Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective.

The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work-up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence-based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results.

Novel Burkholderiales 23S rRNA genes identified in ileal biopsy samples from children: preliminary evidence that a subtype is associated with perianal Crohn's disease.

A novel family of Burkholderiales bacteria was identified in ileal biopsy specimens from children presenting with symptoms of inflammatory bowel disease. A molecular subtyping approach based on sequencing of a variable region of the bacteria's 23S rRNA genes identified three variants. Pilot analysis identified one variant to be significantly associated with perianal Crohn's disease.

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration.

Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.

Agreement of aspiration tests using barium videofluoroscopy, salivagram, and milk scan in children with cerebral palsy.

To study the agreement between three tests for aspiration, barium videofluoroscopy, salivagram, and milk scan we studied 63 children with severe non-ambulant spastic quadriplegic cerebral palsy (CP) aged 14 months to 16 years (32 males, 31 females). The salivagram was most frequently positive (56%, 95% confidence interval 43 to 68%); the next most frequently positive was barium videofluoroscopy when aspiration was defined as the presence of either laryngeal penetration of material or frank aspiration (39%, 95% confidence interval 26 to 53%). The milk scan was rarely positive (6%, 95% confidence interval 2 to 16%). Agreement between the tests of aspiration was poor. The maximum agreement (kappa=0.20) was between aspiration as diagnosed with the salivagram and by barium videofluoroscopy. Positive tests for aspiration are frequent in children with severe CP. Frequency varies widely depending on the investigation used. There is poor agreement between tests used for the diagnosis of aspiration. This information is of importance in assessing the significance of test results.

Botulinum toxin for achalasia in children.

BACKGROUND: Injection of botulinum toxin (BTx) into the lower esophageal sphincter (LES) of adult patients with achalasia results in the effective relief of symptoms. The aim of the present study was to examine the effectiveness of BTx in pediatric patients suffering from achalasia. METHODS: Seven patients suffering from achalasia with or without prior treatment were treated with intrasphincteric injection of BTx. The median duration of follow up was 15 months. RESULTS: All seven patients improved. The median interval before recurrence of symptoms was 4 months (range 1-14 months). There was an inverse relationship between the pretreatment LES pressure and the duration of response (r=-0.6). The mean pretreatment LES pressure in the subgroup with a response greater than 6 months was 38+/-10 mmHg compared with 61+/-12 mmHg in the other four patients (P= 0.05). All seven patients required retreatment. CONCLUSION: Botulinum toxin is effective in relieving symptoms in pediatric patients suffering from achalasia, producing a sustained response beyond 6 months in 43% of patients.

Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis.

BACKGROUND: Distressed behavior is common in infants and is often attributed to gastroesophageal reflux (GER) or food protein intolerance. OBJECTIVE: To examine the effect of a hypoallergenic amino acid-based infant formula (AAF) on distressed behavior and GER symptoms in infants who failed to respond to extensively hydrolyzed formula and antireflux medications. STUDY DESIGN: Nineteen distressed infants (9 boys and 10 girls; median age, 5.0 months) with presumed GER underwent gastroscopy (n = 17) and esophageal 24-hour pH monitoring (n = 14). Double-blind placebo-controlled (DBPC) formula challenges of AAF versus previously besttolerated formula were conducted. RESULTS: Nine infants had histologic evidence of esophagitis, and 9 had inflammatory changes in the stomach and/or duodenum. Symptoms remitted in all infants within 2 weeks of the start of feeding with AAF. On DBPC challenge after a median period of 3 months of receiving AAF, 12 infants were intolerant to active formula (distress score, 287 vs 580 min/wk,P =. 01; symptom score, 23.1 vs 36.1, P =.03). Seven infants did not relapse and were considered tolerant (distress score, 470 vs 581, P =.77; symptom score, 29.5 vs 20.2; P =.89). CONCLUSION: Treatment with AAF may reduce distressed behavior and symptoms of GER in infants with food protein intolerance.

Prevalence of coeliac disease and longitudinal follow-up of antigliadin antibody status in children and adolescents with type 1 diabetes mellitus.

Coeliac disease (CD) is more prevalent in individuals with type 1 diabetes mellitus (DM), and when untreated is associated with a number of medical complications, including poor glycaemic control. Identification of patients with CD has been facilitated in recent years by serological screening, including the use of antigliadin antibodies (AGAs) and endomysial antibodies (EMAs). The aim of this study was to assess the prevalence of CD in a clinic-based paediatric population with type 1 DM, and to study longitudinal changes in AGA status. Two-hundred-and-eighty-one children and adolescents with type 1 DM aged 9.9 +/- 3.8 yr were screened using AGAs of immunoglobulin A (IgA) and immunoglobulin G (IgG) classes (AGA-IgA and AGA-IgG). Thirty-five patients had both antibodies positive and underwent gastro-duodenoscopy and multiple biopsies. Fifteen of the 35 patients had histological evidence of CD, and the overall clinic prevalence of CD was 5.7%. A number of patients did not exhibit florid symptoms, and recurrent unexplained hypoglycaemia was a significant finding. Patients who perceived themselves to be asymptomatic had more problems with compliance with a gluten-free diet (GFD). Ninety-seven patients had follow-up AGAs performed after 2.5 +/- 1.5 yr. One patient with initially normal AGAs developed positive antibodies and histological findings of CD. Antibody status has fluctuated in other patients. CD is common in patients with DM, and diagnosis is important to detect to minimize long-term morbidity related to both disorders. Initial normal screening does not exclude CD and repeat screening is indicated.

The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance.

Infants (n = 18) with intolerance to extensively hydrolyzed formulas and soy who responded to an L-amino acid-based elemental formula (AAF) were studied until 3 years of age. By 2 years of age most tolerated non-formula foods, and by 3 years only 3 required AAF. Growth normalized during AAF feeding in 4 infants with failure to thrive.

Posture and gastro-oesophageal reflux: a case for left lateral positioning.

AIM: Prone posture is often recommended for symptomatic gastroesophageal reflux in young infants, but prone positioning has been associated with sudden infant death. The aim of this study was thus to establish the optimal alternative posture for reducing reflux. METHODS: 24 infants (< 5 months) with symptomatic gastro-oesophageal reflux were studied prospectively with 48 h pH monitoring. They were randomly assigned to one of the 24 permutations of the four positions (supine, prone, right, left). During the first 24 hours the infant was held horizontally, and then the permutation was repeated at 30 degrees head elevation, giving a total of eight study segments for each infant. Data were edited to remove all time when the infants were not in the prescribed positions. Results were evaluated using analysis of covariance. RESULTS: Gastro-oesophageal reflux expressed as reflux index (mean % (SEM)) was significantly less in the prone and left lateral positions (6.72 (1.06) and 7.69 (1.03) respectively) than in the supine and right lateral positions (15.33 (2.33) and 12.02 (1.38); p < 0.001). Head elevation did not affect any variables significantly. CONCLUSIONS: Head elevation may not always be of clinical value. The left lateral position is a suitable alternative to prone for the postural management of infants with symptomatic gastro-oesophageal reflux.

Familial adenomatous polyposis in a 5 year old child: a clinical, pathological, and molecular genetic study.

A girl aged 5 years 8 months presented with rectal bleeding; her father had had familial adenomatous polyposis (FAP) and a colectomy at the age of 23. Endoscopy showed extensive polyposis and she had a colectomy. The proband and her father had the common codon 1309 5 bp deletion APC mutation. This mutation predisposes to early onset of FAP, and consideration needs to be given to having molecular testing of at risk members of these families done in childhood.

Androgen and glucocorticoid regulation of androgen receptor cDNA expression.

Androgen receptor (AR) levels are regulated by androgens, other steroids and non-steroidal hormones via complex, tissue-specific processes. Since alterations in receptor levels may influence cellular sensitivity to androgens, understanding AR regulation is of fundamental and potentially therapeutic significance. In most target tissues and AR-containing cell lines, AR mRNA is down-regulated in response to androgens. We have reconstituted this androgen-mediated down-regulation of AR mRNA in COS 1 cells transfected with a human AR cDNA under the control of the cytomegalovirus (CMV) promoter. The sequences mediating receptor mRNA down-regulation are represented within the AR cDNA and not within the CMV promoter. Androgenic down-regulation of AR cDNA expression was time- and dose-dependent, resembling native AR mRNA down-regulation. In addition, androgenic regulation of the receptor cDNA was not dependent on protein synthesis suggesting that AR and/or another pre-existing protein(s) is involved in this process. In COS 1 cells co-transfected with androgen and glucocorticoid receptor cDNAs, dexamethasone mimicked the action of androgen in down-regulating AR mRNA. This response depended on glucocorticoid receptors. Androgen had little effect on steady-state levels of AR protein consistent with reports that androgen down-regulates AR mRNA but increases AR protein half-life (Kemppainen et al. (1992) J. Biol. Chem. 267, 968-974; Zhou et al. (1995) Mol. Endocrinol. 9, 208-218). However, glucocorticoids decreased AR protein levels in cells that co-expressed androgen and glucocorticoid receptors. These results indicate that sequences represented in the AR cDNA mediate AR mRNA down-regulation by both androgens and glucocorticoids. Inhibition of AR mRNA and protein by glucocorticoids suggests that these steroids may modulate androgen action in tissues, such as mammary gland and prostate, which express both androgen and glucocorticoid receptors.

Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance.

BACKGROUND: Many infants with cow's milk protein intolerance have adverse reactions to soy, casein and whey hydrolysate formula and to other foods. The recent development of Neocate, a hypoallergenic, nutritionally complete infant formula composed of individual amino acids and other nutrients, has enabled these infants to be stabilized. OBJECTIVE: We observed the effect of food challenges in infants with reported hypersensitivity to hypoallergenic formulas. METHODS: Eighteen infants (median age, 7 1/2 months) were given Neocate formula for 2 months and then underwent a 7-day double-blind placebo-controlled challenge with the formula previously best tolerated. RESULTS: In 12 of the 18 infants irritability, vomiting, diarrhea, and/or eczema flares developed during the formula challenge. In two patients symptoms developed immediately, but in the remainder adverse reactions evolved within 7 days (range, 4 to 7 days). Adverse reactions were to soy formula (six patients), whey hydrolysate (two), and casein hydrolysate (four). When infants were 12 months of age, parents reported adverse reactions after the ingestion of other low allergen foods (median, six; from a panel of 10 such foods). CONCLUSION: A group of infants with late-onset adverse reactions to soy, extensively hydrolyzed casein, and whey formulas and to other foods has been identified. Neocate formula proved to be an effective substitute formula for these patients.

Role of gastro-oesophageal reflux in infant irritability.

Gastro-oesophageal reflux (GOR) disease may cause excessive crying in infants. The role of GOR was evaluated in infant irritability and an attempt was made to define clinical predictors of pathological reflux. Seventy consecutively admitted infants with irritability and presumptive GOR were retrospectively reviewed. All had undergone prolonged oesophageal pH monitoring. Pathological GOR was defined as a fractional reflux time of > or = 10% and was significantly less common in infants under 3 months (one of 24; 4.2%) than in older infants (10 of 46; 21.7%). All infants with pathological GOR presented with frequent vomiting, and 'silent' pathological reflux did not occur. Poor weight gain, feeding refusal, backarching, and sleep disturbance were not significantly associated with pathological GOR. The results suggest that pathological GOR is an unlikely cause of infant irritability under the age of 3 months.

Is cow's milk protein intolerance a cause of gastro-oesophageal reflux in infancy?

To test the hypothesis that cow's milk protein intolerance (CMPI) might cause or contribute to gastro-oesophageal reflux (GOR), 10 of 14 infants with abnormal GOR on prolonged oesophageal pH monitoring who had failed to respond to conventional antireflux therapy were placed on a hypo-allergenic diet for 1 month. In no child was there significant improvement in pH monitoring indices, and only two showed any symptomatic improvement. Therefore, in these children, CMPI did not appear to contribute to GOR. It is probable that CMPI is rare as a cause of passive GOR, although our results do not exclude CMPI as a cause of active vomiting.

Helicobacter pylori infection in children.

Helicobacter pylori was sought prospectively by culture of antral biopsy, histology and serology (IgG and IgA) in 440 consecutive endoscopies on children to determine the prevalence, clinical presentation and histological features of H. pylori infection in our population. Twenty-eight patients had H. pylori (8% overall). The mean age of infected patients was significantly higher than that of non-infected patients (P less than 0.0001). No patient under 5 years of age had H. pylori isolated. Overall, there was no significant difference in clinical presentation between those with and those without H. pylori infection, but 23% of patients 5 and 26 years of age who presented with abdominal pain as the indication for their endoscopy had H. pylori isolated. Macroscopic changes ranged from no abnormality to frank ulceration, but the typical antral mamilliform changes were 100% predictive of infection. Fifty-eight per cent of patients with duodenal ulcers, but only 17% with gastric ulcers had H. pylori infection. Histological gastritis was present in 144 patients (including all H. pylori positive patients). None of the patients with another definable cause for gastritis had H. pylori isolated. In conclusion, H. pylori is an important cause of primary gastritis in our population, occurring in children over 5 years of age. Culture of an antral biopsy should be performed in children over this age undergoing endoscopy for the investigation of abdominal pain and, more particularly, in those with peptic ulceration.

Upper and lower gastrointestinal endoscopy in children and adolescents with Crohn's disease: a prospective study.

Fifty-six children and adolescents with Crohn's disease were prospectively investigated with gastroscopy and colonoscopy irrespective of localizing symptoms or signs. Routine biopsies were taken from endoscopically normal and abnormal areas. A high incidence (71%) of upper gastrointestinal (GI) involvement was found. In 41%, these findings were instrumental in making the diagnosis. The ileum was viewed in 49 of the 56 cases. Overall, the upper GI tract was involved in 71%, the terminal ileum in 53%, and the colon in 86% (oesophagus 16%, body of stomach 46%, antrum 36%, duodenum 21%, terminal ileum 53%, caecum 69%, transverse colon 71%, sigmoid 60% and rectum 41%). Upper and lower gastrointestinal endoscopy with systematic biopsies should be performed early in the diagnostic assessment of children and adolescents with suspected inflammatory bowel disease to enable accurate diagnosis and assessment of extent of disease.