Molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing.

Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.

Shotgun recoil causing severe acute aortic regurgitation years after replacement of the aortic valve and ascending aorta.

Blunt chest trauma can lead to severe, life-threatening injury to chest organs, including the aorta, heart, lungs, and major airways. We describe a 64-year-old man who had undergone replacement of his aortic valve and ascending aorta 14 years earlier (at age 50) and suddenly developed severe aortic regurgitation after firing his shotgun while hunting. Such an event has not been reported previously.

A preliminary study on enhancing safety of contact features in the terrain park.

OBJECTIVES: Terrain park riders use contact features such as fun boxes and rails. Typical fun box and rail features have a design characteristic that can be changed to improve safety. Fun box edge coping and edges of rails are typically constructed of soft steel. Ski/snowboard edges (HRC50) can easily become engaged in the softer metal, causing a chip to develop, suddenly stopping the rider, probably causing a fall and possible injury. The aim of the study is to examine the effect of terrain park running surface hardness on chip development. DESIGN: Testing on steel specimens was performed to research chip development generated by a ski/snowboard edge on steel used in the construction of contact features and on steel that is proposed for such use. An apparatus was constructed to simulate a ski/snowboard edge moving perpendicular to the long axis of coping or rail edge. METHODS: The author performed observation, photographic documentation, metallurgical testing and environmental testing of various contact features at different ski area terrain parks. Several steel specimens of varying hardness were tested at various load levels to study the propensity of chip development by ski/snowboard edges. RESULTS: Testing of steel samples showed that increasing the hardness of the rail steel or coping steel reduced the propensity for a ski/snowboard edge to engage in the coping or rail. CONCLUSIONS: Increasing steel coping and rail contact surface hardness to HRC 50 and above will likely reduce engagement by steel snowboard/ski edges, which in turn is expected to reduce the chance of a fall and injury.

Mucosal eosinophilia and response to H1/H2 antagonist and cromolyn therapy in pediatric dyspepsia.

Both eosinophils and mast cells have been implicated in the generation of abdominal pain. The purposes of this retrospective study were to determine the prevalence of duodenal eosinophilia in pediatric dyspepsia and to determine the clinical response rate of these patients to combined H1 and H2 receptor antagonist and mast cell stabilizer therapy. Fifty-nine patients (ages 3.5-17.7 years) with dyspepsia undergoing endoscopy were evaluated. All patients had a minimum of 2 forceps biopsies obtained from each of the esophagus, antrum, and duodenal bulb. Routine histologic evaluation was performed and duodenal biopsies were additionally evaluated to determine eosinophil counts. Patients with > 10 eosinophils/hpf were treated with ranitidine and hydroxyzine (H1/H2). Nonresponders were then treated with oral cromolyn. Patients were followed up and response recorded in an abdominal pain database and/or medical chart, which were reviewed for this study. Forty-two patients (71%) had duodenal eosinophilia. Twenty-one (50%) of these were responders to H1/H2. The response rate did not differ between patients with and without noneosinophilic esophagitis, gastritis, or duodenitis, respectively. Two patients were lost to follow-up and considered nonresponders. Seventeen of the remaining 19 (89%) were responders to cromolyn. Overall, the response rate to this treatment pathway was 90%. Duodenal eosinophilia is common in pediatric patients with dyspepsia. These patients appear to be clinically amenable to combination H1/H2 therapy and/or oral cromolyn.

Gallbladder wall inflammatory cells in pediatric patients with biliary dyskinesia and cholelithiasis: a pilot study.

BACKGROUND/PURPOSE: Inflammation has been implicated in functional gastrointestinal disorders, including functional dyspepsia and irritable bowel syndrome. This study was undertaken to evaluate gallbladder wall inflammatory cells in children with abdominal pain related to gallstones and biliary dyskinesia to determine the candidate cell types that may be contributing to the pathophysiology of these entities. METHODS: Gallbladder specimens from 20 patients with cholelithiasis, 20 biliary patients with dyskinesia, and 12 autopsy controls were evaluated in a blinded fashion. Eosinophil, tryptase-positive, and CD3+ cell densities were determined for the lamina propria and muscularis mucosa layers and compared between groups. RESULTS: Patients with biliary dyskinesia and cholelithiasis had a 9- to 12-fold increase in mean and peak mast cell densities, respectively, in both layers as compared with controls. Peak (13.7 vs 8.4) and mean (9.2 vs 5.2) CD3+ cell densities were increased in the muscularis mucosae of cholelithiasis specimens as compared with biliary dyskinesia specimens. CONCLUSION: Gallbladder wall inflammatory cell densities, particularly mast cells, differ between children with cholelithiasis, children with biliary dyskinesia, and controls. Future studies are warranted to define the roles for specific inflammatory cell types.

Chronic gastritis is not associated with gastric dysrhythmia or delayed solid emptying in children with dyspepsia.

To determine if chronic gastritis (CG) is associated with gastric dysrhythmia or delayed solid emptying in children with dyspepsia, 22 patients (7-15 years of age) with dyspepsia and normal gross endoscopies were studied. Antral biopsies were evaluated for chronic gastritis, and immunohistology was performed to determine densities of CD3+, CD20+, CD25+, and tryptase-positive cells. Electrogastrography (EGG) and gastric scintiscan evaluation were performed within 2-7 days of endoscopy. CG and increased immune cell densities were not associated with altered gastric emptying. Mean CD3+ cell counts were positively correlated with the percentage normal slow waves, and patients with a normal EGG had increased CD3+ cell density. In children with dyspepsia, chronic antral inflammation in the setting of a normal gross endoscopy is not associated with EGG abnormalities or delayed solid emptying. Chronic gastritis and gastric dysrhythmia may simply be two separate and distinct mechanisms resulting in the clinical entity of dyspepsia.

Crohn's-associated chronic recurrent multifocal osteomyelitis responsive to infliximab.

We report a case of chronic recurrent clavicular osteomyelitis in association with Crohn disease. Steroid therapy resulted in partial remission; however, intractable shoulder pain and an enlarging clavicular mass subsequently recurred. Infliximab therapy resulted in significant improvement in the degree of bone pain and resolution of the large sclerotic clavicular lesion.

Clinical efficacy and pharmacokinetics of montelukast in dyspeptic children with duodenal eosinophilia.

BACKGROUND: Montelukast, a competitive cysteinyl leucotriene-1 receptor antagonist, reduces airway eosinophilia in asthmatics. We evaluated the effect of this drug in children with eosinophilic duodenitis, defined histologically as duodenal mucosa with peak eosinophil count of more than 10 eosinophils/hpf. METHODS: Forty children and adolescents (6-18 yr) with dyspepsia and duodenal eosinophilia were enrolled in a double blind, randomized, placebo-controlled, cross-over study of monteleukast therapy. Subjects were randomized to receive either 10 mg montelukast or an identical placebo once daily and were evaluated on day 14 for symptomatic and biochemical responses. Subjects were also randomized to one of two blood sampling schemes to evaluate montelukast pharmacokinetics. RESULTS: Using a post treatment global pain assessment, a positive clinical response was observed in 62.1% of patients receiving montelukast compared with 32.4% on placebo (p < 0.02). Pain assessment score deteriorated in 45% of montelukast responders (5/11) after cross-over to placebo and improved in 62% (8/13) of placebo non-responders on cross-over to montelukast. In patients with peak duodenal eosinophil counts between 20-29/hpf (n=19), a positive pain assessment response was observed in 84% of patients receiving montelukast compared to 42% receiving placebo (p < 0.01). Response rate did not differ by age, gender or histologic findings at baseline. Pharmacokinetic analysis yielded parameter estimates for absorption rate constant (Ka), apparent volume of distribution (Vd/F) and elimination rate constant (Kel) of 0.42 h, 0.19 L/kg and 0.26 h, respectively. The relative extent of systemic drug exposure was comparable to that observed in previous pediatric investigations with similar weight-adjusted montelukast doses. Neither dose nor calculated drug exposure were associated with the level of post treatment pain assessment or the change in biochemical markers. CONCLUSIONS: These data suggest a beneficial role for montelukast in the treatment of pediatric patients with dyspepsia associated with duodenal eosinophilia.

Safety of infliximab treatment in pediatric patients with inflammatory bowel disease.

BACKGROUND: Infliximab appears to be efficacious in the treatment of pediatric Crohn disease (CD). There are few large-scale pediatric studies on the complications of infliximab therapy. METHODS: A retrospective review of all infliximab infusions administered to IBD patients at a tertiary children's hospital was undertaken. Data was obtained from an infliximab infusion database maintained in the section of Pediatric Gastroenterology, pharmacy records and patient charts. RESULTS: 594 infusions were administered to 111 IBD patients (88 CD and 23 UC; 55 male and 56 female; ages 4 to 20 years; mean age, 13.4 years). The number of infusions ranged from 1 to 24 with a mean of 5.4/patient. Infusion reactions occurred in 8.1% of patients (seven early and two delayed) and in 1.5% of all infusions. Reactions occurred more frequently in female patients (14% versus 2%; P = 0.03). All reactions were mild and responded rapidly to treatment. Four patients had infections deemed unusual, including three cutaneous tinea infections and one case of shingles. CONCLUSION: Infliximab is safe in pediatric IBD patients with a low incidence of generally mild reactions that respond rapidly to intervention. Infusion reactions are more common in female patients. Our patients had no serious infectious complications, although cutaneous tinea infection may represent a newly reported associated complication.