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J A Walker-Smith

Publications and source records attributed to J A Walker-Smith.

At least 19 recordsLinked to original sources
PubMed2004

Spontaneous T(H)1 cytokine production by intraepithelial but not circulating T cells in infants with or without food allergies.

BACKGROUND: It has been established that the maintenance of immunological tolerance to dietary antigen and the intestinal flora (oral tolerance) is an actively-maintained process dependent upon mucosal lymphocyte populations. Early life exposures appear critical in the development of such tolerance. However little is known about the activation status of mucosal lymphocytes in human infancy and childhood. PATIENTS AND METHODS: We have performed flow cytometric analysis for cell lineage and cytokine-production status in peripheral blood and duodenal intraepithelial lymphocytes taken during endoscopy from 20 children [median age 2.9 +/- 0.6 years (median +/- SE)] in whom investigation found no intestinal abnormalities (histologically normal controls) and 30 children (median age 1.6 +/- 0.4 years) with confirmed allergy to cow's milk and other dietary antigens. RESULTS: Regardless of clinical status, spontaneous production of cytokines was low or undetectable in peripheral blood cells. By contrast, intraepithelial CD4 and CD8 cells isolated from the small intestine were often activated, with 5% or more showing spontaneous production of T(H)1 type [interleukin-2, interferon (IFN)-gamma] cytokines in both normal controls and food-allergic children. Stimulation in vitro strongly induced cytokine production in peripheral blood but not intraepithelial lymphocytes. Immunohistochemistry showed similar density of IFN-gamma(+) intraepithelial lymphocytes in controls and allergic children. CONCLUSIONS: Duodenal intraepithelial lymphocytes in human infants show a state of increased spontaneous activation compared with peripheral blood lymphocytes, and show no significant impairment of T(H)1 responses in food allergic children.

Child↗
PubMed2004

Diagnostic role of upper gastrointestinal endoscopy in pediatric inflammatory bowel disease.

BACKGROUND: Discrimination between ulcerative colitis (UC) and Crohn disease (CD) may be difficult on ileo-colonoscopy alone because of a lack of definitive lesions. Retrospective studies show upper gastrointestinal endoscopy may be helpful in confirming diagnosis in such cases. AIMS: To prospectively determine importance of upper gastrointestinal endoscopy in diagnosis of inflammatory bowel disease (IBD) and assess factors predictive of upper gastrointestinal involvement in IBD. METHODS: All pediatric patients were enrolled prospectively and consecutively over a 2-year period and investigated with an ileo-colonoscopy and barium meal follow-through. Children with procto-sigmoiditis, later confirmed histologically to be typical of UC, were excluded from the study. The remainder underwent upper gastrointestinal endoscopy. The protocol and methodology were determined a priori. RESULTS: 65 children suspected of IBD underwent colonoscopy. Of the total, 11 had recto-sigmoiditis with typical macroscopic appearances of UC; once this was confirmed on histology these patients were excluded from the study. Of the 54 children (males, 31; median age, 11.1 years) remaining, 23 were initially diagnosed with CD on ileo-colonoscopy and 18 (33%) were diagnosed with UC. The diagnosis remained ambiguous in 13 (six colonic, four ileo-colonic, three normal colon) on clinical, radiologic and histologic grounds. Upper GI endoscopy helped to confirm CD in a further 11 (20.4%). Two patients were diagnosed with indeterminate colitis. Upper gastrointestinal inflammation was seen in 29 of 54 (22 CD; 7 UC ). Epigastric and abdominal pain, nausea and vomiting, weight loss and pan-ileocolitis were predictive of upper gastrointestinal involvement (P < 0.05). However, 9 children with upper gastrointestinal involvement were asymptomatic at presentation (31%). Overall upper gastrointestinal tract inflammation was most common in the stomach (67%), followed by the esophagus (54%) and duodenum (22%). CONCLUSIONS: Upper gastrointestinal tract endoscopy should be part of the first-line investigation in all new cases suspected of IBD. Absence of specific upper gastrointestinal symptoms do not preclude presence of upper gastrointestinal inflammation.

Adolescent↗
PubMed2004

Acetylated sialic acid residues and blood group antigens localise within the epithelium in microvillous atrophy indicating internal accumulation of the glycocalyx.

BACKGROUND: Microvillous atrophy, a disorder of intractable diarrhoea in infancy, is characterised by the intestinal epithelial cell abnormalities of abnormal accumulation of periodic acid-Schiff (PAS) positive secretory granules within the apical cytoplasm and the presence of microvillous inclusions. The identity of the PAS positive material is not known, and the aim of this paper was to further investigate its composition. METHODS: Formaldehyde fixed sections were stained with alcian blue/PAS to identify the acidic or neutral nature of the material, phenylhydrazine blocking was employed to stain specifically for sialic acid, and saponification determined the presence of sialic acid acetylation. The specificity of sialic acid staining was tested by digestion with mild sulphuric acid. Expression of blood group related antigens was tested immunochemically. RESULTS: Alcian blue/PAS staining identified a closely apposed layer of acidic material on the otherwise neutral (PAS positive) brush border in controls. In microvillous atrophy, a triple layer was seen with an outer acidic layer, an unstained brush border region, and accumulation within the epithelium of a neutral glycosubstance that contained acetylated sialic acid. Blood group antigens were detected on the brush border, in mucus, and within goblet cells in controls. In microvillous atrophy they were additionally expressed within the apical cytoplasm of epithelial cells mirroring the PAS abnormality. Immuno electron microscopy localised expression to secretory granules. CONCLUSIONS: A neutral, blood group antigen positive, glycosubstance that contains acetylated sialic acid accumulates in the epithelium in microvillous atrophy. Previous studies have demonstrated that the direct and indirect constitutive pathways are intact in this disorder and it is speculated that the abnormal staining pattern reflects accumulation of glycocalyx related material.

ABO Blood-Group System↗
PubMed2003

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.

Administration, Oral↗
PubMed2002

Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism.

We have reported lymphocytic colitis in children with regressive autism, with epithelial damage prominent. We now compare duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation and 18 histologically normal controls. Immunohistochemistry was performed for lymphocyte and epithelial lineage and functional markers. We determined the density of intraepithelial and lamina propria lymphocyte populations, and studied mucosal immunoglobulin and complement C1q localisation. Standard histopathology showed increased enterocyte and Paneth cell numbers in the autistic children. Immunohistochemistry demonstrated increased lymphocyte infiltration in both epithelium and lamina propria with upregulated crypt cell proliferation, compared to normal and cerebral palsy controls. Intraepithelial lymphocytes and lamina propria plasma cells were lower than in coeliac disease, but lamina propria T cell populations were higher and crypt proliferation similar. Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.

Autistic Disorder↗
PubMed2002

Upregulated eotaxin expression and T cell infiltration in the basal and papillary epithelium in cows' milk associated reflux oesophagitis.

BACKGROUND: Cows' milk sensitive reflux oesophagitis is an emerging clinical entity in children, normally indistinguishable from primary gastro-oesophageal reflux (GOR) apart from the response to dietary antigen exclusion. It is conjectural whether a tendency towards mucosal eosinophilia distinguishes this group from primary GOR. AIMS: To determine whether there may be differences in the mucosal lesion within the oesophagus in those children with reflux in association with cows' milk induced small bowel pathology, particularly in relation to the eosinophil chemokine eotaxin. METHODS: A total of 29 children underwent endoscopic assessment, including nine with cows' milk sensitive enteropathy (CMSE) and associated GOR, seven histologically normal controls, six with primary GOR, and seven disease controls. Oesophageal biopsy specimens were examined immunohistochemically for the chemokines eotaxin and MCP-2, and T cell lineage and activation markers. RESULTS: Strong upregulation of eotaxin expression, limited to basal and papillary epithelium, occurred in all CMSE patients. By contrast, weak expression was seen in a minority of controls and in 50% of primary GOR patients. Infiltration of CD3, CD4, and CD8 lymphocytes occurred in similar distribution in CMSE patients, significantly increased above controls. Significant upregulation of activation markers (CD25, HLA-DR) was also seen in the CMSE group within basal and papillary epithelium compared to controls and primary GOR. CONCLUSION: Basal and papillary epithelial eotaxin expression, with focal lymphocyte activation, was seen in infants with CMSE associated GOR. This preliminary study provides early evidence to suggest a pathogenesis distinct from primary GOR, in which specific recruitment of T cells and eosinophils may contribute to oesophageal dysmotility.

Adolescent↗
PubMed2001

Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism.

OBJECTIVES: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. METHODS: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. RESULTS: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. INTERPRETATION: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.

Adolescent↗
PubMed2001

Post-infective diarrhoea.

When diarrhoea caused by gastroenteritis persists for more than two weeks it is referred to as persistent diarrhoea in developing countries. Whilst the Control of Diarrhoeal Diseases programme has decreased mortality from acute diarrhoea, mortality from persistent diarrhoea has not been so responsive. A number of factors have been identified which are determinants for the progression of an acute episode to one which persists in developing communities. In one study from west Africa, current infection with Cryptosporidium parvum was the most significant factor. In studies from Brazil and India, continuing infection with enteropathogenic Escherichia coli was identified in 50% of infants with persistent diarrhoea. Persistent small intestinal mucosal damage is of key importance in such children. Management of established cases is complex and difficult. However, there is clear evidence that zinc is involved in the recovery of small intestinal mucosa after injury. Zinc supplementation may indeed significantly reduce the duration of persistent diarrhoea. However, the whole question of public health supplementation with zinc, vitamin A, or other supplements, is contentious at present.

Animals↗
PubMed2001

Effect of enteral nutrition on antioxidant enzyme systems and inflammation in paediatric Crohn's disease.

UNLABELLED: Crohn's disease is characterized by chronic inflammation of the gastrointestinal mucosa, which can be successfully treated with enteral nutrition. In this study, the activities of the antioxidant metalloenzymes copper/zinc-superoxide dismutase (Cu/Zn-SOD) and selenium-glutathione peroxidase (Se-GPx) were determined in erythrocyte lysates from children with Crohn's disease. Both enzymes exhibited significantly lower activities relative to healthy control subjects: 1.55 +/- 0.33 vs 2.13 +/- 0.75 SOD U mg(-1) protein (p < 0.025) for Cu/Zn-SOD, and 61.9 +/- 17.7 vs 93.6 +/- 28.7 mU mg(-1) protein (p < 0.01) for Se-GPx. Treatment of patients with a specific polymeric diet, CT3211, for a period of 8 wk did not significantly alter the activities of the enzymes. In contrast, clinically, enteral nutritional therapy induced a remission in 13/14 children, and a significant fall in both median serum C-reactive protein and mean serum tumour necrosis factor-alpha levels. CONCLUSION: The results imply that the anti-inflammatory action of enteral nutrition in Crohn's disease is caused by a mechanism other than restitution of these antioxidant enzymes.

Adolescent↗
PubMed2000

Human Peyer's patch T cells are sensitized to dietary antigen and display a Th cell type 1 cytokine profile.

Animal studies have demonstrated that feeding Ags induces regulatory (Th2, Th3) cells in Peyer's patches (PP), which migrate to the periphery and produce immunomodulatory cytokines such as IL-4, IL-10, or TGF-beta. In this work we have attempted to extend this paradigm to man by analyzing the response of human PP T cells to in vitro challenge with the common dietary Ag beta-lactoglobulin (betalg) of cow's milk. PP T cells stimulated with betalg showed enhanced proliferation compared with blood T cells from the same patient. Increased expression of CD25 and the Th1-associated chemokine receptor CCR5 was also seen on CD4(+) and CD8(+) PP T cells, but not blood T cells, stimulated with betalg. By enzyme-linked immunospot assay and RT-PCR, the PP T cell recall response to betalg and casein was dominated by IFN-gamma, with negligible IL-4, IL-5, IL-10, or TGF-beta. To help explain the PP T cell response to betalg, we examined IL-12 expression. Both IL-12p40 and -p35 transcripts were abundantly expressed in PP, but not in adjacent normal ileal mucosa. Immunoreactive IL-12p40-containing cells were present below the PP dome epithelium. Furthermore, in culture, PP, but not paired PBMC, spontaneously released IL-12p70. These results suggest that the human response to oral Ags in the gut may be different from that in rodents.

Adolescent↗
PubMed2000

Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn's disease.

BACKGROUND: Although enteral nutrition is a recognized form of treatment for intestinal Crohn's disease, there are persisting problems with feed palatability and only limited data as to its mode of action. AIM: To assess the effects of a specific oral polymeric diet (CT3211; Nestle, Vevey, Switzerland), which is rich in transforming growth factor beta2, on the mucosal inflammatory process. METHODS: Twenty-nine consecutive children with active intestinal Crohn's disease were treated with CT3211 as the sole source of nutrition for 8 weeks. Patients were assessed clinically, and endoscopically, whilst cytokine mRNA was measured in mucosal biopsies before and after treatment by quantitative reverse transcriptase polymerase chain reaction. RESULTS: After 8 weeks 79% of children were in complete clinical remission. Macroscopic and histological healing in the terminal ileum and colon was associated with a decline in ileal and colonic interleukin-1beta mRNA (pre-treatment to post-treatment ratio 0.008 and 0.06: P < 0.001, P = 0.006). In the ileum there was also a fall in interferon gamma mRNA (ratio 0.15, P < 0.001) with a rise in transforming growth factor beta1 mRNA (ratio 10, P = 0.04), whilst in the colon interleukin-8 mRNA fell with treatment (ratio 0.06, P < 0.05). CONCLUSIONS: The clinical response to oral polymeric diet CT3211 is associated with mucosal healing and a down regulation of mucosal pro-inflammatory cytokine mRNA in both the terminal ileum and colon. In the ileum there was also an increase in transforming growth factor beta1 mRNA.

Adolescent↗
PubMed2000

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.

Acetylglucosamine↗
PubMed2000

Enterocolitis in children with developmental disorders.

OBJECTIVE: Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. METHODS: Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0-3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2-13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely. RESULTS: Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001). CONCLUSIONS: A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.

Adolescent↗
PubMed2000

Topical tacrolimus may be effective in the treatment of oral and perineal Crohn's disease.

BACKGROUND: Crohn's disease of the mouth or perineum is more common in young people, and notably resistant to treatment. However, there is increasing evidence that topical therapy with tacrolimus (FK506) may be effective in skin diseases resistant to cyclosporin because of its high uptake in inflamed skin and subsequent reduction in keratinocyte chemokine production. PATIENTS AND METHODS: Tacrolimus ointment was made up inhouse from the intravenous or oral formulation and suspended in appropriate vehicles for perioral or perianal administration at an initial concentration of 0.5 mg/g. This was administered open label to eight children (aged 5-18 years) with treatment resistant oral (three patients) and/or ulcerating perineal (six patients) Crohn's disease. RESULTS: Marked improvement was seen in 7/8 patients within six weeks and healing within 1-6 months. One child with gross perineal and colonic disease showed little response. Two of the responders showed rebound worsening when tacrolimus was stopped or the dosage reduced rapidly, and one of these eventually required proctectomy. Slower weaning of drug concentration has been successful in 6/8 patients, with four receiving intermittent treatment and two on regular reduced dosage (0.1-0.3 mg/g) with follow up times of six months to 3.5 years. Serum concentrations of tacrolimus were undetectable in all patients. CONCLUSIONS: Topical tacrolimus at low concentrations (0.5 mg/g) shows promise in the management of childhood perineal and oral Crohn's disease, with no evidence of significant systemic absorption. However, rapid weaning or abrupt cessation of therapy may cause rebound worsening of disease. Further controlled studies are required to assess the efficacy and safety of this treatment.

Administration, Topical↗