TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.

OBJECTIVES: Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Frequency of epithelioid granulomas in colonoscopic biopsy specimens from paediatric and adult patients with Crohn's colitis.

AIMS: To test the assumption that epithelioid granulomas found in colonoscopic biopsy specimens in patients with Crohn's colitis are markers of a different clinical behaviour. METHODS: Sections from colonoscopic biopsy specimens from 352 consecutive patients (119 children and 233 adults) were investigated. RESULTS: A total of 1117 colonoscopies were performed: 293 in children (mean 2.46 per patient) and 824 in adults (mean 3.53 per patient) (p<0.05). Granulomas at initial colonoscopy were recorded in 67.2% (43/64) of children and 65.9% (27/41) of adults (p>0.6), and at subsequent colonoscopies in 53.8% (64/119) of children and 17.6% (41/233) of adults (p<0.05). Surgical intervention was required in 6.3% (4/64) of the children having previous granuloma, but also in 14.5% (8/55) of those without previous granuloma, the rate for operated adults being 26.8% (11/41) and 24.5% (47/192), respectively (p>0.6). CONCLUSIONS: Granulomas in entry and/or in subsequent colonoscopic biopsy specimens in patients with Crohn's colitis did not predict the need for subsequent surgical intervention. The fact that the frequency of granulomas was significantly higher in children than in adults with Crohn's colitis (despite a higher mean number of colonoscopic biopsies in adults), and that granulomas were present in colonoscopic biopsy specimens but not in the subsequent surgical specimens from 50% of the paediatric and 36% of the adult patients strengthen the conviction that granulomas in Crohn's colitis might evolve or regress at different time intervals during the course of the disease. This behaviour would reflect a particular immunological reaction, an epiphenomenon from immature tissues-as in children-when challenged by the so far elusive aetiological agent responsible for Crohn's disease.

Radiological findings in children with acute pneumonia: age more important than infectious agent.

PURPOSE: To evaluate whether radiological findings and healing time in children with pneumonia are correlated to etiologic agent. MATERIAL AND METHODS: A total of 346 children with radiologically verified acute pneumonia, and with accomplished serological tests for bacteria and viruses, were included in the study. Five etiological groups were analysed: children with bacterial etiology only, with viral etiology only, with mixed bacterial and viral etiology, with Mycoplasma only, and children with no etiology. RESULTS: The chest films of each etiological group were analysed and the findings were correlated to the children's age. The radiological findings did not differ between the etiological groups. Radiological findings correlated significantly with the patient's age. The radiological healing frequency at check-up X-ray was found to be significantly lower in children with mixed bacterial and viral etiology compared to children in each of the other groups and to the material as a whole. CONCLUSION: Conclusions about the etiology could not be drawn from the chest X-ray findings.

Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990-2001.

BACKGROUND: An increased incidence of paediatric Crohn's disease was reported recently by our group. AIMS: To assess the incidence and characteristics of inflammatory bowel disease (IBD) in northern Stockholm between 1990 and 2001. METHODS: All records of individuals 0-15 years of age with suspected IBD in the population based catchment area of 180000 individuals were scrutinised using defined diagnostic criteria. Patient files were searched for relatives with IBD, and for concomitant autoimmune diseases. RESULTS: A total of 152 children were diagnosed with IBD, corresponding to an overall incidence (per 100000) of IBD of 7.4. The incidence of Crohn's disease (CD) was 4.9, ulcerative colitis (UC) 2.2, and indeterminate colitis 0.2. Between 1990 and 2001, there was a marked increase in the incidence of CD while the incidence of UC was almost unchanged, leading to a net increase in the overall occurrence of IBD. There was a male dominance of CD. Fourteen per cent and 11% of patients with CD and UC, respectively, had a first or second degree relative with IBD. Eighteen per cent and 10% of patients with CD and UC, respectively, had a concomitant autoimmune disease. Ten patients with CD (10%) underwent surgery. CONCLUSIONS: The incidence of CD has increased in northern Stockholm. The current incidence is higher than that reported from other areas. Our results suggest a shift in presentation and diagnosis from UC towards CD, but also a net increase in IBD. Concomitant autoimmune disorders and family history are common in paediatric IBD.

CARD4/NOD1 is not involved in inflammatory bowel disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

Transanastomotic feeding tube after an operation for duodenal atresia.

UNLABELLED: The aim of this study was to answer the question whether or not, after an operation for duodenal atresia, a transanastomotic feeding tube reduces the time to full preanastomotic feeding. The method used was a retrospective study and a prospective observation. 18 consecutive newborns with duodenal atresia, nine from each of two different centres of paediatric surgery, were studied retrospectively. The patients in one centre received a nasogastric tube and a transanastomotic feeding tube during the operation, while in the other centre only a nasogastric tube was used. Seven control patients with duodenal atresia treated postoperatively with a nasogastric tube and a transanastomotic feeding tube were prospectively observed. The main outcome measure used to compare these two groups was the time required to achieve full preanastomotic feeding. RESULTS: The patients who were treated postoperatively with the transanastomotic feeding tube needed significantly less time to achieve full preanastomotic feeding than those with a nasogastric tube only (P < 0.001, Mann-Whitney U test). CONCLUSION: The use of a transanastomotic feeding tube, after an operation for duodenal atresia, leads to earlier full preanastomotic feeding.

Rectal nitric oxide assessment in children with Crohn disease and ulcerative colitis. Indicator of ileocaecal and colorectal affection.

BACKGROUND: Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD). Measurements of luminal NO in Crohn disease and ulcerative colitis have revealed that levels are increased during active disease. We aim to evaluate whether rectal measurements of NO can reveal active disease of the colon as well as ileum. METHODS: Sixteen children with active Crohn disease in the ileocaecal or colorectal regions of the gut and 6 children with active ulcerative colitis were compared to a group of 14 healthy children. Gaseous samples for analysis of luminal NO were collected using a Foley catheter inserted into rectum. The balloon of the catheter was filled with NO-free air and incubated for 10 min. After aspiration, samples were analysed using chemiluminescence. Values are expressed as median and range. RESULTS: In healthy children, rectal NO values were 60 (0-275) ppb. In children with Crohn disease of the colorectal region, NO concentrations were 5,675 (300-49,350) ppb (P < 0.001), while those with Crohn disease of the ileocaecal region had NO levels of 2,625 (300-15,000) ppb (P < 0.01). In children with ulcerative colitis, NO values of 5,500 (950-34,000) ppb were found (P < 0.001). CONCLUSION: Rectal NO levels are greatly increased in children with IBD. Highest values were found in patients with colorectal engagement, but rectal NO was increased also in ileocaecal disease. Rectal sampling of luminal NO is a simple and minimally invasive method and should be considered a diagnostic tool for intestinal inflammatory activity in children regardless of primary disease location.

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Genetic refinement and physical mapping of a chromosome 16q candidate region for inflammatory bowel disease.

Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37x10(-4)) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P<0.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1.

Early development of human gastric H,K-adenosine triphosphatase.

BACKGROUND: Little is known about the early development of the gastric acid secretion in human neonates. The purpose of this study was to examine the early development of gastric H,K-adenosine triphosphatase (ATPase) by analyzing human gastric biopsy specimens. METHODS: Eighty-eight neonates from week 25 to week 42 of gestation who were treated in a neonatal intensive care unit underwent gastroscopy with biopsy specimens obtained from the corpus. The expression of gastric H,K-ATPase protein in the gastric biopsy specimens was assessed by Western blot analysis, using an antibody directed against the gastric H,K-ATPase. The amount of H,K-ATPase expressed was compared with age, gender, clinical factors, diseases, and the macroscopic and histologic findings at endoscopy. RESULTS: The expression of human gastric H,K-ATPase increased significantly with gestational age. There was a significant increase in the expression of gastric H,K-ATPase during the first 82 days after birth. Boys had a significantly higher expression of gastric H,K-ATPase than girls did, when it was adjusted for gestational and postnatal age. Neither the clinical features nor treatments showed significant correlations with the expression of human gastric H,K-ATPase when controlling for gestational and postnatal age. CONCLUSIONS: This study shows that human gastric H,K-ATPase is expressed from week 25 of gestation, which agrees with earlier findings of gastric pH in preterm infants. The amount of enzyme expressed increases with gestational and postnatal age. The authors speculate that the susceptibility to gastric lesions seen in neonates is not related to the amount of H,K-ATPase. However, studies elucidating the ontogeny of gastric mucosal defense mechanisms are warranted.

The effect of a 1-hour training program on the incidence of bacteremia in pediatric patients receiving parenteral nutrition.

The effect of a 1-hour nurse training program on the frequency of bacteremia in patients receiving parenteral nutrition was evaluated in a pediatric tertiary center. All of the nurses had previous instruction on aseptic techniques in nursing school. The current program focused on aseptic management of intravenous catheters and implanted subcutaneous ports in patients receiving parenteral nutrition (PN). One hundred eighty-four nurses had a 1-hour training session in groups of three to five. The frequency of bacteremia in children receiving PN was not reduced (9.2% versus 8.9%), and there was no significant difference in time from the start of PN to the diagnosis of bacteremia (P = 0.31). The authors conclude that a 1-hour training session for the nursing staff was not sufficient. It is suggested that staff training for prevention of bloodstream infections associated with intravascular devices should cover a wider range of topics and take place over a longer period of time.

Incidence of paediatric Crohn's disease in Stockholm, Sweden.

We report an increase in the incidence of Crohn's disease in northern Stockholm, Sweden.

Helicobacter pylori gastritis in children: efficacy of 2 weeks of treatment with clarithromycin, amoxicillin and omeprazole.

Thirty-eight children with Helicobacter pylori gastritis diagnosed by histopathology, and/or bacteriological culture were treated with omeprazole, amoxicillin and clarithromycin. Follow-up endoscopy was performed in 34 children. Outcome was measured by negative histology and culture for H. pylori. Six patients were excluded. Of the 32 remaining children eradication was achieved in 75% (95% confidence interval 60-90%).

Dopamine-dependent inhibition of jejunal Na+-K+-ATPase during high-salt diet in young but not in adult rats.

During high-salt diet endogenous dopamine (DA) reduces jejunal sodium transport in young but not in adult rats. This study was designed to evaluate whether this effect is mediated, at the cellular level, by inhibition of Na+-K+-ATPase activity. Enzyme activity was determined in isolated jejunal cells by the rate of [gamma-32P]ATP hydrolysis. Cells were obtained from weanling and adult rats fed either with high- or normal-salt diet. In 20-day-old but not in 40-day-old rats Na+-K+-ATPase activity was significantly reduced during high-salt diet. This inhibition was abolished by a blocker of DA synthesis. The decreased activity was associated with a decreased alpha1-subunit at the plasma membrane. During high-salt diet there was an increase in DA content in jejunal cells from 20-day-old rats, associated with a parallel decrease in 5-hydroxytryptamine, compared with normal-salt diet. In 40-day-old rats, however, the catecholamine level remained unchanged during high-salt diet. Incubation of isolated jejunal cells with DA resulted in a dose-dependent inhibition of Na+-K+-ATPase activity in 20- but not in 40-day-old rats. We conclude that during high-salt diet, jejunal Na+-K+-ATPase in 20-day-old rats is inhibited, and this effect is likely to be mediated by locally formed DA.

Virulence and colonization-associated properties of Helicobacter pylori isolated from children and adolescents.

Helicobacter pylori isolates from 32 children and adolescents were characterized with respect to putative virulence and colonization-associated properties. Only 3 of the subjects had duodenal ulcer. All but 2 of the remaining 29 had various degrees of chronic gastric inflammation. No significant correlation between degree of inflammation and presence of the cag-pathogenicity island, cytotoxin production, vacA alleles associated with cytotoxin expression, and binding ability to the Lewis(b) (Le[b]) oligosaccharide was found. Only 4 isolates expressed the Le(b)-specific adhesin, of which 3 were also cag region-positive. This is in contrast to adults with gastritis or peptic ulcer disease (or both), in whom most of the H. pylori isolates bind Le(b). In an in situ binding assay H. pylori were less able to adhere to gastric surface mucous cells in biopsies taken from children compared with adults, suggesting a lower expression of the Le(b) oligosaccharide in the children.

Home parenteral nutrition (HPN) in children in Sweden.

This study represents a national survey of all children identified on home parenteral nutrition (HPN) in Sweden via all hospital pharmacy distributors. Indications for HPN from this sample were chronic intestinal pseudo obstruction (n = 5) and short bowel syndrome (n = 7). Linear growth was normal in 9 children and all school-age children attend classes at age-relevant levels. Families appear to have adapted well. There was one divorce among these families, and over the course of the HPN child's illness, younger siblings were born.