Combined impact of mucosal damage and of cystic fibrosis on the small intestinal brush border enzyme activities.

In 61 cystic fibrosis (CF) patients, the small intestinal mucosa was studied at the time of diagnosis before starting therapy. In 19 out of 61 patients, partial villous atrophy on light microscopy and shortened villi on stereomicroscopic examination were seen. On the biopsy specimens, maltase, sucrase, lactase and alkaline phosphatase activities were studied. Comparison of the enzymatic activities in CF patients having damaged mucosa and a group of patients having similar mucosal lesions of unspecified origin (UTID), reveals a significantly more pronounced decrease of the alkaline phosphatase activity (p < 0.005) in the CF patients. This is in agreement with previous reported results in CF patients with normal mucosa. The abnormal mucosal findings could be due to the decreased neutralization of the gastric content delivered into the duodenum, the early inflammatory reaction present in the CF mucosa and/or to the impaired synthesis of membrane glycoproteins and enzymes secondary to the CFTR mutation.

Bilirubin-IXbeta is a marker of meconium, like zinc coproporphyrin.

BACKGROUND: Because meconium accumulates continuously in the fetal intestine, analysis of the postnatally excreted material could yield important information of intrauterine metabolism and maturation. Therefore, a study of the bilirubin pigments in meconium and in the first neonatal stools was carried out. METHODS: Meconium and stools from 37 neonates of various gestational ages were collected carefully, and stored at -20 degrees C, protected by aluminium foil. Samples were defrosted, vortex mixed with an equal amount of dimethyl sulfoxide, centrifuged, and submitted to analysis by high-pressure liquid chromatography using newly developed methods to identify and to quantitate the bilirubin-IXalpha, -IXbeta, -IXgamma, and -IXdelta isomers. In addition, samples were also submitted to diazo coupling with ethyl anthranilate. Total coproporphyrins and zinc coproporphyrin were assayed for comparison. RESULTS: Unconjugated bilirubin-IXalpha and -IXbeta were detected in meconium but not the -IXgamma or the -IXbeta isomer. Bilirubin-IXbeta was the predominant pigment and comprised 63% to 96% of the unconjugated bilirubins in the first sample of meconium excreted. Its amount decreased rapidly during the first 5 days in full-term newborns, but this occurred more slowly in preterm neonates, especially in those with a gestational age less than 30 weeks. The decrease of bilirubin-IXbeta over time correlated with that of coproporphyrin. CONCLUSIONS: Bilirubin-IXbeta is the prevailing bile pigment in the first excreted sample of meconium. It gradually decreases after birth and can be considered a biochemical marker of meconium, like zinc coproporphyrin.

Bilirubin-IXalpha and -IXbeta pigments, coproporphyrins and bile acids in meconium and stools from full-term and preterm neonates during the first month of life.

UNLABELLED: Individual bilirubin pigments in the excreta were quantitated by newly developed methods. In meconium, bilirubin-IXbeta predominated, whereas bilirubin-IXgamma and -IXdelta remained undetectable. The daily excretion of bilirubin-IXalpha plus -IXbeta was 0.03-1.00 and 0.04-2.00 micromoles kg(-1) of birthweight in preterm and full-term infants, respectively. The ratio of bilirubin-IXalpha to -IXbeta in meconium was 0.25 +/- 0.34, 0.32 +/- 0.30 and 0.46 +/- 0.55 in newborns of gestational ages below 30, from 31 to 36 and above 36 wk, respectively. The predominance of bilirubin-IXbeta disappeared within the first week in those with gestational age >31 wk but more slowly in the very preterm group. The ratio of monoconjugated to diconjugated bilirubin-IXalpha was 4 to 5 in full-term infants, whereas this ratio was only reached after 1 mo in preterm infants. The ratio of glucuronide or glucoside to xyloside varied widely, independent of gestational age. No correlation between faecal UCB-IXalpha and beta-glucuronidase was observed. The daily coproporphyrin excretion fell from a median of 500 microg on day 1 to below 20 microg from day 7 onwards; this decrease correlated with that of bilirubin-IXbeta. The daily 3alpha-hydroxylated bile acid loss in the excreta was two- to fivefold higher than in the adult; this, together with the higher neonatal serum levels (12-90 nmoles ml(-1)), indicates an immature intestinal reabsorption and an enhanced bile acid synthesis. CONCLUSION: Both zinc coproporphyrin and bilirubin-lXbeta are characteristic compounds of human meconium, diconjugated bilirubin-IXalpha is low or absent in meconium of very preterm infants, and faecal and serum bile acids are high.

Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders.

UNLABELLED: Reye syndrome, characterised by the combination of liver disease and noninflammatory encephalopathy, is a non-specific clinicopathological entity and a descriptive term covering a group of heterogeneous disorders. Nowadays, some of these patients are diagnosed more correctly as having infectious, metabolic, toxic or other disease. The non-specific case definition implies that the epidemiological studies suggesting a link with acetylsalicylic acid have been performed on a heterogeneous group of children, whereby the value of these studies and their ensuing hypothesis is weakened. Moreover, a detailed analysis of the epidemiological surveys of the Centers for Disease Control, the Yale study and of the British risk factor study provides evidence that not only the use of acetylsalicylic acid but also that of phenothiazines and other anti-emetics is significantly greater in Reye syndrome cases than in controls. As to the decline of Reye syndrome, recent literature data reveal that this is related to more accurate modern diagnosis of infectious, metabolic or toxic disease, reducing the percentage of idiopathic or true cases of Reye syndrome. CONCLUSION: Reye syndrome is a non-specific descriptive term covering a group of heterogeneous disorders. Moreover, not only the use of acetylsalicylic acid but also of antiemetics is statistically significant in Reye syndrome cases. Both facts weaken the validity of the epidemiological surveys suggesting a link with acetylsalicylic acid.

Small intestinal brush border enzymes in cystic fibrosis.

The study concerns the maltase, saccharase, lactase and alkaline phosphatase activity in small intestinal biopsy specimens from 61 consecutively admitted, untreated, Caucasian cystic fibrosis patients. A group of 319 age matched controls admitted during the same time period for undefined gastrointestinal or nutritional disorders acted as the controls. In order to eliminate morphological damage as a confounding factor, the enzyme activities were studied in small intestinal biopsy specimens having both normal stereomicroscopic and histological features. It was shown that neither maltase nor saccharase activity was different in the two groups, in contrast to lactase and alkaline phophatase activity, that was significantly lower in cystic fibrosis patients. The differences could not be explained by the nutritional status as judged by the body mass index. Lactase activity is known to be easily affected by numerous enteropathies. As the information on alkaline phosphatase activity is limited, the low activity is discussed in more detail. Taking into account the literature data, the low alkaline phosphatase activity is tentatively attributed either to enhanced release from the brush border or to the faulty handling of alkaline phophatase protein in the post-golgi compartments secondary to the accumulation of incorrectly glycosylated CFTR in the same cell structures.

Lipid digestion in cystic fibrosis: comparison of conventional and high-lipase enzyme therapy using the mixed-triglyceride breath test.

BACKGROUND: Fat maldigestion occurs in most patients with cystic fibrosis. Conventional pancreatic enzyme replacement therapy partially corrects this defect. In this study, the mixed-triglyceride breath test was used to evaluate whether high-lipase enzymes are equivalent to conventional enzymes in improving fat maldigestion in children with cystic fibrosis. METHODS: Fat digestion was studied in 11 patients with a mean age of 10.5 years. The mean intake of conventional enzyme capsules a day was 19. Four 13C mixed-triglyceride tests were performed on separate days and in random order. One test was taken without enzyme substitution, one with three capsules of 8,000 FIP units Creon (pancreatinum, Kali-chemie Pharma, Hannover, Germany) and one with one capsule of 25,000 FIP units. The fourth test was made with 13C octanoic acid to study gastric emptying time. RESULTS: Without enzyme intake, the mean cumulative percentage of 13C dose exhaled after 6 hours was 7.2+/-3.7%. This increased to 14.4+/-4% with intake of conventional pancreatinum and to 14.3+/-5.1% with intake of high-lipase pancreatinum (p = 0.0008 for both; paired t-test). There was no difference between both treatments. Also, the time course of 13C exhalation measured by percentage of 13CO2 exhaled per hour did not differ between enzyme treatments. CONCLUSIONS: The 13C mixed-triglyceride test is noninvasive and documents improved lipid digestion with pancreatic enzyme replacement therapy. If the lipase dose is kept constant, results obtained with high-lipase preparations are equivalent to those obtained with conventional preparations.

Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.

A model for calculating the hospital costs for pediatric endoscopy.

BACKGROUND: Hospitals increasingly need, besides effectiveness data, accurate and reliable cost data to allocate their resources as efficiently as possible. In this article, a framework to calculate the hospital costs of setting up a new activity is presented and applied to pediatric endoscopy. METHODS: The cost calculations were based on a detailed registration of labor time, materials, space, and equipment needed to perform endoscopy in pediatric patients in a tertiary care hospital, the University Hospital in Leuven, Belgium. RESULTS: The initial investment expenses amount to 70,000 ECU ($91,000 in U.S. money), assuming that the facilities of the adult endoscopy unit can be shared. The additional variable cost for each procedure, including labor time and materials, varies between 100 and about 170 ECU ($130 and $221 U.S.), depending on the type of endoscopy (upper or lower, diagnostic or therapeutic). These basic data can be used to calculate the total costs for pediatric endoscopy under alternative scenarios (e.g., varying total number of procedures). CONCLUSIONS: The costing exercise has given the hospital better insights into the working procedures (and hence costs) of pediatric endoscopy. Other organizations will be able to apply this framework in their setting, since all included cost components, as well as volumes and unit prices, are reported separately.

Somatostatin in the treatment of a pancreatic pseudocyst in a child.

Pancreatic pseudocyst is a know complication of acute pancreatitis and pancreatic trauma. The treatment of pancreatitis remains a challenge and the pancreatic pseudocyst is often approached surgically. Lately, the use of somatostatin and its long-acting analogue octreotide have proved useful in the treatment of pancreatitis and its complications in adults. This is the first report on the use of somatostatin in the treatment of a pancreatic pseudocyst in a child. We present the case of a posttraumatic pancreatic pseudocyst in a 10-year-old boy, regressing rapidly under somatostatin treatment, by which means surgical re-intervention could be avoided.

Gastrointestinal manifestations in cystic fibrosis.

CFTR, or cystic fibrosis transmembrane conductance regulator, the gene product that is defective in cystic fibrosis, is present in the apical membrane of the epithelial cells from the stomach to the colon. In the foregut, the clinical manifestations are not directly related to the primary defect of the CFTR chloride channel. The most troublesome complaints and symptoms originate from the oesophagus as peptic oesophagitis or oesophageal varices. In the small intestinal wall, the clinical expression of CF depends largely on the decreased secretion of fluid and chloride ions, the increased permeability of the paracellular space between adjacent enterocytes and the sticky mucous cover over the enterocytes. As a rule, the brush border enzyme activities are normal and there is some enhanced active transport as shown for glucose and alanine. The results of continuous enteral feeding of CF patients clearly show that the small intestinal mucosa, in the daily situation, is not functioning at maximal capacity. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, meconium ileus equivalent, intussusception, volvulus and silent appendicitis. In recent years colonic strictures, after the use of high-dose pancreatic enzymes, are being increasingly reported; the condition has recently been called CF fibrosing colonopathy. The CF gastrointestinal content itself differs mainly from the normal condition by the lower acidity in the foregut and the accretion of mucins and proteins, eventually resulting in intestinal obstruction, in the ileum and colon. Better understanding of the CF gastrointestinal phenotype may contribute to improvement of the overall wellbeing of these patients.

The 13C-octanoic acid breath test: a noninvasive technique to assess gastric emptying in preterm infants.

Gastric emptying (GE) is difficult to evaluate properly in preterm infants because of the lack of safe and reliable noninvasive methods. The 13C-octanoic acid breath test, a noninvasive method to assess GE, was validated in adults. The aim of this study was to adapt the methodology of the 13C-octanoic acid breath test regarding test meal and sampling methods and to define normal values for healthy preterm infants. We tested 11 clinically stable preterm infants who demonstrated normal fetal growth. The infants mean gestational age at birth was 33 weeks, mean birth weight was 1754 g, mean postnatal age at the day of study was 26 days, and mean weight was 2296 g. After a fasting period of 3 h, the subject was fed a test meal with low and stable 13C background activity mixed with 50 microliters of 13C-labeled octanoic acid and 1 g polyethylene glycol 3350. Breath samples were collected using a nasal prong in basal conditions and after the test meal. CO2 production according to weight and age was used in the calculations for 13CO2 enrichment of exhaled air. Results were expressed as percentage of 13C dose excretion per hour and percentage of cumulative 13C after 4h. gastric emptying coefficient (GEC), and gastric half-emptying time (t1/2b). The values for percent of cumulative 13C after 4 h ranged from 30.7 to 52.6% (mean, 40.2%), GEC ranged from 2.7 to 3.4 (mean, 3.0), and the values for t1/2b ranged from 17 to 100 min (mean, 57 min). We conclude that the 13C-octanoic acid breath test can be adapted to preterm infants to allow the study of GE in various conditions.

Paucity of intrahepatic bile ducts, solitary kidney and atrophic pancreas with diabetes mellitus: atypical Alagille syndrome?

UNLABELLED: A child with the tentative diagnosis of Alagille syndrome is reported. Additional renal abnormalities are unilateral kidney agenesis and a kidney with subcortical cysts with decreased function. At the age of 5 years, insulin-dependent diabetes mellitus developed, with the pancreas being atrophic and negative pancreatic islet cell antibodies. CONCLUSION: This observation extends the picture of Alagille syndrome and suggests an overlap with renal-hepatic-pancreatic dysplasia (Ivemark syndrome).

Juvenile fibrosarcoma of the temporal bone.

A case of juvenile fibrosarcoma arising from the head and neck region is described. This type of tumour should be considered as a separate entity different from the fibrosarcoma in adults because of the different clinical behaviour. The symptomatology, the radiographic features and the literature data are reviewed.

[Long-term results following premature birth]. / Langetermijnresultaten na preterme geboorte.

Along the second half of this century, survival rates of low birth weight infants, admitted to the K.U. Leuven Neonatal Intensive Care Unit, progressively increased to 67% for the < 1000 g birth weight group, to 84% for the 1000-1499 group, and to 92% for the 1500-1999 g group. At follow-up, psychomotor development at the age of 1 year was considered to be normal in about 70% of the surviving infants with birthweight < 1000 g, in about 75% in the 1000-1499 g group and in about 80% of the 1500-1999 g group. At the end of the second year of grammar school 77% succeeded, 3% failed and 18% followed special schools. A significant correlation is found between the Bailey developmental scale at the age of 7 months and the WPPSI intelligence score at the age of 5 years.

Birth weight and early lung compliance as predictors of short-term outcome in premature infants with respiratory distress syndrome.

In addition to birth weight (BW), respiratory mechanics during the first week of life have been reported to predict outcome in ventilated newborn infants with respiratory distress syndrome (RDS). Most measuring techniques are invasive, requiring the placement of an oesophageal tube or balloon. In the present study the compliance (Crs) and resistance (Rrs) of the total respiratory system were measured without an oesophageal tube , using a commercially available system (PEDS; MAS Inc., Hatfield, Pa.) . The Crs and Rrs were determined once, within 24 hours of birth, in 28 preterm infants requiring mechanical ventilation for RDS. Variables such as gestational age (GA) and BW were also evaluated for their predictive role in outcome. Poor outcome was defined as death from respiratory failure or the development of bronchopulmonary dysplasia (BPD) at 28 days. All non-survivors died of refractory respiratory failure, at a median of age of 6 days. The median Crs of the 21 survivors was 0.5 ml/cm H2O and of the non-survivors 0.21 ml/cm H2O (P = 0.01). Crs below 0.45 ml/cm H2O predicted 15 of the 16 infants who either developed BPD or died (positive predictive value 100%; negative predictive value 92%; sensitivity 94%; specificity 100%). Nine survivors, who subsequently developed B PD, had a median Crs of 0.38 ml/cm H2O. Their Crs was significantly lowe r than that of the infants without evidence of BPD (Crs = 0.61 ml/cm H2O ) (P = 0.01). All of the 12 babies without BPD who survived had median C rs values above 0.45 ml/cm H2O. The median Rrs of the 9 infants with BPD (96 cm H2O/l/s) was also significantly higher than the Rrs value of the non-BPD group (59 cm H2O/l/s) (P = 0.05). When stepwise multiple logistic regression was applied to predict outcome, the only variable that could be entered at a 0.05 level of significance was BW. Uncorrected compliance entered the second step, but did not reach statistical significance. We conclude that in premature infants with RDS, BW is a strong predictor of outcome. Although determination of the Crs within the first 24 hours after birth did not add significance to this predictive model, it was nevertheless a useful parameter to determine respiratory morbidity and mortality.

Specific decrease of anti-pseudomonal IgA after anti-pseudomonal therapy in cystic fibrosis.

UNLABELLED: In patients with cystic fibrosis (CF) and chronic colonisation with Pseudomonas aeruginosa, specific anti-pseudomonal IgG and IgA, as well as serum immunoreactive protein C, WBC and differential count, ESR, pulmonary function and chest radiograph score were determined before and after a 2 week intravenous course of anti-pseudomonal antibiotics in 32 cases of acute exacerbation of pulmonary infection. Specific anti-pseudomonal IgA but not specific anti-pseudomonal IgG decreased significantly after treatment. Log of anti-pseudomonal IgA but not log anti-pseudomonal IgG correlated well with disease severity as assessed by the Brasfield chest radiograph score (r 0.57), forced expiratory volume in 1 s (r 0.6) as well as C-reactive protein (r 0.62). CONCLUSION: Specific anti-pseudomonal IgA may be a better parameter than specific IgG in the follow up of lung infection in patients with CF, probably because it more closely reflects ongoing endobronchial infection, the major pathology in CF lungs.