4 - New Papers From The International Meeting for Autism Research * I Just Can't Eat That Stuff

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4 - New Papers From The International Meeting for Autism Research

[Fourth positing in a series. For previous instalments, go to FEAT

Newsletter news morgus at above address. This information is from the IMFAR

website: http://www.imfar.org/index2.html Abstract listing continues after

following article.]

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I Just Can't Eat That Stuff

Many people are changing diets in a belief that they have a food

intolerance. But, 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

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

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-. 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 land, 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. , 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 (, 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,

, 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. , F. Castro, M. Kerr, and M. Margolis. Arizona State

University, Tempe, AZ 85287, F. , Arizona Biological Research

Foundation, sdale, 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

times open. Please reply to: rubino7@...

******

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

pchojar@...

******

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

doctor who is willing to try amantadine therapy. stevendri@...

******

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

old daughter (PDD). cjbovard@...

******

If anyone had the opportunity to attend the 7th Annual Trends in Autism

Conference in Boston over November 2-4, and is willing to share information,

could you contact me at maryschmitt@...? I am interested in

treatment options in the Boston area.

******

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

years old, dealing with middle school social issues. OlyT@...

******

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

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

. 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)

http://www.wkbw.com/ambuff/default.shtml

******

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