Note: I left some citations in for which there was no text to refer to and for which I couldn't be sure what the conclusion was, in case it might be relevant. Please do not assume the position taken based on the title. When I am able to add text, I will do so. - SM
Testimony by Arthur Krisgman, M.D. before the Committee on Government Reform
In a series of 43 autistic children, mostly regressive, with chronic gastrointestinal symptoms, the majority were found to have pathologic inflammation of the colon and terminal ileum. 90% had pathologic lymphonodular hyperplasia of the terminal ileum. Moreover, the findings were similar and consistent from patient to patient within the affected group.
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Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism.
Singh VK, Lin SX, Newell E, Nelson C.
Department of Biology and Biotechnology Center, Utah State University, Logan, Utah, USA.
Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism. Copyright 2002 National Science Council, ROC and S. Karger AG, Basel
PMID: 12145534 [PubMed - in process]
| J Biomed Sci 2002 Jul-Aug;9(4):359-64 | Related Articles, Links |
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Enterocolitis, autism and measles virus.
Wakefield AJ.
Centre for Gastroenterology, Dept of Medicine & Centre for Paediatric Gastroenterology, Royal Free & University College Medical School, London, UK.
Molecular Psychiatry (2002) 7, S44-S46. doi:10.1038/sj.mp.4001178
PMID: 12142948 [PubMed - in process]
| Mol Psychiatry 2002;7 Suppl 2:S44-6 | Related Articles, Links |
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The gut-brain axis in childhood developmental disorders.
Wakefield AJ.
Experimental Gastroenterology, Centre for Gastroenterology, Royal Free and University College Medical School, London, United Kingdom. awakefield@rfc.ucl.ac.uk
Publication Types:- Review
- Review, Tutorial
PMID: 12082381 [PubMed - indexed for MEDLINE]
| J Pediatr Gastroenterol Nutr 2002 May-Jun;34 Suppl 1:S14-7 | Related Articles, Links |
Comment in:
Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism.
Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH.
Centre for Paediatric Gastroenterology, Royal Free & University College Medical School, London, UK.
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.
PMID: 11986981 [PubMed - indexed for MEDLINE]
| Mol Psychiatry 2002;7(4):375-82, 334 | Related Articles, Links |
Comment in:
Potential viral pathogenic mechanism for new variant inflammatory bowel disease.
Uhlmann V, Martin CM, Sheils O, Pilkington L, Silva I, Killalea A, Murch SB, Walker-Smith J, Thomson M, Wakefield AJ, O'Leary JJ.
Department of Pathology, Coombe Women's Hospital, Dublin 8, Ireland.
AIMS: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis. METHODS: Formalin fixed, paraffin wax embedded and fresh frozen biopsies from the terminal ileum were examined from affected children and histological normal controls. The measles virus Fusion (F) and Haemagglutinin (H) genes were detected by TaqMan reverse transcription polymerase chain reaction (RT-PCR) and the Nucleocapsid (N) gene by RT in situ PCR. Localisation of the mRNA signal was performed using a specific follicular dendritic cell antibody. RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.
PMID: 11950955 [PubMed - indexed for MEDLINE]
| Mol Pathol 2002 Apr;55(2):84-90 | Related Articles, Links |
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Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.
Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH.
Inflammatory Bowel Disease Study Group, Centre for Gastroenterology, Department of Medicine, Royal Free and University College Medical School, London, UK. wakers@aol.com
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.
Publication Types:- Review
- Review, Tutorial
PMID: 11929383 [PubMed - indexed for MEDLINE]
| Aliment Pharmacol Ther 2002 Apr;16(4):663-74 | Related Articles, Links |
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Inflammatory bowel disease and laterality: is left handedness a risk?
Morris DL, Montgomery SM, Galloway ML, Pounder RE, Wakefield AJ.
Inflamatory Bowel Disease Study Group, Royal Free and University College Hospital Medical School, London, UK. Wisemail@compuserve.com
BACKGROUND: Left handedness has been associated with inflammatory bowel disease (IBD) and autoimmune diseases. AIMS: To determine whether left handedness is associated with IBD in two prospective national birth cohorts. METHODS: Subjects with Crohn's disease (CD) and ulcerative colitis (UC) were identified from two national longitudinal birth cohorts at age 26 years (1970 British Cohort Study (BCS70), born in 1970) and age 33 years (National Child Development Study (NCDS), born in 1958). Laterality was determined at age 10 (BCS70) or seven (NCDS) years, based on hand preference for writing and foot preference for kicking a ball (BCS70 only). Multiple logistic regression was used to assess the relationship of handedness with CD, UC, and IBD in the cohorts combined and adjusted for sex. RESULTS: Both cohorts combined showed increased adjusted relative odds of 2.13 (95% confidence interval (CI) 0.97--4.65; p=0.059), 2.13 (95% CI 0.92--4.91; p=0. 077), and 2.13 (95% CI 1.20--3.78; p=0.010) for CD, UC, and IBD, respectively in left handers. CONCLUSIONS: The study suggests a link between IBD and left handedness which may be genetic and/or environmental in origin.
PMID: 11454794 [PubMed - indexed for MEDLINE]
| Gut 2001 Aug;49(2):199-202 | Related Articles, Links |
Comment on:
Immunohistochemical analysis of measles related antigen in IBD.
Wakefield AJ, Montgomery SM.
Publication Types:- Comment
- Letter
PMID: 11200076 [PubMed - indexed for MEDLINE]
| Gut 2001 Jan;48(1):136-7 | Related Articles, Links |
|
Neuropsychobiology 2002 Jan;45(1):1-6 |
Books
Activation of the inflammatory response
system in autism.
Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M.
University Center of Child and Adolescent Psychiatry, Antwerp, Belgium.
Background/Aim: There is now some evidence
that autism may be accompanied by abnormalities in the inflammatory response
system (IRS). Products of the IRS, such as proinflammatory cytokines,
may induce some of the behavioral symptoms of autism, such as social
withdrawal, resistance to novelty and sleep disturbances. The main aim of the
present study was to examine whether autism is accompanied by an activation of
the IRS. Methods: We measured the production of interleukin (IL)-6, IL-10, the
IL-1 receptor antagonist (IL-1RA), interferon (IFN)-gamma and tumor necrosis
factor (TNF)-alpha by whole blood and the serum concentrations of IL-6, the
IL-2 receptor (IL-2R) and IL-1RA. Results: This study showed a significantly
increased production of IFN-gamma and IL-1RA and a trend toward a
significantly increased production of IL-6 and TNF-alpha by whole blood of
autistic children. There were no significant differences in the serum
concentrations of IL-6, IL-2R and IL-1RA between autistic and normal children.
Conclusions: These results suggest that
autism may be accompanied by an activation of the monocytic (increased IL-1RA)
and Th-1-like (increased IFN-gamma) arm of the IRS. It is hypothesized that
increased production of proinflammatory cytokines could play a role in the
pathophysiology of autism. Copyright 2002 S. Karger AG, Basel
PMID: 11803234 [PubMed - in process]
|
Med Sci Monit 2002 Sep-Oct;8(1):BR22-6 |
Books
Use of secretin in the treatment of
childhood autism.
Kaminska B, Czaja M, Kozielska E, Mazur E, Korzon M.
Department and Clinic of Pediatrics, Gastroenterology and Pediatric Oncology,
Medical University, Gdansk, Poland.
The paper presents current views concerning childhood autism. The authors
present the concepts of etiology of this disorder, emphasizing the role of
negative psychical stimuli in early childhood and the role of mother's contact
with the child. Organic factors, including genetic background, developmental
abnormalities of the nervous system, teratogenic factors and perinatal traumas
are also taken into consideration. The role of metabolic factors and
enterohormones, particularly those belonging to the secretin group and their
effect on the function of the gastrointestinal tract and central nervous
system is emphasized. We discuss signs which may be indicative of first
symptoms of autism in different age groups. A typical symptom of autism is no
development of speech, observed from infancy, taking the form of complete
mutism at later stages. It has been emphasized that most pathologic symptoms
result from altered perception of external stimuli, which arouse fear and
anxiety. Autistic patients may suffer from
gastrointestinal tract disturbances such as abdominal pains and diarrhea.
Methods used hitherto in the therapy of childhood autism, mainly by
psychologists and psychiatrists, as well as some attempts of pharmacological
treatment, are presented. The structure and function of secretin, as well as
its effects on the motor and secretory function of the stomach and the
exocrine function of the pancreas are discussed. The role of secretin in
diagnostic tests, among others in the diagnosis of gastrinoma, is emphasized.
We also present the history of the application of secretin in the therapy of
childhood autism.
PMID: 11782669 [PubMed - in process]
|
J Child Neurol 2001 May;16(5):357-63 |
A study of novel polymorphisms in the
upstream region of vasoactive intestinal peptide receptor type 2 gene in
autism.
Asano E, Kuivaniemi H, Huq AH, Tromp G, Behen M, Rothermel R, Herron J,
Chugani DC.
Department of Pediatrics, Children's Hospital of Michigan and Wayne State
University School of Medicine, Detroit 48201, USA.
We investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene
as a candidate gene for autism. We searched for mutations in the VIPR2 gene in
autistic individuals, and 10 novel polymorphisms were identified. Three
polymorphisms in the upstream region were studied in detail, and there was no
significant difference in the frequencies between the autistic group (n = 14)
and unrelated controls (n = 52). The
distribution of the genotypes in two of the three polymorphisms differed
somewhat between autistic subjects with gastrointestinal problems and those
without. Moreover, there was a trend
showing a correlation between the genotypes for the third polymorphism and the
severity of stereotypical behavior as ranked by the Gilliam Autism Rating
Scale. These preliminary results suggest that VIPR2 may have a role in
gastrointestinal symptoms and stereotypical behaviors in autism, although a
larger collection of samples suitable for transmission disequilibrium tests is
necessary to validate the results.
PMID: 11392521 [PubMed - indexed for MEDLINE]
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Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism.
Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH.
University Department of Paediatric Gastroenterology, the Inflammatory Bowel Diseases Study Group, Royal Free and University College School of Medicine, London, United Kingdom.
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.
PMID: 11241044 [PubMed - indexed for MEDLINE]
| : J Pediatr 2001 Mar;138(3):366-72 | Related Articles, Links |
|
Med Hypotheses 2001 Aug;57(2):186-91 |
Application of genomeceuticals to the
molecular and immunological aspects of autism.
Brudnak MA.
MAK Wood Inc., Thiensville, Wisconsin 53024, USA. makwood@earthlink.net
Autism is a developmental disease affecting as many as 1 in 300 children and
is often characterized as a mental disorder originating in infancy that is
associated with self-absorption, inability to interact socially, behavior, and
language dysfunction (e.g. echolalia). Current theories indicate an important
role of diet in the development of disease. It is thought that, as a result of
maldigestion of casein and gluten, opioid-type peptides, or exorphins, are
produced. Additionally, because of the time-frame of development of the
disease, there has been an association with childhood vaccination.
Consequently, prevailing therapies attempt to address these causes in one, or
a combination, of three ways: diet restriction (removing casein and gluten);
supplementation with exogenous enzymes; and probiotic bacteria. Until
recently, none of the therapies addressed the molecular mechanisms that may be
at work in the development and progression of autism. This paper presents
potential molecular and cellular mechanism related to autism as well as
discusses their application to the treatment of the disease through the
application of genomeceuticals. Additionally,
a link between developmentally associated aberrant immune and inflammatory
responses, and autism is suggested and explored. Copyright 2001
Harcourt Publishers Ltd.
PMID: 11461171 [PubMed - indexed for MEDLINE]
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Measles vaccination and inflammatory bowel disease: a national British Cohort Study.
Morris DL, Montgomery SM, Thompson NP, Ebrahim S, Pounder RE, Wakefield AJ.
Department of Medicine, Royal Free and University College Medical School, London, UK.
OBJECTIVE: Measles vaccination has been suggested as a risk for inflammatory bowel disease. Atypical age of measles infection has also been associated with Crohn's disease. This study was designed to examine the relationship of measles vaccination and age of measles vaccination with later inflammatory bowel disease. METHODS: A prospective population-based national birth cohort was used, of those born in 1 wk in April 1970 in Great Britain. The data are from 7616 responding members of the 1970 British Cohort Study with complete vaccination data, who were traced at age 26 yr. A diagnosis of Crohn's disease, ulcerative colitis, and diabetes mellitus (a control disease) was obtained by survey at age 26 yr, and confirmed by physicians. Vaccination data were from survey at age 5 yr. Measles and mumps infection data were obtained from the survey at age 10 yr. Adjustment was made for sex, household crowding in childhood, and father's social class at birth. RESULTS: No statistically significant association was found between measles vaccination status at 5 yr and Crohn's disease (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.27-1.63), ulcerative colitis (adjusted OR 0.57, 95% CI 0.20-1.61), or diabetes (adjusted OR 0.75, 95% CI 0.33-1.74). There was a statistically significant trend (p = 0.040) with increasing age of measles vaccination for risk of Crohn' s disease, although this was based on very few cases vaccinated after age 2 yr. CONCLUSIONS: In this cohort, monovalent measles vaccination status is not associated with inflammatory bowel disease by age 26 yr. Older age at measles vaccination needs to be examined in other studies to confirm whether it is a genuine risk for Crohn's disease.
PMID: 11151885 [PubMed - indexed for MEDLINE]
| : Am J Gastroenterol 2000 Dec;95(12):3507-12 | Related Articles, Links |
Comment in:- Adverse Drug React Toxicol Rev. 2001 Mar;20(1):37-45.
- Adverse Drug React Toxicol Rev. 2001 Mar;20(1):47-55.
Measles, mumps, rubella vaccine: through a glass, darkly.Wakefield AJ, Montgomery SM.
From the article: "In summary, analysis of pre-licensure trials of MMR reveals that gastrointestinal, and other possible adverse events were evident in children from developed countries. Although evidence of gastrointestinal adverse events was a recurring feature of post-licensure studies, they were not considered to be of clinical significance. Follow up for detection of adverse events was reduced from 4 weeks in the initial controlled trial, to 3 weeks in subsequent studies. This was despite the fact that, in the original controlled trial, possible adverse events were still evident in American children at 4 weeks. There was evidence beyond 1968, that the component viruses of MMR could exert both dose- and strain-dependent interference upon the clinical and immunological response of the host to the individual constituent viruses. This effect, for which the influence of mumps virus upon the measles virus component was particularly evident, merits thorough investigation. Clearly, one plus one, plus one never did equal three. There is more than a theoretical risk, supported by more more recent studies, that interference with clearance of measles virus might increase the risk of persistent infection and/or delayed disease. The official argument that the mumps vaccine is less effect alone, but potentiated by combination in MMR, is tacit admission of "interference". Finally, two-dose MMR vaccine schedules appear to be unsatisfactorily tested for safety."
Publication Types:- Editorial
- Review
- Review, Tutorial
PMID: 11212459 [PubMed - indexed for MEDLINE]
| Adverse Drug React Toxicol Rev 2000 Dec;19(4):265-83; discussion 284-92 | Related Articles, Links |
Comment on:
Measles virus and autism.
O'Leary JJ, Uhlmann V, Wakefield AJ.Sir--Contrary to supposition by Masahiro Iizuka and colleagues (July 8, p 160),1 our data from molecular virological studies examining the role of measles virus infection in children with autism and enterocolitis have been peer-reviewed, presented, and published at four international scientific meetings.2-4 We would have been happy to share this information with Iizuka and colleagues if asked. The antibody used in our studies is not that used by Iizuka and colleagues. For the purpose of clarification, our studies involved the use of in-situ hybridisation, in-cell reverse transcriptase, real-time quantitative Taq Man PCR using complementary RNA standards for quantitation and sequencing of complementary DNA measles virus amplicon. In addition, three genes N, F, and H of measles virus were examined. We have also provided data in relation to sub-cellular localisation of measles virus, concordant with the molecular biological findings.*J J O'Leary, V Uhlmann, A J Wakefield
*Coombe Women's Hospital and Trinity College Dublin, Dublin 8, Ireland; and Royal Free and University College Medical School, London, UK
1 Iizuka M, Itou H, Chiba M, et al. The MMR question. Lancet 2000; 356: 160.
Publication Types:- Comment
- Letter
PMID: 11085720 [PubMed - indexed for MEDLINE]
| Lancet 2000 Aug 26;356(9231):772 | Related Articles, Links |
Comment in:
Enterocolitis in children with developmental disorders.
Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Berelowitz M, Walker-Smith JA.
University Department of Medicine, Royal Free and University College Medical School, London, United Kingdom.
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.
PMID: 11007230 [PubMed - indexed for MEDLINE]
| Am J Gastroenterol 2000 Sep;95(9):2285-95 | Related Articles, Links |
Comment on:
Measles virus as a risk for inflammatory bowel disease: an unusually tolerant approach.
Wakefield AJ, Montgomery SM.
Publication Types:- Comment
- Editorial
- Review
- Review, Tutorial
PMID: 10894567 [PubMed - indexed for MEDLINE]
| Am J Gastroenterol 2000 Jun;95(6):1389-92 | Related Articles, Links |
Early determinants of inflammatory bowel disease: use of two national longitudinal birth cohorts.
Thompson NP, Montgomery SM, Wadsworth ME, Pounder RE, Wakefield AJ.
Inflammatory Bowel Disease Study Group, Royal Free Hospital School of Medicine, London, UK.
OBJECTIVE: To examine previously cited early risk factors for inflammatory bowel disease. DESIGN: The 1946 National Survey of Health & Development (NSHD) and the 1958 National Child Development Study (NCDS) are on-going, longitudinal birth cohort studies. A nested case-control design was used combining data from both cohorts; eight controls per case, matched for gender and social class, were selected randomly. METHODS: Data concerning maternal infection in pregnancy (NCDS only), childhood infection (measles, mumps and whooping cough), birth order, appendicectomy, breast-feeding and measures of poor housing conditions in childhood were analysed. In both cohorts, the member's hospital physician or medical records were used to confirm the diagnosis. RESULTS: Twenty-six cases of Crohn's disease and 29 cases of ulcerative colitis were identified. No significant association was found between the development of Crohn's disease or ulcerative colitis and any of the studied factors. There was a trend that those with Crohn's disease were more likely not to have been breast-fed (OR 0.4, 95% CI 0.15-1.03) and not to have had an appendicectomy (OR < 1.00). The opposite was true of those with ulcerative colitis (OR 2.76, 95% CI 0.86-9.81 and OR 2.34, 95% CI 0.69-7.46, respectively). The prevalence of inflammatory bowel disease was 5.12/1000 by the age of 43 years in NSHD and 2.02-2.54/1000 by the age of 33 years in NCDS. CONCLUSIONS: The prevalence of inflammatory bowel disease in these cohorts is among the highest recorded in Europe. Childhood factors may be different for those with Crohn's disease and ulcerative colitis. These cohorts will be increasingly valuable data sources.
PMID: 10656206 [PubMed - indexed for MEDLINE]
| Eur J Gastroenterol Hepatol 2000 Jan;12(1):25-30 | Related Articles, Links |
|
Dig Dis Sci 2000 Apr;45(4):723-9 |
Detection and sequencing of measles virus
from peripheral mononuclear cells from patients with inflammatory bowel
disease and autism.
Kawashima H, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A.
Department of Paediatrics, Tokyo Medical University, Japan.
It has been reported that measles virus may be present in the intestine of
patients with Crohn's disease. Additionally, a new syndrome has been reported
in children with autism who exhibited developmental regression and
gastrointestinal symptoms (autistic enterocolitis), in some cases soon after
MMR vaccine. It is not known whether the virus, if confirmed to be present in
these patients, derives from either wild strains or vaccine strains. In order
to characterize the strains that may be present, we have carried out the
detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in
eight patients with Crohn's disease, three patients with ulcerative colitis,
and nine children with autistic enterocolitis. As controls, we examined
healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases).
RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription
using AMV; cDNAs were subjected to nested PCR for detection of specific
regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples
were sequenced directly, in nucleotides 8393-8676 (H region) or 5325-5465
(from noncoding F to coding F region). One of eight patients with Crohn
disease, one of three patients with ulcerative colitis, and three of nine
children with autism, were positive. Controls were all negative. The sequences
obtained from the patients with Crohn's disease shared the characteristics
with wild-strain virus. The sequences
obtained from the patients with ulcerative colitis and children with autism
were consistent with being vaccine strains. The results were concordant
with the exposure history of the patients. Persistence of measles virus was
confirmed in PBMC in some patients with chronic intestinal inflammation.
PMID: 10759242 [PubMed - indexed for MEDLINE]
Comment on:- Isr Med Assoc J. 1999 Nov;1(3):176-7
Autism, viral infection and measles-mumps-rubella vaccination.
Wakefield AJ, Montgomery SM.
Department of Medicine, Royal Free and University College Medical School, London, UK. awakefield@rfc.ucl.ac.ukFrom the article: "Does any of this evidence implicate MMR vaccination as a potential risk for either inflammatory bowel disease, autism, or other immune-mediated diseases? We believe that it is both biologically plausible and consistent with temporal trends. The virological and immunological evidence is supportive. It is therefore legitimate to hypothesize that the combination of three viruses that have been associated both independently and in combination with autism, may represent - through mechanisms that are not yet fully understood - a compound risk for the disorder. Clearly, although the case is not proven, MMR vaccination is a candidate worthy of investigation."
Publication Types:- Comment
- Review
- Review, Tutorial
PMID: 10731332 [PubMed - indexed for MEDLINE]
| : Isr Med Assoc J 1999 Nov;1(3):183-7 | Related Articles, Links |
Comment on:
MMR vaccination and autism.
Wakefield AJ.From the letter: "Taylor et al tested the hypothesis that there should be no temporal clustering of first parenteral concerns with measles, mumps, and rubella (MMR) vaccination. They identified a statistically significant excess risk by 6 months after MMR, which they dismiss, post hoc, as indicating parental recall bias. Had this been the case it should have been seen in both of their vaccine groups - those receiving MMR and those receiving any measles-containing vaccine. The excess risk was seen only in the MMR group; this is a fundamental flaw.
However, it pales into insignificance compared with their failure to declare the fact of an MMR catch-up campaign that was initiated in 1988 with the introduction of this vaccine. This campaign was targeted at children, whatever their age, who presumably had not received either monovalent mumps or rubella vaccine whatever their exposure status. As such it was a a novel and, in terms of safety, untested policy. On the basis of Taylor and colleagues'' inclusion criteria, and taking account of the catch-up campaign, then those first birth cohorts who actually received MMR (circa 1986) were precisely those in whom a doubling of the seen numbers of cases of autism were seen. Thereafter these numbers continue to increase strikingly. Omission of this essential fact - the catch-up campaign - requires explanation lest it be misconstrued."
Publication Types:- Comment
- Letter
PMID: 10489978 [PubMed - indexed for MEDLINE]
| Lancet 1999 Sep 11;354(9182):949-50 | Related Articles, Links |
Asian ethnic origin and the risk of inflammatory bowel disease.
Montgomery SM, Morris DL, Pounder RE, Wakefield AJ.
Department of Medicine, Royal Free & University College Medical School, London, UK.
OBJECTIVE: To assess whether inflammatory bowel disease (IBD) is more prevalent in young Asians than Europeans living in Great Britain. DESIGN: Longitudinal birth cohort study of all those born 5-11 April 1970 in Great Britain--the 1970 British Cohort Study (BCS70). METHODS: The relationship of a diagnosis of ulcerative colitis or Crohn's disease by age 26 years with ethnic origin was investigated among 8,432 cohort members with complete data using multiple logistic regression. We adjusted for potential confounding factors, household crowding and sex, as well as for a family history of IBD. RESULTS: Young Asians born in Britain were significantly more likely than indigenous Europeans to have a diagnosis of IBD by age 26 years, with relative odds of 6.10 (95% CI 2.14-17.33). This group of cohort members had ethnic origins in India, Pakistan or Bangladesh (although none of those from Bangladesh had IBD). This relationship remained statistically significant after adjustment for the potential confounding factors and family history of IBD. CONCLUSION: Young Asians who were born in Britain are at a significantly higher risk of developing IBD than the indigenous European population. This may reflect a greater genetic predisposition to IBD that is uncovered by exposure to environmental factors.
PMID: 10755259 [PubMed - indexed for MEDLINE]
| Eur J Gastroenterol Hepatol 1999 May;11(5):543-6 | Related Articles, Links |
Crohn's disease: the case for measles virus.
Wakefield AJ, Montgomery SM, Pounder RE.
Department of Medicine, Royal Free Hospital, Hampstead, London, UK. Wakersa@aol.com
Crohn's disease has the epidemiological and pathological hallmarks of an infection with a long natural history. Its emergence in developed countries in the middle of the 20th Century represents an instant in the continuum of human evolution, indicating either a new infection or, as with poliomyelitis, a changing pattern of exposure to a common childhood pathogen. Both short- and long-term outcomes from viral infection are largely dependent upon age and dose of exposure. We and others have suggested that measles virus may be causally related to Crohn's disease, and that the associated risk is an atypical pattern of exposure. Early, intensive, and concurrent infections have been identified as risks for subacute sclerosing panencephalitis, a delayed sequelae to measles virus infection, possibly through a process of high zone immunological tolerance and persistent infection. The data for Crohn's disease suggest that persistent infection may follow early low dose exposure and low zone immunological tolerance. The changing pattern of measles virus exposure this century would be consistent with a shift towards lower dose of infection. Such an exposure would also be consistent with persistence of the virus at very low copy number within discrete foci of granulomatous inflammation. The ability of measles virus to profoundly disrupt mucosal immune responses may provide the human counterpart of the cytokine-gene knockout.
Publication Types:- Review
- Review, Tutorial
PMID: 10379489 [PubMed - indexed for MEDLINE]
| : Ital J Gastroenterol Hepatol 1999 Apr;31(3):247-54 | Related Articles, Links |
Comment in:- Gastroenterology. 1999 Apr;116(4):988-90
- Gastroenterology. 1999 Nov;117(5):1253-5.
Paramyxovirus infections in childhood and subsequent inflammatory bowel disease.
Montgomery SM, Morris DL, Pounder RE, Wakefield AJ.
Inflammatory Bowel Disease Study Group, Department of Medicine, Royal Free and University College Medical School, London, England. smm@rfhsm.ac.uk
BACKGROUND & AIMS: Measles virus has been implicated in the etiology of both inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. Subacute sclerosing panencephalitis (SSPE) is caused by atypical measles infection. This study investigated the patterns of infection that are risks for SSPE, early infection and a close temporal relationship between measles and another infection, as potential risks for IBD. METHODS: The data are from 7019 members of a nationally representative 1970 British Cohort Study. The ages of five childhood infections were recorded before onset of IBD symptoms. Diagnoses of IBD and insulin-dependent diabetes mellitus (IDDM), as a control disease, were identified by age 26 years. RESULTS: Mumps infection before age 2 years was a risk for ulcerative colitis (odds ratio, 25.12; 95% confidence interval, 6. 35-99.36). Measles and mumps infections in the same year of life were significantly associated with ulcerative colitis and Crohn's disease, with odds ratios of 7.47 (2.42-23.06) and 4.27 (1.24-14.46), but not with IDDM. These relationships are independent of each other as well as sex, social class at birth, household crowding in childhood, and family history of IBD. CONCLUSIONS: Atypical paramyxovirus infections in childhood may be risk factors for later IBD.
PMID: 10092301 [PubMed - indexed for MEDLINE]
| Gastroenterology 1999 Apr;116(4):796-803 | Related Articles, Links |
|
J Pediatr 1999 Nov;135(5):559-63 |
Comment in:
·
J Pediatr. 1999 Nov;135(5):533-5.
Gastrointestinal abnormalities in children
with autistic disorder.
Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT.
Department of Pediatrics, University of Maryland School of Medicine,
Baltimore, USA.
OBJECTIVES: Our aim was to evaluate the structure and function of the upper
gastrointestinal tract in a group of patients with autism who had
gastrointestinal symptoms. STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2
years, mean +/- SD) with autistic disorder underwent upper gastrointestinal
endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and
bacterial and fungal cultures. The most frequent gastrointestinal complaints
were chronic diarrhea, gaseousness, and abdominal discomfort and distension.
RESULTS: Histologic examination in these 36 children revealed grade I or II
reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic
duodenitis in 24. The number of Paneth's cells in the duodenal crypts was
significantly elevated in autistic children compared with non-autistic control
subjects. Low intestinal carbohydrate digestive enzyme activity was reported
in 21 children (58.3%), although there was no abnormality found in pancreatic
function. Seventy-five percent of the autistic children (27/36) had an
increased pancreatico-biliary fluid output after intravenous secretin
administration. Nineteen of the 21 patients with diarrhea had significantly
higher fluid output than those without diarrhea. CONCLUSIONS:
Unrecognized gastrointestinal disorders,
especially reflux esophagitis and disaccharide malabsorption, may contribute
to the behavioral problems of the non-verbal autistic patients. The
observed increase in pancreatico-biliary secretion after secretin infusion
suggests an upregulation of secretin receptors in the pancreas and liver.
Further studies are required to determine the possible association between the
brain and gastrointestinal dysfunctions in children with autistic disorder.
PMID: 10547242 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9930068&dopt=Abstract
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9756729&dopt=Abstract
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Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism.
Singh VK, Lin SX, Yang VC.
College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065, USA.
Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism. Copyright 1998 Academic Press.
PMID: 9756729 [PubMed - indexed for MEDLINE]
| Clin Immunol Immunopathol 1998 Oct;89(1):105-8 | Related Articles, Links |
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Absence of Escherichia coli, Listeria monocytogenes, and Klebsiella pneumoniae antigens within inflammatory bowel disease tissues.
Walmsley RS, Anthony A, Sim R, Pounder RE, Wakefield AJ.
Department of Medicine, Royal Free Hospital School of Medicine, London, UK.
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, paraffin 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.
PMID: 9930068 [PubMed - indexed for MEDLINE]
| : J Clin Pathol 1998 Sep;51(9):657-61 | Related Articles, Links |
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9789132&dopt=Abstract
Comment in:- Ital J Gastroenterol Hepatol. 1998 Aug;30(4):383-4
Measles IgM immunoreactivity in patients with inflammatory bowel disease.
Balzola FA, Khan K, Pera A, Bonino F, Pounder RE, Wakefield AJ.
Inflammatory Bowel Disease Study Group, Royal Free Hospital School of Medicine, London, United Kingdom.
AIM: The purpose of our study was to examine measles IgM immunoreactivity in patients with inflammatory bowel disease. PATIENTS AND METHODS: In an International collaborative study, serum measles IgM immunoreactivity was assayed in consecutive outpatients with Crohn's disease (n = 95), ulcerative colitis (n = 79), viral hepatitis (n = 63) and blood donors (n = 30). Two commercial measles assays--enzyme linked immunosorbent assay and indirect fluorescence assay--and a Public Health Laboratory Service (PHLS) "in house" antibody capture radioimmunoassay were used. Results were compared with serum rubella and Epstein-Barr virus-specific IgM immunoreactivity, total serum IgM, and measles IgG immunoreactivity. Twenty patients with inflammatory bowel disease were studied serially over a 4-month period. RESULTS: By enzyme linked immunosorbent assay, the prevalence of raised serum measles IgM immunoreactivity was significantly greater in patients with Crohn's disease 23/95 (24%) and ulcerative colitis 20/79 (27%) compared with hepatitis patients 2/63 (3%) and normal controls 0/30 (0%) (p < 0.001). Indirect fluorescence assay produced significantly more positive results than enzyme linked immunosorbent assay in both Crohn's disease (50/87; 57%) and ulcerative colitis (35/68; 51%) but not in controls (0%) (p < 0.001). In contrast, no sera were positive using MCRIA. In the enzyme linked immunosorbent assay, measles IgM immunoreactivity did not correlate with either total IgM, rubella or Epstein-Barr virus IgM immunoreactivities-which were not raised-measles IgM immunoreactivity, or disease activity. Patients not receiving steroids were more likely to have raised measles IgM immunoreactivity (p < 0.5). All sera tested for Rheumatoid factor were negative. Of 20 patients with inflammatory bowel disease studied by ELISA over a 4-month period, 50% showed raised measles IgM immunoreactivity at some stage. CONCLUSION: The data suggest a specific and fluctuating immune response to measles virus in patients with Crohn's disease and ulcerative colitis, that may be modified by corticosteroid therapy.
PMID: 9789132 [PubMed - indexed for MEDLINE]
| Ital J Gastroenterol Hepatol 1998 Aug;30(4):378-82 | Related Articles, Links |
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9661840&dopt=Abstract
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Measles virus RNA is not detected in inflammatory bowel disease using hybrid capture and reverse transcription followed by the polymerase chain reaction.
Chadwick N, Bruce IJ, Schepelmann S, Pounder RE, Wakefield AJ.
Inflammatory Bowel Disease Study Group, Royal Free Hospital, London, England, United Kingdom.
Recent epidemiological and immunohistochemical studies have indicated a possible link between measles virus and inflammatory bowel disease (IBD). The aim of this study was to use a sensitive and robust method for the detection of measles virus RNA in IBD and control clinical samples. Peripheral blood mononuclear cells and intestinal resection tissue from IBD and control patients were studied. Two methods were used to determine the presence of measles virus RNA: hybrid capture, using measles virus-specific oligonucleotides linked to paramagnetic solid-phase supports, was carried out on total cellular RNA to enrich for measles virus RNA sequences. Reverse transcription followed by the polymerase chain reaction (RT-PCR) using rTth DNA polymerase was employed for amplification of measles virus N-gene sequences amongst the enriched species. Total RNA was also used for RT-PCR of a housekeeping mRNA species to assess RNA quality. RT-PCR for another region of the measles genome (the haemagglutinin (H) gene) was also undertaken in order to confirm the results obtained using N-gene primers for analysis of these samples. None of the samples were positive for measles N- or H-gene RNA using RT-PCR. Positive control samples confirmed the sensitivity of the methods employed. These results show that either measles virus RNA was not present in the samples, or was present below the sensitivity limits known to have been achieved.
PMID: 9661840 [PubMed - indexed for MEDLINE]
| J Med Virol 1998 Aug;55(4):305-11 | Related Articles, Links |
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9500320&dopt=Abstract
Comment in:- Lancet. 1998 Feb 28;351(9103):611-2.
- Lancet. 1998 Jul 18;352(9123):234-5.
- Lancet. 1998 Mar 21;351(9106):905-6; discussion 908-9.
- Lancet. 1998 Mar 21;351(9106):906-7; discussion 908-9.
- Lancet. 1998 Mar 21;351(9106):906; discussion 908-9.
- Lancet. 1998 Mar 21;351(9106):907-8; discussion 908-9.
- Lancet. 1998 Mar 21;351(9106):907; discussion 908-9.
- Lancet. 1998 Mar 21;351(9106):907; discussion 908-9.
- Lancet. 1998 Mar 21;351(9106);905; discussion 908-9
- Lancet. 1998 May 2;351(9112):1355-6; discussion 1356.
- Lancet. 1998 May 2;351(9112):1355; discussion 1356.
- Lancet. 1998 May 2;351(9112):1355; discussion 1356.
- Lancet. 1998 May 2;351(9112):1356.
| Lancet 1998 Feb 28;351(9103):637-41 | Related Articles, Links |