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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]
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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]
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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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J Pediatr 2001 Mar;138(3):366-72 |
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]
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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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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]
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Am
J Gastroenterol 2000 Sep;95(9):2285-95 |
Comment in:
· Am
J Gastroenterol. 2000 Sep;95(9):2154-6.
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]
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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]
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Lancet
1998 Feb 28;351(9103):637-41 |
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 May 2;351(9112):1357.
· Lancet.
1998 May 2;351(9112):1357.
· Lancet.
1998 May 2;351(9112):1357-8.
· Lancet.
1998 May 2;351(9112);1358
· Lancet.
2000 Jul 8;356(9224):160-1.
· Lancet.
2000 Jul 8;356(9224):161.
· Lancet.
2000 Jul 8;356(9224):161-2.
Ileal-lymphoid-nodular hyperplasia,
non-specific colitis, and pervasive developmental disorder in children.
Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz
M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA.
Inflammatory Bowel Disease Study Group, University Department of Medicine,
Royal Free Hospital and School of Medicine, London, UK.
BACKGROUND: We investigated a consecutive series of children with chronic
enterocolitis and regressive developmental disorder. METHODS: 12 children (mean
age 6 years [range 3-10], 11 boys) were referred to a paediatric gastroenterology
unit with a history of normal development followed by loss of acquired skills,
including language, together with diarrhoea and abdominal pain. Children
underwent gastroenterological, neurological, and developmental assessment and
review of developmental records. Ileocolonoscopy and biopsy sampling,
magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar
puncture were done under sedation. Barium follow-through radiography was done
where possible. Biochemical, haematological, and immunological profiles were
examined. FINDINGS: Onset of behavioural symptoms was associated, by the
parents, with measles, mumps, and rubella vaccination in eight of the 12
children, with measles infection in one child, and otitis media in another. All
12 children had intestinal abnormalities, ranging from lymphoid nodular
hyperplasia to aphthoid ulceration. Histology showed patchy chronic
inflammation in the colon in 11 children and reactive ileal lymphoid
hyperplasia in seven, but no granulomas. Behavioural disorders included autism
(nine), disintegrative psychosis (one), and possible postviral or vaccinal
encephalitis (two). There were no focal neurological abnormalities and MRI and
EEG tests were normal. Abnormal laboratory results were significantly raised
urinary methylmalonic acid compared with age-matched controls (p=0.003), low
haemoglobin in four children, and a low serum IgA in four children.
INTERPRETATION: We identified associated
gastrointestinal disease and developmental regression in a group of previously
normal children, which was generally associated in time with possible
environmental triggers.
PMID: 9500320 [PubMed - indexed for MEDLINE]
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J
Assoc Acad Minor Phys 1998;9(1):9-15 |
Improved social and language skills after secretin
administration in patients with autistic spectrum disorders.
Horvath K, Stefanatos G, Sokolski KN, Wachtel R, Nabors L, Tildon JT.
Department of Pediatrics, University of Maryland School of Medicine, Maryland,
USA.
We report three children
with autistic spectrum disorders who underwent upper gastrointestinal
endoscopy and intravenous administration of secretin to stimulate
pancreaticobiliary secretion. All three had an increased pancreaticobiliary
secretory response when compared with nonautistic patients (7.5 to 10 mL/min
versus 1 to 2 mL/min). Within
5 weeks of the secretin infusion, a significant amelioration of the children's
gastrointestinal symptoms was observed, as was a dramatic improvement in
their behavior, manifested by improved eye contact, alertness, and expansion of
expressive language. These
clinical observations suggest an association between gastrointestinal and brain
function in patients with autistic behavior.
PMID: 9585670 [PubMed - indexed for MEDLINE]
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Acta
Paediatr 1996 Sep;85(9):1076-9 |
Abnormal intestinal permeability in children
with autism.
D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M,
Cardi E, Giardini O.
Institute of Pediatrics, La Sapienza University of Rome, Italy.
We determined the occurrence of gut mucosal damage using the intestinal
permeability test in 21 autistic children who had no clinical and laboratory
findings consistent with known intestinal disorders. An altered intestinal
permeability was found in 9 of the 21 (43%) autistic patients, but in none of
the 40 controls. Compared to the controls, these nine patients showed a similar
mean mannitol recovery, but a significantly higher mean lactulose recovery
(1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We
speculate that an altered intestinal permeability could represent a possible
mechanism for the increased passage through the gut mucosa of peptides derived
from foods with subsequent behavioural abnormalities.
PMID: 8888921 [PubMed - indexed for MEDLINE]