Management guidelines of eosinophilic esophagitis in childhood.

OBJECTIVES: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor-responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. RESULTS: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid-based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. CONCLUSIONS: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease.

OBJECTIVE: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

Chemometric Analysis of Cannabinoids: Chemotaxonomy and Domestication Syndrome.

Cannabis is an interesting domesticated crop with a long history of cultivation and use. Strains have been selected through informal breeding programs with undisclosed parentage and criteria. The term "strain" refers to minor morphological differences and grower branding rather than distinct cultivated varieties. We hypothesized that strains sold by different licensed producers are chemotaxonomically indistinguishable and that the commercial practice of identifying strains by the ratio of total THC and CBD is insufficient to account for the reported human health outcomes. We used targeted metabolomics to analyze 11 known cannabinoids and an untargeted metabolomics approach to identify 21 unknown cannabinoids. Five clusters of chemotaxonomically indistinguishable strains were identified from the 33 commercial products. Only 3 of the clusters produce CBDA in significant quantities while the other 2 clusters redirect metabolic resources toward the THCA production pathways. Six unknown metabolites were unique to CBD-rich strains and/or correlated to CBDA and 3 unknowns were found only in THC-rich strains. Together, these data indicate the domestication of the cannabis germplasm has resulted in a loss of the CBDA pathway in some strains and reallocation of resources between CBDA and THCA pathways in others. The impact of domestication is a lack of chemical diversity and loss of biodiversity in modern cannabis strains.

Eosinophilic esophagitis that develops during therapy with proton pump inhibitors : case series and possible mechanisms.

Therapy with proton-pump inhibitors (PPIs) results in remission in at least one third of patients with esophageal eosinophilia, presumably because of both their acid-related and anti-inflammatory mechanisms of action. However, eosinophilic esophagitis (EoE) may also develop during therapy with PPIs. We present a case series of four children who were initially diagnosed with infectious esophagitis, gastroesophageal reflux disease or gastric ulcer, who had no eosinophilic infiltration of the esophagus, but subsequently developed symptoms, endoscopic features and histological picture of typical EoE. We discuss mechanisms of action of PPIs of likely relevance to an increased risk of development of EoE in some patients, such as their influence on mucosal barrier function, interference with pH-related protein digestion by pepsin, and antigen processing by immune cells.

Simultaneous induction of jasmonic acid and disease-responsive genes signifies tolerance of American elm to Dutch elm disease.

Dutch elm disease (DED), caused by three fungal species in the genus Ophiostoma, is the most devastating disease of both native European and North American elm trees. Although many tolerant cultivars have been identified and released, the tolerance mechanisms are not well understood and true resistance has not yet been achieved. Here we show that the expression of disease-responsive genes in reactions leading to tolerance or susceptibility is significantly differentiated within the first 144 hours post-inoculation (hpi). Analysis of the levels of endogenous plant defense molecules such as jasmonic acid (JA) and salicylic acid (SA) in tolerant and susceptible American elm saplings suggested SA and methyl-jasmonate as potential defense response elicitors, which was further confirmed by field observations. However, the tolerant phenotype can be best characterized by a concurrent induction of JA and disease-responsive genes at 96 hpi. Molecular investigations indicated that the expression of fungal genes (i.e. cerato ulmin) was also modulated by endogenous SA and JA and this response was unique among aggressive and non-aggressive fungal strains. The present study not only provides better understanding of tolerance mechanisms to DED, but also represents a first, verified template for examining simultaneous transcriptomic changes during American elm-fungus interactions.

A distinct subset of chemokines dominates the mucosal chemokine response in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is characterised by intense mucosal recruitment of activated leukocytes. Chemokines determine inflammatory leukocyte recruitment and retention. AIM: To compare expression of the entire chemokine family within colonic mucosa from IBD patients and uninflamed controls. METHODS: A microarray of cDNAs, representing every member of this superfamily and their cognate receptors, was hybridised with probes derived from colonoscopic biopsies. RESULTS: A distinct subset of chemokines, consisting of CXCLs 1-3 and 8 and CCL20, was upregulated in active colonic IBD, compared with uninflamed areas or tissue from controls. Increased expression of their cognate receptors, CXCR1, CXCR2 and CCR6, was confirmed by quantitative PCR and immunohistochemistry. An identical chemokine response was induced in Caco-2 cells by stimulation with interleukin (IL)-1beta, but not tumour necrosis factor-alpha (TNF-alpha). By contrast, IL-1beta and TNF-alpha were synergistic in an HT29 cell line and primary keratinocytes. CONCLUSIONS: IL-1beta and TNF-alpha appear to be the pivotal mediators of a previously unidentified coordinated epithelial chemokine response that dominates the mucosal chemokine environment in inflamed IBD tissue.

A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease.

BACKGROUND: The breakdown of glycosaminoglycans is an important consequence of inflammation at mucosal surfaces, and inhibition of metalloprotease activity may be effective in treating chronic inflammation. AIM: To report an alternative approach, using the nutriceutical agent N-acetyl glucosamine (GlcNAc), an amino-sugar directly incorporated into glycosaminoglycans and glycoproteins, as a substrate for tissue repair mechanisms. METHODS: GlcNAc (total daily dose 3-6 g) was administered orally as adjunct therapy to 12 children with severe treatment-resistant inflammatory bowel disease (10 Crohn's disease, 2 ulcerative colitis). Seven of these children suffered from symptomatic strictures. In addition, similar doses were administered rectally as sole therapy in nine children with distal ulcerative colitis or proctitis resistant to steroids and antibiotics. Where pre- and post-treatment biopsies were available (nine cases), histochemical assessment of epithelial and matrix glycosaminoglycans and GlcNAc residues was made. FINDINGS: Eight of the children given oral GlcNAc showed clear improvement, while four required resection. Of the children with symptomatic Crohn's stricture, only 3 of 7 have required surgery over a mean follow-up of > 2.5 years, and endoscopic or radiological improvement was detected in the others. Rectal administration induced remission in two cases, clear improvement in three and no effect in two. In all cases biopsied there was evidence of histological improvement, and a significant increase in epithelial and lamina propria glycosaminoglycans and intracellular GlcNAc. CONCLUSIONS: GlcNAc shows promise as an inexpensive and nontoxic treatment in chronic inflammatory bowel disease, with a mode of action which is distinct from conventional treatments. It may have the potential to be helpful in stricturing disease. However, controlled trials and an assessment of enteric-release preparations are required to confirm its efficacy and establish indications for use.

Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.

There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin. Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.

High-dose azathioprine in children with inflammatory bowel disease.

BACKGROUND: Azathioprine is widely used as maintenance therapy in children with moderate to severe inflammatory bowel disease (IBD). There is no data on safety at higher doses and its impact on growth and surgical morbidity in children. METHODS: This retrospective cohort study included all children treated with azathioprine and diagnosed with IBD between 1996-2001. Outcome measures included indications for azathioprine use, adverse-effects and reasons for treatment discontinuation. Height and weight at diagnosis, treatment onset and current follow-up was recorded, and Z scores for height standardised for time. RESULTS: 107 children received azathioprine at 3 mg/kg. 61% had Crohn's disease and 83% started azathioprine within 2 years of diagnosis. Only 2/107 children had to stop azathioprine because of persistent adverse effects and 16/107 required surgery. There was a trend toward better growth in a group of children with Crohn's disease following treatment with high dose azathioprine therapy (P = 0.08). CONCLUSIONS: Azathioprine is a safe and well-tolerated maintenance therapy at 3 mg/kg for children with IBD. The prevalence of surgery and growth failure in a cohort of children with moderate to severe IBD appears less than previously reported. In children with Crohn's disease, growth velocity may be maximised by an emphasis on nutritional therapy and the use of high dose azathioprine.

Improvement in quality of life of children with acute Crohn's disease does not parallel mucosal healing after treatment with exclusive enteral nutrition.

BACKGROUND: Crohn's disease is a chronic debilitating disorder affecting a child's physical and emotional well-being. Recent emphasis on 'quality of life' (QOL) has led to re-evaluation of available medical treatments. AIM: To assess prospectively change in QOL, clinical disease activity and intestinal mucosal inflammation in active paediatric Crohn's disease after treatment with exclusive enteral nutrition. In addition, we evaluated whether change in QOL could predict changes in paediatric Crohn's disease activity index (PCDAI) and mucosal inflammation (endoscopic and histologic). METHODS: The IMPACT II questionnaire was used prospectively and longitudinally in 26 consecutively recruited children [16 males (67%), median 14 years, s.d. = 1.7 years] with active Crohn's disease (PCDAI > 20). They were treated with a new polymeric enteral feed (ACD004, Nestle) for a period of 8 weeks. All had PCDAI, QOL and endoscopic assessment at the time of diagnosis and after 8 weeks of treatment. RESULTS: Twenty-three of 26 children achieved a clinical remission at 8 weeks, with improvement in the QOL scores (P < 0.05). The change in QOL score after treatment was predictive of achieving a clinical remission, but not of histological improvement. CONCLUSIONS: Although children may find dietary restrictions difficult, this study confirms a clear improvement in QOL after treatment with exclusive enteral nutrition. However, improvement in QOL scores is not reflected by improvement in mucosal inflammation. Whilst improving QOL remains a core principal in patient management, the long-term consequences of ongoing mucosal inflammation must be better understood before relying only on short-term QOL measures to dictate treatment choices.

Low-dose intravenous azathioprine may be effective in the management of acute fulminant colitis complicating inflammatory bowel disease.

BACKGROUND: The management of acute fulminant colitis unresponsive to intravenous steroids is usually surgical. However, recent evidence suggests that intravenous administration of azathioprine at very high doses may allow more rapid onset of clinical efficacy, although its use has not previously been reported in the emergency situation. AIM: To report the successful use of intravenous azathioprine in the management of acute fulminant colitis complicating both Crohn's disease and ulcerative colitis. METHOD: We initially used intravenous azathioprine because of the refusal of the family of the first patient to accept surgery following failure of conventional medical management. Importantly the azathioprine was successful at the low dose of 3 mg/kg.day, equivalent to standard oral doses. Two subsequent patients demonstrated a similar resolution. All were weaned successfully to oral azathioprine and have remained in long-term endoscopic and histological remission. CONCLUSION: These preliminary data suggest that low-dose intravenous azathioprine may be helpful adjunct therapy in selected cases of severe fulminant colitis. However, the need for close monitoring and daily surgical assessment remains paramount, and a formal trial of low-dose intravenous azathioprine is required before it may be more widely recommended.

Artemisia judaica L.: micropropagation and antioxidant activity.

Artemisia judaica L., an Egyptian medicinal plant used in the treatment of gastrointestinal disorders, was mass-propagated and grown using solid, paper-bridge-support liquid, liquid-flask and bioreactor cultures. The liquid-flask culture using 50 ml MS liquid medium in 250 ml flask yielded significantly greater shoot proliferation than either solid cultures or paper-bridge-support liquid cultures. Increasing flask capacity from 100 to 500 ml improved shoot proliferation and growth. Mass-propagation efficiencies of various bioreactor systems, viz. temporary immersion reactors and bubble column reactors, were also compared. The temporary immersion bioreactor was found to have significant advantages for A. judaica shoot proliferation. The shoot cultures from the temporary immersion reactor formed complete plantlets when subcultured onto a medium containing 1 micromoll(-1) indole-3-butyric acid (IBA), and mature plants were established, acclimatized and thrived in standard greenhouse conditions. Assays of antioxidant activity and total flavonoid content of in vitro and in vivo grown tissues were evaluated as gross parameters of medicinal efficacy. Significantly higher antioxidant activity and flavonoid contents were observed in the tissues of mature greenhouse-grown plants. The efficient in vitro production systems developed in this study provided sterile, consistent tissues for investigation of bioactivity and germplasm conservation of A. judaica.

Diarrhoeal disease: current concepts and future challenges. Intestinal cytokines in inflammatory bowel disease and invasive diarrhoea.

In the intestine large numbers of bacteria and their products are separated by a single epithelial layer from resident inflammatory cells (macrophages and lymphocytes). Many of these bacterial products, such as lipopolysaccharides and peptidoglycans, are potent stimulators of free radical and inflammatory cytokine production by macrophages. This can occur in vivo in response to mucosal invasion by enteropathogenic bacteria or because of inappropriate activation of these cells, as in chronic inflammatory bowel disease. In this review we present evidence for production of cytokines in normal intestine and in intestinal inflammatory conditions. The adverse effects of cytokine production upon intestinal homeostasis, in particular disruption of epithelial integrity and prothrombotic changes in the vascular endothelium, are also discussed.

Immunoepidemiology of intestinal helminthic infections. 3. Mucosal macrophages and cytokine production in the colon of children with Trichuris trichiura dysentery.

Mucosal macrophages and accessory cells have been studied by immunohistochemistry in the lamina propria of the colon of children with Trichuris trichiura dysentery syndrome (TDS). No difference was found in the numbers of cells recognized by the monoclonal antibodies CD11c, CD68, or RFD7 between TDS children and local controls. However, large numbers of cells were recognized by an antibody against calprotectin (an anti-bacterial glycoprotein found in tissue infiltrating-monocytes) in TDS colonic mucosa, but few in control colon. Large numbers of cells containing tumour necrosis factor alpha (TNF alpha) were also seen in TDS mucosa; cells isolated from TDS mucosa secreted more TNF alpha than cells from control mucosa; and children with TDS had high levels of circulating TNF alpha. Non-specific macrophage-mediated inflammation and local cytokine production may therefore play a role in the pathogenesis of TDS.

Refeeding syndrome with enteral nutrition in children: a case report, literature review and clinical guidelines.

Refeeding syndrome is a potentially fatal complication of the nutritional management of severely malnourished patients. The syndrome almost always develops during the early stages of refeeding. It can be associated with a severe derangement in electrolyte and fluid balance, and result in significant morbidity and mortality. It is most often reported in adults receiving total parenteral nutrition (TPN), although refeeding with enteral feeds can also precipitate this syndrome. We report what we believe to be the first case of refeeding syndrome in an adolescent with newly diagnosed Crohn's disease. This developed within a few days of starting exclusive polymeric enteral nutrition. A systematic literature review revealed 27 children who developed refeeding syndrome after oral/enteral feeding. Of these, nine died as a direct result of complications of this syndrome. We discuss the implications of this syndrome on clinical practice and propose evidence-based guidelines for its management.

Unusual enteropathies.

There is increasing recognition of childhood enteropathies that are distinct from classic conditions, such as celiac disease. In several cases, an underlying molecular basis has not been determined. The findings at endoscopy and routine histopathology, however, may be nonspecific in many cases. This article focuses on the specific diagnostic features and underlying pathophysiology of these uncommon and challenging conditions.

Local and systemic effects of macrophage cytokines in intestinal inflammation.

The activation of macrophages and newly recruited monocytes appears to be common to both Crohn's disease and ulcerative colitis, despite different inductive stimuli. Similar activation occurs acutely during the course of invasive intestinal infections such as shigellosis, but is then usually downregulated. The macrophage cytokines tumor necrosis factor-alpha and interleukin-1 (IL-1) are centrally involved in the local inflammatory response, and blockade of either cytokine greatly attenuates the inflammatory lesion. Induction of focal vascular thrombosis and matrix degradation are thought to be an important component of this focal damage. Both cytokines and IL-6 are now recognized to contribute to the systemic effects of intestinal disease, including growth suppression, anorexia, and chronic anemia. Disturbance of sleep patterns, mood, and affect may also occur, and recent evidence points towards bidirectional interplay between macrophage cytokines and central nervous system function.

Tryptophan is a precursor for melatonin and serotonin biosynthesis in in vitro regenerated St. John's wort (Hypericum perforatum L. cv. Anthos) plants.

HYPERICUM PERFORATUM: cv. Anthos) is presented. Isotope tracer experiments were performed on plantlets regenerated from thidiazuron-induced stem explants and grown on MS basal medium for 2 months. Radiolabel from 14C-tryptophan was recovered as 14C-indoleacetic acid, 14C-tryptamine, 14C-5-hydroxytryptophan, 14C-serotonin and 14C-melatonin in the treated St. John's wort plantlets. Chromatographic peak identity was confirmed by high performance liquid chromatography-mass spectrometry-mass spectrometry and quantification of melatonin by radioimmunoassay. Significantly more radiolabel was recovered in serotonin relative to melatonin under low light conditions with this ratio being reversed under increased lighting, indicating that the rate of flow through this biosynthetic pathway is regulated, at least in part, by light.

Thidiazuron-induced plant regeneration from hypocotyl cultures of St. John's wort (Hypericum perforatum. cv 'Anthos').

St. John's wort (Hypericum perforatum. cv 'Anthos') is a medicinal plant with evidence of efficacy as an anti-depressant. The present report describes the development of an in vitro regeneration system that utilizes thidiazuron [N-phenyl-N'-(1,2,3-thidiazol-yl)urea] for the induction of de novo shoots on etiolated hypocotyl segments of St. John's wort seedlings. The optimum level of thidiazuron supplementation to the culture medium was 5 µmol·l-1 for a 9-day induction period followed by subculture of induced hypocotyl explants on basal medium. Other plant growth regulators including benzyladenine and indoleacetic acid were not effective in inducing regeneration on St. John's wort hypocotyls. Histological examination of the cultures revealed that the regenerated plants were derived from de novo developed shoots. Transfer of the regenerated shoots into a liquid medium with no plant growth regulators resulted in the rapid and prolific growth of viable plantlets. The rapid and efficient micropropagation system for St. John's wort may be useful for both the genetic improvement of this crop and the production of high-quality phytopharmaceutical preparations for the treatment of neurological disorders.

Acute ENT admission in Kawasaki disease.

Kawasaki disease (mucocutaneous lymph node syndrome) is an acute vasculitis of childhood carrying a 1-2 per cent mortality from cardiovascular complications. Despite the extensive literature on Kawasaki disease in paediatric journals, there has been a paucity of documentation in the otolaryngology literature. This is despite the fact that Kawasaki disease may present as an otolaryngological emergency before the diagnosis is established. We describe three cases of Kawasaki disease, all of which presented to the ENT department of this hospital within a period of two months. These cases illustrate the slow evolution characteristic of the disease and highlight the difficulties of diagnosis in the initial febrile stage. We emphasize the importance of considering the diagnosis when treating a young child with a pyrexia resistant to antibiotics, as prompt introduction of therapy may decrease the risk of fatal coronary artery or cardiac involvement.