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Papers by Andrew Anthony

Research paper thumbnail of Acute indomethacin-induced jejunal injury in the rat: Early morphological and biochemical changes

Acute indomethacin-induced jejunal injury in the rat: Early morphological and biochemical changes

Gastroenterology, 1994

Gastrointestinal injury induced by nonsteroidal anti-inflammatory drugs includes smooth muscle co... more Gastrointestinal injury induced by nonsteroidal anti-inflammatory drugs includes smooth muscle contraction, endothelial cell injury, and neutrophil infiltration. The aim of this study was to correlate early morphological changes with those in the metabolism of arachidonic acid. Rats administered a single oral dose of indomethacin (15 mg/kg) or vehicle were killed and their intestines perfusion-fixed at 1, 2, 3, 6, and 48 hours after dosage. Serial sections of affected small intestine were immunostained for neutrophils, macrophages, actin, and fibrinogen. In addition, rats receiving either indomethacin (15 mg/kg) or vehicle were killed at 1 and 6 hours after dosage; blood and small intestinal tissue were assayed for blood thromboxane B2, intestinal tissue prostaglandin E2, and the intestinal production of leukotriene B4. At 2-6 hours, both intravascular and extravascular fibrin deposition were evident at the villus tip, and vertical alignment of villus smooth muscle cells was prominent. Significant neutrophil infiltration associated with a significant increase in leukotriene production was observed 6 hours after dosage. The extracted prostaglandin E2 content that was suppressed at 1 hour had recovered by 6 hours, whereas the blood thromboxane B2 levels were suppressed throughout the experiment. This study identifies an early neutrophil-independent phase of indomethacin-induced enteropathy that involves rapid cyclooxygenase inhibition and both microvascular and smooth muscle changes.

Research paper thumbnail of Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis

The American journal of gastroenterology, 2004

Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's dise... more Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepi...

Research paper thumbnail of Enterocolitis in children with developmental disorders

Enterocolitis in children with developmental disorders

The American journal of gastroenterology, 2000

Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammati... more 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. 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 a...

Research paper thumbnail of Detection of Measles Virus Genomic RNA in Cerebrospinal Fluid of Children with Regressive Autism: a Report of Three Cases

In light of encephalopathy presenting as autistic regression (autistic encephalopathy, AE) closel... more In light of encephalopathy presenting as autistic regression (autistic encephalopathy, AE) closely following measles-mumps- rubella (MMR) vaccination, three children underwent cerebrospinal fluid (CSF) assessments including studies for measles virus (MV). All three children had concomitant onset of gastrointestinal (GI) symptoms and had already had MV genomic RNA detected in biopsies of ileal lymphoid nodular hyperplasia (LNH). Presence of MV Fusion (F) gene was examined by TaqMan real- time quantitative polymerase chain reaction (RT-PCR) in cases and control CSF samples. The latter were obtained from three non- autistic MMR-vaccinated children with indwelling shunts for hydrocephalus. None of the cases or controls had a history of measles exposure other than MMR vaccination. Serum and CSF samples were also evaluated for antibodies to MV and myelin basic protein (MBP). MV F gene was present in CSF from all three cases, but not in controls. Genome copy number ranged from 3.7x10 to 2....

Research paper thumbnail of Colonic CD8 and γδ T-cell infiltration with epithelial damage in children with autism

The Journal of Pediatrics, 2001

in over 150 subsequently evaluated children with autism, in whom the main gastrointestinal presen... more in over 150 subsequently evaluated children with autism, in whom the main gastrointestinal presentation was abdominal pain and either constipation or diarrhea. 2 It remains unclear whether this inflammation is characteristic for autism in general or found only in a subgroup with gastrointestinal symptoms. In view of striking recent increases in autistic spectrum disorders in both the United Kingdom and the United States, 3,4 this required further study. A preliminary report in 12 children with regressive autism described unexpected colonic inflammation in association with ileal lymphoid nodular hy-Colonic CD8 and γδ T-cell infiltration with epithelial damage in children with autism

Research paper thumbnail of The Β3‐ADRENOCEPTOR Agonist CL316243 Prevents Indomethacin‐Induced Jejunal Ulceration in the Rat by Reversing Early Villous Shortening

The Β3‐ADRENOCEPTOR Agonist CL316243 Prevents Indomethacin‐Induced Jejunal Ulceration in the Rat by Reversing Early Villous Shortening

The Journal of Pathology, 1996

Abstract Jejunal villi undergo early histological shortening and vascular injury in indomethacin-... more Abstract Jejunal villi undergo early histological shortening and vascular injury in indomethacin-induced ulcerative enteropathy in the rat. The protective effects of the β 3-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were ...

Research paper thumbnail of Ulceration of the ileum in Crohn's disease: correlation with vascular anatomy

Journal of Clinical Pathology, 1997

Background-Ileal ulcers in Crohn's disease tend to lie along the same side of the bowel wall as t... more Background-Ileal ulcers in Crohn's disease tend to lie along the same side of the bowel wall as the mesenteric attachment; the mesenteric and antimesenteric borders are supplied by short and long arteries, respectively. Aim-To examine the localisation of ileal Crohn's ulcers and to test the hypothesis that predilection of Crohn's ulcers for the ileal mesenteric margin is explained by the existence of end arteries that supply the mesenteric margin. Methods-The localisation of ulcers in the bowel wall was examined in eight resection specimens of Crohn's disease of the terminal ileum. The vascular anatomy of normal terminal ileum (n = 8) and proximal jejunum (n = 8) postmortem specimens was studied; isolated long and short vessels were ligated before perfusion in four of these specimens. Results-All eight specimens of Crohn's disease of the terminal ileum showed longitudinal ulceration along the mesenteric margin. In the postmortem study, the submucosal vascular plexus derived from ileal, but not jejunal short vessels, comprised end arteries with little or no communication with the submucosal plexus arising from long vessels. Prior ligation of ileal, but not jejunal, short vessels resulted in a filling defect of the submucosal plexus along the mesenteric margin in three of the four specimens. Ligation of ileal and jejunal long vessels did not affect carbon ink perfusion of the bowel wall. Conclusions-In the human terminal ileum, the short vessels supplying the mesenteric margin are end arteries, and their pathological occlusion might cause ischaemia of this region. These findings support a vascular hypothesis for Crohn's disease and may explain, in part, both the ileal and mesenteric distribution of Crohn's disease ulcers.

Research paper thumbnail of Absence of Escherichia coli, Listeria monocytogenes, and Klebsiella pneumoniae antigens within inflammatory bowel disease tissues

Journal of Clinical Pathology, 1998

Background-Escherichia coli, listeria, and streptococcal antigens have been found in Crohn's dise... more Background-Escherichia coli, listeria, and streptococcal antigens have been found in Crohn's disease tissues. Antibodies to Klebsiella pneumoniae have been found in patients with inflammatory bowel disease and ankylosing spondylitis. The presence of these bacterial antigens in Crohn's granulomas would be of aetiological interest, while their presence in ulcers alone would be more likely to indicate secondary infection. Aim-To investigate inflammatory bowel disease tissues for the presence of these bacteria. Methods-Formalin fixed, paraYn processed sections from 53 patients (19 ulcerative colitis, 23 Crohn's disease; 11 normal tissues from cancer resections) were studied by immunohistochemistry. Control tissue consisted of normal human small bowel injected submucosally with either E coli, Listeria monocytogenes, Proteus mirabilis, or Klebsiella pneumoniae serotypes K2, 3, 17, 21, 26, 36, and 50, and colonic biopsies from a child with E coli 0114 infection. Tissues were stained by Gram-Twort, and with specific antibodies for E coli (Dako B357), L monocytogenes (Difco 2302-50), and K pneumoniae (Biogenesis 5580-5208) using an immunoperoxidase technique. Results-Positive staining for E coli was observed on the luminal surface epithelium and in ulcers in 35% of Crohn's disease patients, 26% of ulcerative colitis patients, and no normal controls. Superficial staining for L monocytogenes was observed in one case of ulcerative colitis only. Staining for K pneumoniae was observed in one case of ulcerative colitis and one of Crohn's disease. No granulomas, giant cells, or germinal centres stained positively for any of the three bacterial antigens. Conclusions-These data do not support a primary role for E coli, L monocytogenes, and K pneumoniae in inflammatory bowel disease. The presence of E coli antigens in ulcers suggests secondary infection in these lesions.

Research paper thumbnail of Spontaneous Mucosal Lymphocyte Cytokine Profiles in Children with Autism and Gastrointestinal Symptoms: Mucosal Immune Activation and Reduced Counter Regulatory Interleukin-10

Journal of Clinical Immunology, 2004

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum diso... more A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced proinflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal pediatric controls, of which 38 had signs of histological inflammation. Detection of CD3 + lymphocyte staining for spontaneous intracellular TNFα, IL-2, IL-4, IFNγ , and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3 + lymphocyte counts were elevated in ASD children compared with noninflamed controls (p < 0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3 + TNFα + cells in ASD children was significantly greater compared with noninflamed controls (p < 0.002) but not coeliac disease controls. In addition, LP and epithelial CD3 + IL-2 + and CD3 + IFNγ + , and epithelial CD3 + IL-4 + cells were more numerous in ASD children than in noninflamed controls (p < 0.04). In contrast, CD3 + IL-10 + cells were fewer in ASD children than in noninflamed controls (p < 0.05). In the A1 colon, LP CD3 + TNFα + and CD3 + IFNγ + were more frequent in ASD children than in noninflamed controls (p < 0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3 + IL-10 + cells were fewer in ASD children than in

Research paper thumbnail of Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Extensive Mucosal Immunopathology

Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Extensive Mucosal Immunopathology

Journal of Clinical Immunology, 2003

Research paper thumbnail of Focal reduction of villous blood flow in early indomethacin enteropathy: a dynamic vascular study in the rat

Gut, 1998

Background—Oral indomethacin causes villous shortening, microvascular damage, and distortion, whi... more Background—Oral indomethacin causes villous shortening, microvascular damage, and distortion, which might induce mucosal ischaemia and necrosis.Aims—In order to determine the early events in indomethacin induced jejunal injury we examined the temporal relations between morphological damage and changes in villous blood flow following indomethacin.Methods—In anaesthetised rats, mid jejunal villi were exteriorised in a chamber and observed by fluorescence microscopy. Blood flow in surface capillaries was calculated from velocities and diameters. Indomethacin was applied by both luminal and intravenous routes for 90 minutes, after which the animal was perfusion fixed and the villi were processed for histological examination. Control animals received intravenous or luminal bicarbonate (1.25%).Results—Blood flow slowed in individual villi at 20 minutes, and progressed to complete stasis (in another group) by 45 minutes. Histological examination at 20 minutes revealed microvascular distort...

Research paper thumbnail of COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice

Gastroenterology, 2002

Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is... more Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is controversial, but it is thought that cyclooxygenase-1 (COX-1) inhibition is of pivotal importance. We compared small intestinal function and morphology in untreated wildtype, COX-1-and COX-2-deficient mice and the effect of indomethacin, selective COX-1 (SC-560), and COX-2 (celecoxib) inhibition. Methods: Intestinal permeability (51 CrEDTA), inflammation (fecal granulocyte marker protein), prostaglandin E 2 (PGE 2) levels, and macroscopic and microscopic appearances were assessed at baseline and after the drugs. Results: COX-1 ؊/؊ animals were normal except for a 97% decrease in intestinal PGE 2 levels. COX-1 ؉/؉ and COX-1 ؊/؊ animals reacted in a similar way to indomethacin. However, celecoxib, having caused no damage in COX-1 ؉/؉ animals, caused small bowel ulcers in COX-1 ؊/؊ animals. Selective inhibition of COX-1 decreased intestinal PGE 2 levels in COX-2 ؉/؉ and COX-2 ؊/؊ animals by 95%-97%, but caused only small bowel ulcers in the latter group. Dual inhibition of COX-1 and COX-2 in wild-type animals resulted in similar small bowel damage. Between 40% and 50% of untreated COX-2 ؊/؊ animals had increased intestinal permeability and inflammation. Some had ileal ulcers that were distinctively different from indomethacin-induced ulcers. Furthermore, long-term celecoxib administration in wildtype animals was associated with similar damage as in the COX-2 ؊/؊ mice. Conclusions: COX-1 deficiency or inhibition and short-term COX-2 inhibition are compatible with normal small intestinal integrity. Dual inhibition of the COX enzymes leads to damage similar to that seen with indomethacin. Long-term COX-2 deficiency or inhibition is associated with significant intestinal pathology despite normal intestinal PGE 2 levels, suggesting a role for COX-2 in the maintenance of small intestinal integrity in the mouse.

Research paper thumbnail of Faecal calprotectin levels correlate with acute inflammation in autistic enterocolitis

Gastroenterology, 2000

Background: Patients with gastroparesis requiring IV access are at risk for catheter-related thro... more Background: Patients with gastroparesis requiring IV access are at risk for catheter-related thrombosis (CRT). In this group of patients at risk for thrombosis, the incidence of Protein S deficiency and the occurrence of subsequent CRT is not known. Methods: We aimed to evaluate the occurrence of a baseline hematologic or autoimmune abnormalities in patients (pts) with Upper GI motor disorders (UGIMD) needing IV access who were followed for subsequent catheter-related thrombosis (CRT). We studied 53 pts (6 m, 47 f, mean age 39) with gastroparesis (6 with diabetes mellitus and 47 with idiopathic disease) who underwent evaluation for hypercoagulable states and/or auto antibodies by Western blot (GE 108(4): A734, 1995). After IVA placement, pts were classified into 2 groups: those with clinical thrombosis (CLOT) vs. those without (NO CLOT). Results were analyzed by T-tests and reported as mean ± SE. Results: 53 pts with baseline hematologic and autoimmune evaluations are summarized below. CRT was noted in 14 out of 53 pts (26%) See Tables Conclusions: A high frequency of protein S deficiency was noted in this group of pts with GI motor disorders and catheter related thrombosis. Protein S deficiency as seen in these pts, might result from underlying inflammation and acute phase protein release. Further prospective studies are indicated to explore possible underlying mechanisms of this observed increase of thrombosis in pts with gastrointestinal motor disorders.

Research paper thumbnail of Indomethacin-induced jejunal villous contraction and microvascular occulusion: A detailed morphological study

Research paper thumbnail of Persistent messles virus (MV) infection of lleal lymphoid tissue in children with lise-colonic lymphoid nodular hyperplasia, entero-colitis and developmental disorder

Research paper thumbnail of Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: Preliminary evidence for an entero-colonic encephalopathy?

Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: Preliminary evidence for an entero-colonic encephalopathy?

Gastroenterology, 2001

Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: ... more Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: Preliminary evidence for an entero-colonic encephalopathy? ... No abstract is available. To read the body of this article, please view the PDF online.

Research paper thumbnail of Endothelial changes precede epithelial disruption in early nsaid damage: An ultrastructural study in rat jejunal villi

Endothelial changes precede epithelial disruption in early nsaid damage: An ultrastructural study in rat jejunal villi

Gastroenterology, 1998

Research paper thumbnail of Ileo-colonic lymphonodular hyperplasia, non-specific colitis and autistic spectrum disorder in children: A new syndrome?

Research paper thumbnail of Granulomatous vasculitis in Crohn's disease: Association with the extra-mural vasculature

Gastroenterology, 2000

Mice with the targeted deletion of the G protein subunit ad2 (Gai2-/-) develop chronic colitis. W... more Mice with the targeted deletion of the G protein subunit ad2 (Gai2-/-) develop chronic colitis. While disease pathogenesis is characterized by infiltration of the colonic mucosa by activated CD4+ cells and the production of THI pro-inflammatory cytokines, little is known about the stimulus or the identity of the cell type responsible for the inflammatory process. To determine if the normal enteric flora is necessary for disease

Research paper thumbnail of The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder

European Journal of Gastroenterology & Hepatology, 2005

What are we to make of the paper by Wakefield and colleagues entitled 'The significance of ileo-c... more What are we to make of the paper by Wakefield and colleagues entitled 'The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder' [1] in the August issue of the journal? There are a number of issues that may be important in its evaluation. The children studied were a series apparently referred to the Department of Paediatric Gastroenterology at the Royal Free Hospital in London. It should be explained why neither the lead clinician, in charge of these patients, nor the consultant paediatric gastroenterologists who performed the endoscopies and generated the data on lymphoid hyperplasia are listed as co-authors, although these data have previously been published in abstract form in 2003 under all their names [2]? The authors of the present paper include Ms Kirsten Limb who is apparently affiliated with the charity Visceral in Bath, UK, which supported the work, and of which the paper's first author is apparently an officer. It is stated in the acknowledgements that Ms Limb collated the data and conducted the analyses. However, the data appear to have been previously collated and analysed for the 2003 abstract [2], but on that occasion seemingly without crediting Ms Limb with authorship. Bearing in mind that the title and summaries of the present paper and the 2003 abstract are essentially identical, this is another matter that should be clarified by the authors.

Research paper thumbnail of Acute indomethacin-induced jejunal injury in the rat: Early morphological and biochemical changes

Acute indomethacin-induced jejunal injury in the rat: Early morphological and biochemical changes

Gastroenterology, 1994

Gastrointestinal injury induced by nonsteroidal anti-inflammatory drugs includes smooth muscle co... more Gastrointestinal injury induced by nonsteroidal anti-inflammatory drugs includes smooth muscle contraction, endothelial cell injury, and neutrophil infiltration. The aim of this study was to correlate early morphological changes with those in the metabolism of arachidonic acid. Rats administered a single oral dose of indomethacin (15 mg/kg) or vehicle were killed and their intestines perfusion-fixed at 1, 2, 3, 6, and 48 hours after dosage. Serial sections of affected small intestine were immunostained for neutrophils, macrophages, actin, and fibrinogen. In addition, rats receiving either indomethacin (15 mg/kg) or vehicle were killed at 1 and 6 hours after dosage; blood and small intestinal tissue were assayed for blood thromboxane B2, intestinal tissue prostaglandin E2, and the intestinal production of leukotriene B4. At 2-6 hours, both intravascular and extravascular fibrin deposition were evident at the villus tip, and vertical alignment of villus smooth muscle cells was prominent. Significant neutrophil infiltration associated with a significant increase in leukotriene production was observed 6 hours after dosage. The extracted prostaglandin E2 content that was suppressed at 1 hour had recovered by 6 hours, whereas the blood thromboxane B2 levels were suppressed throughout the experiment. This study identifies an early neutrophil-independent phase of indomethacin-induced enteropathy that involves rapid cyclooxygenase inhibition and both microvascular and smooth muscle changes.

Research paper thumbnail of Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis

The American journal of gastroenterology, 2004

Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's dise... more Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepi...

Research paper thumbnail of Enterocolitis in children with developmental disorders

Enterocolitis in children with developmental disorders

The American journal of gastroenterology, 2000

Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammati... more 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. 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 a...

Research paper thumbnail of Detection of Measles Virus Genomic RNA in Cerebrospinal Fluid of Children with Regressive Autism: a Report of Three Cases

In light of encephalopathy presenting as autistic regression (autistic encephalopathy, AE) closel... more In light of encephalopathy presenting as autistic regression (autistic encephalopathy, AE) closely following measles-mumps- rubella (MMR) vaccination, three children underwent cerebrospinal fluid (CSF) assessments including studies for measles virus (MV). All three children had concomitant onset of gastrointestinal (GI) symptoms and had already had MV genomic RNA detected in biopsies of ileal lymphoid nodular hyperplasia (LNH). Presence of MV Fusion (F) gene was examined by TaqMan real- time quantitative polymerase chain reaction (RT-PCR) in cases and control CSF samples. The latter were obtained from three non- autistic MMR-vaccinated children with indwelling shunts for hydrocephalus. None of the cases or controls had a history of measles exposure other than MMR vaccination. Serum and CSF samples were also evaluated for antibodies to MV and myelin basic protein (MBP). MV F gene was present in CSF from all three cases, but not in controls. Genome copy number ranged from 3.7x10 to 2....

Research paper thumbnail of Colonic CD8 and γδ T-cell infiltration with epithelial damage in children with autism

The Journal of Pediatrics, 2001

in over 150 subsequently evaluated children with autism, in whom the main gastrointestinal presen... more in over 150 subsequently evaluated children with autism, in whom the main gastrointestinal presentation was abdominal pain and either constipation or diarrhea. 2 It remains unclear whether this inflammation is characteristic for autism in general or found only in a subgroup with gastrointestinal symptoms. In view of striking recent increases in autistic spectrum disorders in both the United Kingdom and the United States, 3,4 this required further study. A preliminary report in 12 children with regressive autism described unexpected colonic inflammation in association with ileal lymphoid nodular hy-Colonic CD8 and γδ T-cell infiltration with epithelial damage in children with autism

Research paper thumbnail of The Β3‐ADRENOCEPTOR Agonist CL316243 Prevents Indomethacin‐Induced Jejunal Ulceration in the Rat by Reversing Early Villous Shortening

The Β3‐ADRENOCEPTOR Agonist CL316243 Prevents Indomethacin‐Induced Jejunal Ulceration in the Rat by Reversing Early Villous Shortening

The Journal of Pathology, 1996

Abstract Jejunal villi undergo early histological shortening and vascular injury in indomethacin-... more Abstract Jejunal villi undergo early histological shortening and vascular injury in indomethacin-induced ulcerative enteropathy in the rat. The protective effects of the β 3-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were ...

Research paper thumbnail of Ulceration of the ileum in Crohn's disease: correlation with vascular anatomy

Journal of Clinical Pathology, 1997

Background-Ileal ulcers in Crohn's disease tend to lie along the same side of the bowel wall as t... more Background-Ileal ulcers in Crohn's disease tend to lie along the same side of the bowel wall as the mesenteric attachment; the mesenteric and antimesenteric borders are supplied by short and long arteries, respectively. Aim-To examine the localisation of ileal Crohn's ulcers and to test the hypothesis that predilection of Crohn's ulcers for the ileal mesenteric margin is explained by the existence of end arteries that supply the mesenteric margin. Methods-The localisation of ulcers in the bowel wall was examined in eight resection specimens of Crohn's disease of the terminal ileum. The vascular anatomy of normal terminal ileum (n = 8) and proximal jejunum (n = 8) postmortem specimens was studied; isolated long and short vessels were ligated before perfusion in four of these specimens. Results-All eight specimens of Crohn's disease of the terminal ileum showed longitudinal ulceration along the mesenteric margin. In the postmortem study, the submucosal vascular plexus derived from ileal, but not jejunal short vessels, comprised end arteries with little or no communication with the submucosal plexus arising from long vessels. Prior ligation of ileal, but not jejunal, short vessels resulted in a filling defect of the submucosal plexus along the mesenteric margin in three of the four specimens. Ligation of ileal and jejunal long vessels did not affect carbon ink perfusion of the bowel wall. Conclusions-In the human terminal ileum, the short vessels supplying the mesenteric margin are end arteries, and their pathological occlusion might cause ischaemia of this region. These findings support a vascular hypothesis for Crohn's disease and may explain, in part, both the ileal and mesenteric distribution of Crohn's disease ulcers.

Research paper thumbnail of Absence of Escherichia coli, Listeria monocytogenes, and Klebsiella pneumoniae antigens within inflammatory bowel disease tissues

Journal of Clinical Pathology, 1998

Background-Escherichia coli, listeria, and streptococcal antigens have been found in Crohn's dise... more Background-Escherichia coli, listeria, and streptococcal antigens have been found in Crohn's disease tissues. Antibodies to Klebsiella pneumoniae have been found in patients with inflammatory bowel disease and ankylosing spondylitis. The presence of these bacterial antigens in Crohn's granulomas would be of aetiological interest, while their presence in ulcers alone would be more likely to indicate secondary infection. Aim-To investigate inflammatory bowel disease tissues for the presence of these bacteria. Methods-Formalin fixed, paraYn processed sections from 53 patients (19 ulcerative colitis, 23 Crohn's disease; 11 normal tissues from cancer resections) were studied by immunohistochemistry. Control tissue consisted of normal human small bowel injected submucosally with either E coli, Listeria monocytogenes, Proteus mirabilis, or Klebsiella pneumoniae serotypes K2, 3, 17, 21, 26, 36, and 50, and colonic biopsies from a child with E coli 0114 infection. Tissues were stained by Gram-Twort, and with specific antibodies for E coli (Dako B357), L monocytogenes (Difco 2302-50), and K pneumoniae (Biogenesis 5580-5208) using an immunoperoxidase technique. Results-Positive staining for E coli was observed on the luminal surface epithelium and in ulcers in 35% of Crohn's disease patients, 26% of ulcerative colitis patients, and no normal controls. Superficial staining for L monocytogenes was observed in one case of ulcerative colitis only. Staining for K pneumoniae was observed in one case of ulcerative colitis and one of Crohn's disease. No granulomas, giant cells, or germinal centres stained positively for any of the three bacterial antigens. Conclusions-These data do not support a primary role for E coli, L monocytogenes, and K pneumoniae in inflammatory bowel disease. The presence of E coli antigens in ulcers suggests secondary infection in these lesions.

Research paper thumbnail of Spontaneous Mucosal Lymphocyte Cytokine Profiles in Children with Autism and Gastrointestinal Symptoms: Mucosal Immune Activation and Reduced Counter Regulatory Interleukin-10

Journal of Clinical Immunology, 2004

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum diso... more A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced proinflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal pediatric controls, of which 38 had signs of histological inflammation. Detection of CD3 + lymphocyte staining for spontaneous intracellular TNFα, IL-2, IL-4, IFNγ , and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3 + lymphocyte counts were elevated in ASD children compared with noninflamed controls (p < 0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3 + TNFα + cells in ASD children was significantly greater compared with noninflamed controls (p < 0.002) but not coeliac disease controls. In addition, LP and epithelial CD3 + IL-2 + and CD3 + IFNγ + , and epithelial CD3 + IL-4 + cells were more numerous in ASD children than in noninflamed controls (p < 0.04). In contrast, CD3 + IL-10 + cells were fewer in ASD children than in noninflamed controls (p < 0.05). In the A1 colon, LP CD3 + TNFα + and CD3 + IFNγ + were more frequent in ASD children than in noninflamed controls (p < 0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3 + IL-10 + cells were fewer in ASD children than in

Research paper thumbnail of Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Extensive Mucosal Immunopathology

Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Extensive Mucosal Immunopathology

Journal of Clinical Immunology, 2003

Research paper thumbnail of Focal reduction of villous blood flow in early indomethacin enteropathy: a dynamic vascular study in the rat

Gut, 1998

Background—Oral indomethacin causes villous shortening, microvascular damage, and distortion, whi... more Background—Oral indomethacin causes villous shortening, microvascular damage, and distortion, which might induce mucosal ischaemia and necrosis.Aims—In order to determine the early events in indomethacin induced jejunal injury we examined the temporal relations between morphological damage and changes in villous blood flow following indomethacin.Methods—In anaesthetised rats, mid jejunal villi were exteriorised in a chamber and observed by fluorescence microscopy. Blood flow in surface capillaries was calculated from velocities and diameters. Indomethacin was applied by both luminal and intravenous routes for 90 minutes, after which the animal was perfusion fixed and the villi were processed for histological examination. Control animals received intravenous or luminal bicarbonate (1.25%).Results—Blood flow slowed in individual villi at 20 minutes, and progressed to complete stasis (in another group) by 45 minutes. Histological examination at 20 minutes revealed microvascular distort...

Research paper thumbnail of COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice

Gastroenterology, 2002

Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is... more Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is controversial, but it is thought that cyclooxygenase-1 (COX-1) inhibition is of pivotal importance. We compared small intestinal function and morphology in untreated wildtype, COX-1-and COX-2-deficient mice and the effect of indomethacin, selective COX-1 (SC-560), and COX-2 (celecoxib) inhibition. Methods: Intestinal permeability (51 CrEDTA), inflammation (fecal granulocyte marker protein), prostaglandin E 2 (PGE 2) levels, and macroscopic and microscopic appearances were assessed at baseline and after the drugs. Results: COX-1 ؊/؊ animals were normal except for a 97% decrease in intestinal PGE 2 levels. COX-1 ؉/؉ and COX-1 ؊/؊ animals reacted in a similar way to indomethacin. However, celecoxib, having caused no damage in COX-1 ؉/؉ animals, caused small bowel ulcers in COX-1 ؊/؊ animals. Selective inhibition of COX-1 decreased intestinal PGE 2 levels in COX-2 ؉/؉ and COX-2 ؊/؊ animals by 95%-97%, but caused only small bowel ulcers in the latter group. Dual inhibition of COX-1 and COX-2 in wild-type animals resulted in similar small bowel damage. Between 40% and 50% of untreated COX-2 ؊/؊ animals had increased intestinal permeability and inflammation. Some had ileal ulcers that were distinctively different from indomethacin-induced ulcers. Furthermore, long-term celecoxib administration in wildtype animals was associated with similar damage as in the COX-2 ؊/؊ mice. Conclusions: COX-1 deficiency or inhibition and short-term COX-2 inhibition are compatible with normal small intestinal integrity. Dual inhibition of the COX enzymes leads to damage similar to that seen with indomethacin. Long-term COX-2 deficiency or inhibition is associated with significant intestinal pathology despite normal intestinal PGE 2 levels, suggesting a role for COX-2 in the maintenance of small intestinal integrity in the mouse.

Research paper thumbnail of Faecal calprotectin levels correlate with acute inflammation in autistic enterocolitis

Gastroenterology, 2000

Background: Patients with gastroparesis requiring IV access are at risk for catheter-related thro... more Background: Patients with gastroparesis requiring IV access are at risk for catheter-related thrombosis (CRT). In this group of patients at risk for thrombosis, the incidence of Protein S deficiency and the occurrence of subsequent CRT is not known. Methods: We aimed to evaluate the occurrence of a baseline hematologic or autoimmune abnormalities in patients (pts) with Upper GI motor disorders (UGIMD) needing IV access who were followed for subsequent catheter-related thrombosis (CRT). We studied 53 pts (6 m, 47 f, mean age 39) with gastroparesis (6 with diabetes mellitus and 47 with idiopathic disease) who underwent evaluation for hypercoagulable states and/or auto antibodies by Western blot (GE 108(4): A734, 1995). After IVA placement, pts were classified into 2 groups: those with clinical thrombosis (CLOT) vs. those without (NO CLOT). Results were analyzed by T-tests and reported as mean ± SE. Results: 53 pts with baseline hematologic and autoimmune evaluations are summarized below. CRT was noted in 14 out of 53 pts (26%) See Tables Conclusions: A high frequency of protein S deficiency was noted in this group of pts with GI motor disorders and catheter related thrombosis. Protein S deficiency as seen in these pts, might result from underlying inflammation and acute phase protein release. Further prospective studies are indicated to explore possible underlying mechanisms of this observed increase of thrombosis in pts with gastrointestinal motor disorders.

Research paper thumbnail of Indomethacin-induced jejunal villous contraction and microvascular occulusion: A detailed morphological study

Research paper thumbnail of Persistent messles virus (MV) infection of lleal lymphoid tissue in children with lise-colonic lymphoid nodular hyperplasia, entero-colitis and developmental disorder

Research paper thumbnail of Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: Preliminary evidence for an entero-colonic encephalopathy?

Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: Preliminary evidence for an entero-colonic encephalopathy?

Gastroenterology, 2001

Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: ... more Glutamine and glutamate: Glutamine ratios in children with regressive autism and entero-colitis: Preliminary evidence for an entero-colonic encephalopathy? ... No abstract is available. To read the body of this article, please view the PDF online.

Research paper thumbnail of Endothelial changes precede epithelial disruption in early nsaid damage: An ultrastructural study in rat jejunal villi

Endothelial changes precede epithelial disruption in early nsaid damage: An ultrastructural study in rat jejunal villi

Gastroenterology, 1998

Research paper thumbnail of Ileo-colonic lymphonodular hyperplasia, non-specific colitis and autistic spectrum disorder in children: A new syndrome?

Research paper thumbnail of Granulomatous vasculitis in Crohn's disease: Association with the extra-mural vasculature

Gastroenterology, 2000

Mice with the targeted deletion of the G protein subunit ad2 (Gai2-/-) develop chronic colitis. W... more Mice with the targeted deletion of the G protein subunit ad2 (Gai2-/-) develop chronic colitis. While disease pathogenesis is characterized by infiltration of the colonic mucosa by activated CD4+ cells and the production of THI pro-inflammatory cytokines, little is known about the stimulus or the identity of the cell type responsible for the inflammatory process. To determine if the normal enteric flora is necessary for disease

Research paper thumbnail of The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder

European Journal of Gastroenterology & Hepatology, 2005

What are we to make of the paper by Wakefield and colleagues entitled 'The significance of ileo-c... more What are we to make of the paper by Wakefield and colleagues entitled 'The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder' [1] in the August issue of the journal? There are a number of issues that may be important in its evaluation. The children studied were a series apparently referred to the Department of Paediatric Gastroenterology at the Royal Free Hospital in London. It should be explained why neither the lead clinician, in charge of these patients, nor the consultant paediatric gastroenterologists who performed the endoscopies and generated the data on lymphoid hyperplasia are listed as co-authors, although these data have previously been published in abstract form in 2003 under all their names [2]? The authors of the present paper include Ms Kirsten Limb who is apparently affiliated with the charity Visceral in Bath, UK, which supported the work, and of which the paper's first author is apparently an officer. It is stated in the acknowledgements that Ms Limb collated the data and conducted the analyses. However, the data appear to have been previously collated and analysed for the 2003 abstract [2], but on that occasion seemingly without crediting Ms Limb with authorship. Bearing in mind that the title and summaries of the present paper and the 2003 abstract are essentially identical, this is another matter that should be clarified by the authors.