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November 9, 2001       News Morgue Search  www.feat.org/search/news.asp

4 - New Papers From The International Meeting for Autism Research

[Fourth positing in a series. For previous installments, go to FEAT Newsletter news morgues at above address.  This information is from the IMFAR website: http://www.imfar.org/index2.html  Abstract listing continues after following article.]

·        Also, Reader’s Posts

I Just Can’t Eat That Stuff

Many people are changing diets in a belief that they have a food intolerance. But, Roger Dobson asks, is the diagnosis the real problem?

http://news.independent.co.uk/uk/health/story.jsp?story=103493

When man first settled down and began to grow cereals 10,000 or so years ago, it was a key moment in the beginnings of civilisation. It heralded the arrival of settlements, long-term planning, teamwork, domesticity, and an all-year supply of food. But it gave birth to something else too. The wheat that they grew for the first time sowed the seeds for what some would say is one of the biggest epidemics the world has seen, food intolerance.

According to some estimates, one in five people, perhaps even half the population, suffer with some kind of intolerance to foods as diverse as cheese, coffee, bread, milk, and yeast as well as wheat. Food intolerance is linked to conditions as varied as irritable bowel syndrome, asthma, autism, eczema, arthritis, hyperactivity and chronic fatigue syndrome, and it has also spawned a huge industry, turning out alternative diets, supplements, and self-help books and videos.

But there is now growing scepticism about the scale of the food intolerance epidemic, and an increasing concern that people may be eating an unbalanced diet as a result of omitting but not replacing what is perceived to be the trigger food. A new study by the British Nutrition Foundation suggests that only one to two per cent of adults are food intolerant, and that although around five to eight per cent of children are affected too, up to 90 per cent of them have outgrown the intolerance by the age of three.

But others disagree, and say that the problem is underestimated: “Many

people don’t know the symptoms they have are caused by food, so the

underestimate of food intolerance must be substantial,” says Professor

Jonathan Brostoff, professor of allergy and environmental health at King’s

College, London. “It is a very real problem. Patients come to the clinic who

are really ill, with headaches, a fuzzy brain, irritable bowel, aching

joints, and desperately tired. Put them on a diet and six to eight weeks

later, they walk in, upright, pink cheeks, no longer with bags under the

eyes, saying, ‘Gosh, where have the last 20 years gone?’ “

One of the problems with estimating the scale of the food intolerance problem is that it is often confused with food allergy. Allergies occur when the body’s immune system responds abnormally to a protein found in a particular food, resulting in antibodies going on the offensive and triggering reactions such as swelling, inflammation, and irritation.

Food intolerance does not usually involve the immune system and is caused by a physical reaction to a food. In some cases the reaction is a result of the body lacking a sufficient amount of an enzyme needed to digest that food. Lactose intolerance, for instance, is the inability to digest significant amounts of lactose, the predominant sugar in milk, and coelic disease is an inflammation of the gut caused by eating cereals such as wheat which contain gluten. Large intakes of caffeine and curry can also cause gut irritations, while amines in strong cheeses, Chianti, chocolate and tomatoes can result in flushing and headaches. Food additives have been linked to provoking urticaria, rhinitis and asthma.

Allergy and food intolerance have different symptoms too. In an allergic reaction, irritant chemicals are rapidly released into the tissues, resulting in difficulties in breathing, swelling of the lips or tongue, asthma, rashes, vomiting, and a drop in blood pressure. With food intolerance, reactions usually take several hours to develop, and the symptoms are mostly non-specific, like headaches, fatigue, and diarrhoea.

Although there is little doubt that some people are intolerant to some foods, especially lactose and gluten, it is the apparent scale of the problem and the effects of the resulting dietary changes on long-term health, that are causing concern. “It is estimated that true food intolerance affects no more than five to eight per cent of children and less than one to two per cent of adults. This is much lower than the 20 per cent of people who perceive themselves to have an intolerance,” says Claire MacEvilly, nutrition scientist with the British Nutrition Foundation, whose study reviewed what research there is. “It seems to have become the thing to do, to blame problems on food intolerance. Reactions to food are blamed for weight gain, headaches, spots, rashes and general aches and pains. Our concern is that people are excluding food from their diet and not replacing it, and their diet is becoming unbalanced.”

The foundation is dismissive of many of the diagnostic tests for food intolerance, some of which cost up to £250: “The vast majority of so-called methods of diagnosis advocated in magazines and via the internet are without scientific basis and have not been independently validated. Such tests include hair and nail assessment, electro-magnetic conductivity tests and kinesiology. At best the patient is likely just to have wasted money, at worst these tests can result in misdiagnosis and the unnecessary treatment of a disease that does not exist by the use of an inappropriate and potentially dangerous diet,” says its report.

But Professor Brostoff says that diet is a therapy that works. “I know that if I had multiple food intolerance, I’d go on a diet, clean myself out, and add one food back at a time. You are the only barometer of your own intolerance.”

* * *

Gastroenterology and Toxicology

Frequency Of Gastrointestinal Symptoms Among Children With Autism And ASD C. A. Molloy, P. Manning-Courtney. Cincinnati Center for Developmental Disorders, University of Cincinnati College of Medicine, Cincinnati, OH 45229.

The objective of this study was to describe the frequency distributions of gastrointestinal symptoms among a sample of children with autism or autism spectrum disorder (ASD). The sampling frame was a center for pervasive developmental disorders. Consecutive referrals for the Autism Diagnostic Observation Schedule-Generic (ADOS-G) between 12/ 1/ 99 and 5/ 8/ 01 were retrospectively reviewed. Children age 24 to 96 months with a classification of autism or ASD were included. 137 children met eligibility criteria. Mean age was 55.6 months. 84% were male.

A history of diarrhea was present in 12.4%; constipation in 8.8%. One child had intermittent diarrhea and constipation. Nine children (6.6%) had a history of reflux or recurrent vomiting. Referrals for GI evaluation were dependent on duration and severity of symptoms. 67% of children with reflux or vomiting were referred to a gastroenterologist; 31% of children with diarrhea or constipation were referred.

This study sample is more representative of the population of children with autism/ ASD than samples in published reports of children referred for GI evaluation. There was a history of night wakening in 35%. Of these, 85.4% had no known history of reflux or vomiting. There was a history of regression in 23.4%.

There was no association between regression and any GI symptom or wakening. Gastrointestinal symptoms occur with increased frequency among children with autism/ ASD. How these symptoms are related to etiology and outcome, and who needs referral for GI evaluations are areas that warrant further study.

Supported by Grant # 4 T73 MC 00032-10 awarded by the Maternal and

Child Health Bureau, Human Resources and Service Administration, DHHS

* * *

Characterization Of Gastrointestinal Dysfunction In Autistic Children.

J Perrault*, K. Horvath, W. Chey, R. Melmed, C. Schneider, R. Hansen, J.  Rusche, P. Rioux, W. Herlihy, and the Clinical Study Group. *Mayo Clinic, Rochester MN.

Children with autistic spectrum disorder (ASD) have varied gastrointestinal (GI) symptoms and inflammatory changes of the upper and lower GI tract (J Peds 1999; 135: 559; Am J Gastro 2000; 95: 2285). We report our findings of GI dysfunction in children enrolled in a clinical trial.

METHOD: 126 children were evaluated over twelve weeks. GI symptoms (stool frequency, consistency, abdominal pain, gaseousness, bloating) were each scored on a scale of 0 (none) to 2 (max) for each feature and scored weekly. Blood and stool samples were used to measure pancreatic function (Chymotrypsin; serum immunoreactive trypsinogen, SIRT) and GI inflammation (Calprotectin) at weeks 1 and 10. 29/ 126 patients underwent endoscopy and were assigned endoscopic and histologic scores.

RESULTS: The average GI symptom score at entry was 6.6. 21% of subjects had an extensive constellation of GI symptoms (GI score > 8). Three features occured at a frequency higher than expected. At baseline, diarrhea (watery stool) was present in 42% of the patients, 29% had abnormally low chymotrypsin in stool, and 26% had elevated calprotectin in stool.  Pancreatic dysfunction as indicated by low chymotrypsin was not matched by low SIRT. 20/ 22 fluid cultures from endoscopy were identified as abnormal in cultured organisms. 10/ 22 received an endoscopic score indicating abnormalities. 2/ 7 colonoscopies scored mild lymphoid nodular hyperplasia.

CONCLUSIONS: These studies confirm previously reported GI dysfunction in ASD and provide some suggestion of specific abnormalities, either in pancreatic secretion or mucosal inflammation.

Clinical Research supported by Repligen Corporation*.

* * *

Hyperplasia And Increased Lysozyme Content In The Paneth Cells Of Children With Autistic Spectrum Disorder (ASD).

A. Rabsztyn, P. Panigrahi, *C. Bevins, J. A. Perman, K. Horvath. University

of Maryland, Baltimore, MD 21201, * Cleveland Clinic Foundation, Cleveland,

OH 44195

A significant percentage of children with ASD have inflammation in the upper part of the gastrointestinal( GI) tract. Hyperplasia of the duodenal Paneth cells in ASD has earlier been reported by our group. Aims: To further examine the granule content of the Paneth cells in children with ASD And age-matched controls.

Patients: The histological slides of the duodenum of nine autistic children (mean age: 6.28 yrs) with GI symptoms were selected. The control group consisted of nine age-matched children.

Methods: The slides were stained with polyclonal anti-lysozyme and monoclonal anti-defensin antibody. Pictures were taken from the crypt layer with a digital camera and the intensity of the staining was evaluated using the Image J analysis program.

Results: Children with ASD had Paneth cell hyperplasia (3.09± 0.46/ crypt vs controls: 2.07± 0.32/ crypt). There was an increase in the intensity of the staining in the slides of the children with ASD. All nine children with ASD had a higher concentration of lysozyme in the granules compared to controls (mean 41.63 vs 72.87 U, p< 0.05). There was no significant difference in the staining intensity for defensin (mean 76.81 vs 90.15U p> 0.05)

Conclusion: Children with ASD have Paneth cell hyperplasia with an increase in the number of cells, granule size and lysozyme content.  Anti-microbial peptides, play an important role in mucosal immune defense.

However, only lysozyme has been shown elevated in autoimmune diseases.  Differential expression of these peptides in this study may play an important role in pathogenesis of ASD.

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* * *

Bacterial Overgrowth In Autism.

S. M. Finegold, D. Molitoris, Y. Song, C. Liu, M. McTeague, and A. Kaul.  Wadsworth Anaerobic Bacteriology Laboratory, VAGLAHS and UCLA School of Medicine, Los Angeles and Div. of Pediatric Gastroenterology & Nutrition, Childrens Hospital Medical Center, Cincinnati.

Objective: Children with late onset autism may improve on oral vancomycin therapy (J Child Neurol 15: 429-435,2000) suggesting an abnormal gastrointestinal (GI) flora. We studied the upper GI flora of autistic children.

Methods: Three children underwent upper GI endoscopy. Serial ten-fold dilutions of intestinal fluid were made in an anaerobic chamber, were plated on various selective and non-selective media, and then incubated in both aerobic and anaerobic atmospheres. Identification included the usual phenotypic tests plus analysis of metabolic end-products and cellular fatty acids, PCR of the 16S-23S spacer region and 16S rRNA sequencing.

Results: Anaerobic collection and transport procedures were not used for specimens from the first two children. Nevertheless, jejunal aspirate from the first child yielded 2.4 x 10/ 3 cols/ ml of Eubacterium sp., 3.4 x 10/ 3 cols/ ml of aerobic cocci, and 10 cols/ ml each of Clostridium perfringens and C. orbiscindens. Duodenal fluid from the second child grew 1.7 x 10/ 5 streptococci/ ml, 10/ 4 C. ramosum/ ml, and 10/ 3 each of Clostridium sp. and Actinomyces sp./ ml. The third child’s specimens were collected optimally; preliminary results are given here.

Gastric juice (pH 6.0) grew 10/ 4 C. subterminale, 2 x 10/ 2 C.  disporicum, 10 C. glycolicum, 2 x 10/ 6 tiny gram-negative anaerobic rods per ml + aerobic streptococci. Duodenal fluid (pH 6.8) showed 1.2 x 10/ 7 probable C. ghoni, 4.5 x 10/ 6 C. disporicum, 10/ 5 C. ramosum-like orgs, 2 x 10/ 3 Clostridium sp., 10/ 6 Bifidobacterium sp. per ml + other anaerobes and aerobic streptococci.

Conclusions: This small study showed significant abnormal colonization, particularly with clostridia, of the upper GI tract in 3 autistic children.

Funded by personal funds, S. Finegold.

* * *

Identification Of Clostridium Isolates From Stool Specimens By Spacer Region-PCR (SR-PCR) and 16S rRNA Sequencing.  1Y. Song, 1C. Liu, 1D. Molitoris, 1M. McTeague, 1,2S. M. Finegold.

1Wadsworth Anaerobic Bacteriology laboratory, VAGLAHS, Los Angeles, CA90073,

2UCLA School of Medicine, Los Angeles, CA90095

Objective: based on our hypothesis that clostridial organisms may contribute to the behavioral abnormalities associated with autism, we wished to determine which Clostridium species are present in the intestinal tract of children. Ultimately, we will compare clostridia from the intestinal tract of autistic children with those from control normal children.

Methods: a primer pair, 16S and 23-10, was designed and used to amplify the 16S-23S rRNA SR of the presumptive clostridium isolates. PCR was performed in standard fashion. Amplicons were analyzed by electrophoresis on a 5% polyacrylamide gel. PCR products of the16S rRNA gene were gel purified and sequenced directly with ABI Prim 377 DNA sequencer (Applied Biosystems, Perkin-Elmer Corporation).

Results: by using this method, 238 presumptive clostridia isolates were found to fall into 19 groups and were then further identified to the likely species level. C. perfringens, C. orbiscindens, C. paraputrificum, C.  disporicum and C. glycolicum( the latter two were 98% related to their respective species and therefore cannot be definitely identified as yet) were the most commonly isolated species.

Conclusions: we successfully established a rapid and reliable system for identifying clostridia isolates by a two-step scheme; first, SR-PCR for grouping of clostridia, followed by 16S rRNA sequencing of representative strains selected from each SR-PCR group to identify to the likely species level. Some phenotypic tests may be required in addition for definitive identification.

Source of Funding-IntraBiotics, VA Merit Review Fund

* * *

Antimicrobial Susceptibility Of Intestinal Anaerobes.

1S. St. John, 1A. Vu, 1D. Molitoris, 1,2H. M. Wexler, and 1,2S. M. Finegold.  1Wadsworth Anaerobic Bacteriology Laboratory, VAGLAHS, and 2UCLA School of Medicine, Los Angeles, CA 90073.

A recent study (Journal of Child Neurology, 15: 429-435) indicated that children with late onset autism may improve on oral vancomycin therapy suggesting a role of bowel flora in autism.

We tested the susceptibility of a wide range of intestinal bacteria to vancomycin and included four comparator drugs. Clostridia were tested primarily because there is evidence to suggest that this genus may be an important contributor to autism. Susceptibility testing was done using the NCCLS-approved Agar Dilution Method.

The drugs tested were ampicillin (A), bacitracin (B), metronidazole (M), trimethoprim-sulfamethoxazole (1: 5) (T), and vancomycin (V). Thus far, 226 strains of bacteria isolated from stool specimens have been tested. The overall geometric mean MICs were: A, 0.5; B, 1.9; M, 0.7; T (sulfamethoxazole concentration), 38.9; and V, 2.4. Genera tested included Bacteroides, Catenabacterium, Clostridium, Coprobacillus, Coriobacterium, Eggerthella, Ruminococcus, and Sarcina. Some organisms (85 strains) are not yet identified. For the clostridia (95 strains), geometric mean MICs were:

A, 0.4; B, 2.6; M, 0.6; T-S, 36.5; and V, 2.6.

T shows poor activity against clostridia, consistent with stool overgrowth of these organisms reported with T therapy in patients. The potential utility of various drugs for use in autistic patients will depend on levels achieved in the bowel, susceptibility to inactivation by beta-lactamases produced by intestinal bacteria, toxicity, and other factors.

Funding: Pharmaceutical companies.

* * *

Environmental Risk Factors In The Etiology Of Autism: Mechanisms Altering Cellular Ca2+ Signaling.

I. N. Pessah, P. W. Wong. Dept. Molecular Biosciences, Univ. California, Davis, CA 95616.

There is growing concern from both parents and health professionals that prenatal and postnatal exposure to xenobiotic mixtures (e. g.  mercurials, halogenated aromatics, and pesticides) and biotic (e. g. vaccine antigens) factors may act synergistically to alter the penetrance of as yet unidentified genetic factors conferring susceptibility to autism.

Non-coplanar polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) are major co-contaminants of human food, and ehtyl mercury has been used in high levels as vaccine preservatives.

Both contaminants have been causally linked to behavioral and developmental deficits in infants, though virtually nothing is known about their influence on regions of the brain important to development of social behavior. We have investigated the molecular mechanisms by which non-coplanar PCBs and thimerosal alter temporal and spatial aspects of Ca2+ signaling in primary neurons and neurogenic cell lines.

Non-coplanar PCBs (100 nM-10 mM) alter Ca2+ signaling by selective modulation of the immunophilin FKBP12/ ryanodine receptor (RyR) complex whereas thimerosal alters the redox-sensing properties of Ca2+-release units. These contaminants, in combination, act synergistically to alter the fidelity of Ca2+ signals important for growth and development of dendritic processes. The implications of these finding as possible risk factors in autism will be discussed.

* * *

Investigation Of Heavy Metal Toxicity In People With Autism.  C. Holloway, J. B. Adams, F. Castro, M. Kerr, and M. Margolis. Arizona State University, Tempe, AZ 85287, F. George, Arizona Biological Research Foundation, Scottsdale, AZ, and MyDentist, Mesa, AZ.

We have conducted a comparison of heavy metal toxicity between 50 people with autism and 50 age-and gender-matched controls, and their mothers. The study has included hair testing of essential and toxic metals, a dental evaluation of mercury amalgam status, urine tests (pH, sulphation, and mercury content), GARS test of the severity of autism, and a questionnaire on exposure to heavy metals including a full vaccination history.

The results of this study will be reported at the meeting. It is hypothesized that there may be a statistically significant association between levels of heavy metal toxicity and the severity of autism (as measured by the GARS). Should a positive association be observed, it would provide preliminary evidence for conducting further research into the mechanism of effect that involves exposure to one or more heavy metals and the development of autism.

Funded by Arizona State Univerity, the Greater Phoenix Chapter of the ASA, and the Pima County Chapter of the ASA.

* * *

Reader’s Posts

Due to a Naval Reserve call-up, we will be relocating to North San Diego, CA

for 1 yr next month.  Looking for experienced tutor (4 hours/wk) to work

with PDD-nos/Hyperlexic 8 yr old son.  Emphasis on

language/communication/social skills.  Home program in place.  All days and

Having a tough time finding good reinforcers for my ASD 5-year-old son

undergoing ABA treatment. He does work for food and electronic toys but

loses interest pretty soon. It’s very hard to keep him focused if he doesn’t

care for the reinforcer.  Any suggestions? Please contact

San Diego, CA parents of a six yr old autistic boy are looking for a local

Contemplating relocation to Los Angeles from Chicago in 3-6 months.  Please

advise as to the most cooperative schools/programs and neurologist for 5 yr

Looking for a good Speech Therapist with experience working with high functioning autistic children in the North County Area of San Diego.

(Oceanside, Vista, San Marcos, Escondido, Carlsbad, Encinitas) My son is 12

NAAR on TV, on AM Buffalo, Wednesday, November 14, 2001 at 10:00 AM. Dr.

Susan Hyman, developmental pediatrician specializing in autism spectrum

disorders, from Strong Center for Developmental Disabilities, University of

Rochester will be featured on the program along with my eight yr old son

Alexander. You will also hear about the plans for the first Autism Walk in

Buffalo (to be held on September 29, 2002) http://www.naar.org For more info

on AM Buffalo (WKBW-TV, Ch. 7 - ABC)

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