mineral content increased significantly on lansoprazole (p = 0.008 and p = 0.005, respectively). We conclude that lansoprazole as adjuvant therapy significantly improves both steatorrhoea and the nutritional status in CF children who maintain steatorrhoea while on pancreatic enzymes.

The role of endogenous IFN-gamma, TNF-alpha and IL-10 in LPS-induced nitric oxide release in a mouse model.

Mice injected with lipopolysaccharide (LPS) develop lethal septic shock, accompanied by elevated serum NOx, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha) and TNF-receptor levels. Elevated NO levels are thought to play a central role in tissue damage observed during septic shock. In vitro data indicate that IFN-gamma and TNF-alpha play an important role in LPS-induced NO release. Further, interleukin 10 (IL-10) has been shown to inhibit the release of pro-inflammatory cytokines such as IFN-gamma and TNF-alpha. Therefore, in the present study, we investigated the role of IFN-gamma, TNF-alpha, and IL-10 in LPS-induced NO release. To this end, mice were pretreated with anti-IFN-gamma, anti-TNF-alpha, anti-IL-10 mAbs or combinations of these 2 h before LPS-challenge. The results indicate that IFN-gamma, TNF-alpha as well as IL-10 are involved in the regulation of LPS-induced NO release. Blocking either IFN-gamma or TNF-alpha has no effect on LPS-induced NO release, however, blocking both IFN-gamma and TNF-alpha nearly completely prevents NO release after LPS challenge, suggesting that the presence of either TNF-alpha or IFN-gamma is essential for induction of NO release after LPS challenge. Further, the results obtained with anti-IL-10 treatment suggest the presence of an IL-10 inducible factor which together with IFN-gamma and TNF-alpha regulates LPS-induced NO release.

Long-term growth of children with congenital heart disease: a retrospective study.

This retrospective study evaluates long-term growth of children with congenital heart disease (CHD) and looks for possible relationships between postsurgical catch-up growth and both severity of preoperative growth failure and operation age. Growth data of 123 children with isolated CHD were available. Mean z-scores and 95% confidence intervals for weight, height and weight-for-height were plotted for age-periods as well as for pre- and postoperative periods. Growth of children with a large VSD or a Tetralogy of Fallot was most abnormal and improved but did not normalize after operation. Catch-up growth for length was strongly correlated with severity of the preoperative growth failure (r = 0.92, p < 0.05) but not with operation age (r = 0.20, NS). We conclude that surgical correction results in catch-up growth for most individuals. Catch-up growth is positively correlated with the severity of the initial growth disturbance and not with age at the moment of surgical correction.

Spermine induces maturation of the immature intestinal immune system in neonatal mice.

BACKGROUND: In mice, immunological adaptation of the gut to microbial and nutritional antigens occurs at weaning in parallel with biochemical and morphological maturation. Because oral administration of spermine to neonatal rats has been shown to induce biochemical and morphological maturation, we investigated whether spermine also affects maturation of the mucosal immune system. METHODS: Swiss mice 7, 12, and 27 days old were given spermine orally (0.5 mumol/g body weight) during 3 days. Intestinal length was measured, and lactase and sucrase activities were determined. The phenotype of intraepithelial and lamina propria lymphocytes was assessed by FACS analysis using markers for CD3, TCR alpha beta, TCR gamma delta, CD4, CD8 alpha, CD8 beta, CD5, CD18, CD54, and CD49d. RESULTS: Similar to what occurs during natural development, spermine treatment of neonatal mice increased intestinal length, decreased lactase activity, and increased sucrase activity. The percentage of intraepithelial lymphocytes expressing TCR alpha beta, CD4, CD5, and CD54, as well as the levels of expression of these antigens, increased after spermine treatment on day 12, similarly to natural maturation. The increase in expression of CD3, TCR gamma delta, CD18, and CD49d did not reach statistical significance. No effect was observed on CD8 expression. The phenotype of lamina propria lymphocytes was not affected. Spermine administration to 7- and 27-day-old mice had no effect on the phenotype of either intraepithelial or lamina propria lymphocytes. CONCLUSIONS: Oral spermine administration to neonatal mice induced, in parallel with biochemical maturation, precocious maturation of the murine intestinal immune system and particularly affected differentiation of the intraepithelial lymphocyte population.

Clinical use of acid steatocrit.

Malabsorption of fat is an important gastrointestinal cause of malnutrition and growth retardation in childhood. The gold standard for the evaluation of fat malabsorption is the faecal fat balance method. The acid steatocrit method has recently been introduced as a simple method to evaluate faecal fat. The present study was aimed at evaluating the acid steatocrit in clinical practice. Faecal fat excretion and acid steatocrit results were determined in 42 children, half with and half without fat malabsorption. Acid steatocrit results correlated significantly with both faecal fat excretion (p < 0.01) and faecal fat concentration (p < 0.001). Sensitivity and specificity of the acid steatocrit for the diagnosis of malabsorption were 90% and 100%, respectively. We consider the acid steatocrit method useful for the screening and monitoring of patients with steatorrhoea.

Fasting gastric fluid and fecal polyamine concentrations in premature infants.

BACKGROUND: The role of milk polyamines in the development of the gastrointestinal tract of human infants is presently unknown. Polyamine concentrations are higher in human milk than in infant formulas. The aim of the present study was to gather data on luminal polyamines by measuring gastric fluid and fecal polyamine concentrations in premature infants during the postnatal period. We further compared gastric fluid polyamine concentrations with those reported for milk and looked for possible relationships between luminal polyamine concentrations, age, and growth rate. METHODS: High-performance liquid chromatography was used for the measurement of polyamine concentrations in both fecal and gastric fluid samples. RESULTS: Ninetieth centiles for gastric polyamines during the first week were 62, 28, 82, and 14 microM for putrescine, spermidine, spermine, and cadaverine, respectively. These values are higher than those reported for human milk and infant formulas. Polyamine concentrations were unrelated to either age or growth rate. Ninetieth centiles for fecal polyamines during the first week were 7668, 5176, 53, and 75 microM for cadaverine, putrescine, spermidine, and spermine, respectively. CONCLUSIONS: Fasting gastric fluid polyamine concentrations in premature infants are higher than those reported for either human milk or infant formulas. The high fecal cadaverine and putrescine concentrations are probably of bacterial origin.