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What is autism?

Autism is a developmental delay that includes symptoms such as speech difficulties, lack of eye contact, isolation and no fear of danger.

Autistic children act and sound like much younger children. What causes autism specifically is not known. Some experts believe there are bio-chemical reasons for autism; others suspect that it is a psychiatric disorder. Some believe that a combination of the wrong foods and too many antibiotics and environmental toxins can damage the colon and lead to physical and behavioral problems, including autism.

The behavioral syndrome of autism includes abnormalities of language and thinking skills; repetitive behavior such as rocking; abnormal responses to sensations, people, events and objects; and self-injurious behavior.

New Note: Before going on to explore this in-depth section concerning the theories of autism, you may want to read a summary overview article by Dr. Lewis Mehl-Madrona, "Effective Therapies for Autism and Other Developmental Disorders", recently published in Autism/Asperger's Digest Magazine. books on autism and autistic children

Theories of Autism

Quick Index to the Theories of Autism

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Information for Non-Professionals to Better Understand Theories

The following websites may help you better understand the physiological functions discussed in the theories section:

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Opioid Excess Theories

The opioid excess theory of autism says that autistic children are symptomatic due to excess opioid-like substances, whose effects on the brain produce the symptoms of autism.

Opioids and opioid-like substances, especially when in excess, have many effects upon hormones and hormonal regulation.

Among humans, opioids stimulate diminish both ACTH and corticosterone 1. Naloxone, an opiate antagonist, stimulates the release of ACTH. Both types of action are probably mediated within the hypothalamus. Lutenizing Hormone (LH), important in reproduction, is decreased by opioids, while opiate antagonists stimulate LH, both apparently by modulating LHRH release. Opioids affect the regulation of other gonadotropins (sex hormones). Exogenous opiates potently stimulate prolactin and gonadotropin hormone secretion. Opiate antagonists do not affect these hormones.

In rats, opiate antagonists decrease basal and stress-induced secretion of prolactin. Data regarding Thyroid Stimulating Hormone (TSH) are quite contradictory. Both inhibitory and stimulatory effects have been described.

Oxytocin and vasopressin release are inhibited by opioids at the posterior pituitary level. There is good evidence for an opioid inhibition of suckling-induced oxytocin release. Opioids also seem to play a role in the regulation of vasopressin under some conditions of water balance. The pancreatic hormones, insulin and glucagon, are elevated by opioids apparently by an action at the islet cells. Somatostatin, on the contrary, is inhibited. An effect of naloxone on pancreatic hormone release has been observed after meals which contain opiate active substances.

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Opioid-like substances:

Dr. Alan Friedman, a physical chemist at Johnson and Johnson, has isolated and identified peptides in urine or serum using a single and triple electrospray quadropole mass spectrometer. The "MassSpec" sprays the material into a chamber, where it is spun by electromagnetic forces, and followed sequentially into two more chambers. The materials can then be charted by atomic weight.

Dr. Friedman contrasted the samples of normal children with autistic children. The amount and volume of particles in the autistic children was an order of magnitude more in volume and in number of them. Some of these particles include Casomorphine, A-Glaidin, Desmorphin, Deltophin II, Morphine modulating peptide, Novel Autism Peptide I, and Novel Autism Peptide III. These peptides have interaction with other neuro-peptides. Desmorphin is only found in Autistic Children and on the backs of non-captive poison dart frogs. These opioid-like molecules are thought to cause the symptoms of autism.

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Dipeptydal peptidase deficiency:

Alan Friedman and colleagues have pioneered the potential role of DPP IV deficiency in autism. Some have gone so far as to suggest that DPP-IV deficiency may explain all of the abnormalities seen in autism. Dipeptidyl peptidase IV (DPP-IV) is a serine peptidase that removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided the penultimate residue is proline.

The only known enzyme to break down casomorphine, dipeptidyl peptidase IV or DDP-IV, appears to be absent or reduced in autistic children. The gene for this enzyme is distal to other suspected autism genes on 2 and Q of 7 and is expressed in the kidney, the small intestine, the liver, the blood-brain barrier, and has involvement in T-Cell activation. Also found in the urine were undigested food particles, suggesting a leaky gut syndrome.

Mice with the a defective casomorphine enzyme gene will die if not on a gluten free diet. Later we will discuss the possible role of glutein and cassein in autism, and the elimination of these substances from the diet as a treatment. The toxicity of gluten and cassein may result from the lack of DPP IV. Thus, DPP deficiency may be important in explaining opioid excess.

DPP IV has a number of different names. When it is present on the surface of a T-cell it is called CD26.

Dr. Friedman postulates that DPP-IV is either absent via a genetic mechanism (probably through two recessive genes) or that the enzyme has been inactivated, possibly through autoimmune mechanisms (a theory of autism which we will cover later). It has been postulated that people, autistic from birth, produce no DPP-IV, and those who developed normally and then regressed, had their DPP-IV inactivated through an acquired mechanism (such as auto-immunity).

One such compound is dermorphin, a mu-opioid agonist that acts as an hallucinogen. Another is deltorphin II. Some researchers theorize that these compounds appear because the enzyme which cleaves certain peptide bonds (DPP IV) is either missing or inactivated. Gluten and casein are two of the proteins from which these opioids can be produced. There may be additional proteins for which this is true as well.

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Theories of Potential Therapies for DPP IV Deficiency [Unevaluated]:

If DPP IV deficiency results in autism, what can be done? If the enzyme is missing, replacing it should solve the deficiency. DPP IV is found on intestinal mucosal cells, epithelial cells in the GU tract, and on the surface of T-cells. It might be possible to hook the DNA sequence coding for DPP IV onto some type of delivery mechanism (such as a plasmid) and infuse the plasmids into the patient so that the desired sequence would be incorporated into the patient's DNA. Another alternative is stem cell therapy or live cell therapy. Injected cells might produce DPP IV which would migrate to areas in which it is needed.

If the enzyme is inactivated by an autoimmune mechanism, replaced enzyme would probably be inactivated as well.

Here is a the skeleton for a future treatment: Drucker, et al. 2 studied DPP-IV deficicient rats. Administration of GLP-2 to these rats was associated with a markedly increased bioactivity of rat GLP-2 resulting in a significant increase in small bowel weight. A synthetic GLP-2 analog, r[Gly2]GLP-2, with an alanine to glycine substitution at position 2, was resistant to cleavage by both DPP-IV and rat serum in vitro. Treatment of wild-type rats with r[Gly2]GLP-2 produced a statistically significant increase in small bowel mass. DPP-IV-mediated inactivation of GLP-2 is a critical determinant of the growth factor-like properties of GLP-2. The possibility exists that treatment of autistic people with sufficient quantities of GLP-2 or with synthetic r[Gly2]GLP-2 which cannot be cleaved by DPP-IV would alleviate symptoms associated with autism.

Drucker DJ, DeForest L, and Brubaker PL have shown that GLP-2-like compounds have potential use for enhancement of mucosal regeneration in patients with intestinal disease 3. This may relate to autistic children who have gastrointestinal symptoms. Findings such as these may explain the usefulness of hormonal therapies for autistic children's gut problems.

GLP-2 is part of proglucagon, which also contains GLP-1. Proglucagon is secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 is accounted for in part by dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage are more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease.

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Dermorphin and Sauvagine:

The abnormal opioid peptides found in the urine of autistic children are known to have a number of important effects, many of which may relate to the symptoms of autism. Some of these effects may relate to other gut disorders, especially the so-called hollow organ dysmotility syndromes, in which pain arises from uncoordinated electrical activity and peristalsis in the gut, including the production of spasm and chronically elevated gut wall muscle tension. Some of the gastrointestinal disorders of autistic children (especially their abdominal pain) may be explainable on this basis.

Dermorphin consists of the amino acid sequence Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 30. It is a mu-opioid agonist and is displaced by naloxone or morphine; hence, the justification for using naloxone with autistic children to block the effects of dermorphin and its relatives. The D-configuration of the amino acid residue in position 2 is of crucial importance for its binding ability. Replacing the D-Ala2 with L-Ala makes a compound that is only 1/5000th as potent in binding to the receptor.

Shorter dermorphin homologs, dermorphin-(1-4)-NH2 and dermorphin-(1-3)-NH2, are 20 and 40-fold less potent, respectively, than dermorphin. The C-terminal carboxamide function is of significant importance for manifestation of the full intrinsic binding potency of dermorphin. Deamidated dermorphin has 1/5th the potency of the parent peptide. While the whole dermorphin sequence is required for expression of its full binding activity, the N-terminal tripeptide contains the features which allow receptor recognition.

30.   Amiche M, Delfour A, Nicolas P. Structural Requirements for Dermorphin Opioid Receptor Binding. Int J Pept Protein Res 1988 Jul 32:1 28-34

Dermorphin and other opioid-like peptides can affect stomach acid output, and therefore, digestion 31. Intracerebroventricularly (i.c.v.) injected dermorphin suppresses the stimulation of gastric acid output by water distension of the stomach in a dose-dependent manner. Insulin stimulated gastric secretion is also partially blocked. Subcutaneous injections of dermorphin inhibite basal and water distension-induced gastric secretion and are antagonized by subcutaneous naloxone (at a dose of 1 mg/kg).

Injections (i.c.v.) of dermorphin have no effect on histamine-induced gastric secretion, but a close relative, Dermorphin N-terminal-tetrapeptide-amide (NTT), does [3]. NTT also increases pentagastrin-induced gastic acid secretion. The opioid antagonist, N-methyl-levallorphan-methanesulphonate also blocks this effect. Thus, the brain plays a role in regulating gastric secretion.

Can these abnormal peptides explain many of the increased gastrointestinal problems of autistic children, or even of other patients with intestinal motility and spastic disorders? Time will tell, but the presence of increased intestinal permeability may explain how these molecules pass into the bloodstream from the gut to affect adults with gastrointestinal disorders.

In support of these ideas is the finding that a premature phase III of the migrating myoelectric complex (MMC) in the duodeno-jejunum is triggered by NTT 32. The activity of the gastic antrum is not significantly modified. NTT also increased the contractile activity of both proximal and distal portions of the colon, including a long-lasting period of increased muscle tone in the distal colon. Either naloxone or N-methyl-levallorphan-methanesulphonate completely prevented these motor effects of NTT on gastrointestinal tract. This opiate-like activity on gastric acid secretion and intestinal motility of the dog is thought to occur through the activation of peripheral mu opioid receptors.

Certainly justification exists for treatment of autistic children with gastrointestinal disturbances with naloxone.

31.   Improta G, Broccardo M, Lisi A, Melchiorri P Neural Regulation of Gastric Acid Secretion in Rats: Influence of Dermorphin. Regul Pept 1982 Mar 3:3-4 251-6

32.   Soldani G, Del Tacca M, Bernardini MC, Bardon T, Ruckebusch Y Peripheral Opioid Receptors Mediate Gastrointestinal Secretory and Motor Effects of Dermorphin N-terminal tetrapeptide (NTT) in the Dog. Neuropeptides 1987 Jul 10:1 67-76

Intravenous infusion of dermorphin significantly increases plasma levels of prolactin, human growth hormone, thyrotropin stimulating hormone (TSH) and plasma renin activity, but decreased plasma levels of cortisol. Dermorphin produced a small decrease in adrenocorticotropic hormone (ACTH), and a small increase in plasma aldosterone. Pretreatment with the opioid receptor antagonist naloxone suppressed the prolactin and TSH response, blunted the human growth hormone and plasma renin activity increase, completely prevented the plasma cortisol decrease, and enhanced plasma cortisol and ACTH levels.

These actions are thought to be mediated through opioid receptors. Dermorphin is thought to increase plasma renin levels through stimulation of the sympathetic nervous system. Dermorphin does suppress plasma cortisol levels by affecting ACTH secretion, potentially explaining altered pituitary-adrenocortical axis function found among developmental delayed children.

Reference:  Degli Uberti EC, Trasforini G, Salvadori S, Margutti A, Tomatis R, Pansini R The Effects of Dermorphin on the Endocrine System in Man. Peptides 1985 6 Suppl 3 171-5


Sauvagine is another opioid-like peptide found in higher concentrations among autistic children. It and dermorphin affect both ACTH and beta-endorphin release from pituitary cells, inhibit prolactin and human growth hormone release. When dermorphin is administered by intracerebroventricular injection, it induces analgesia and catalepsy, along with conspicuous EEG and behavioral changes and a sharp reduction in gastric emptying time and gastric acid output. Prolactin release is stimulated.

Reference:  Erspamer V, Melchiorri P, Broccardo M, Erspamer GF, Falaschi P, Improota G, Negri L, Renda T The brain-gut-skin triangle: new peptides. Peptides 1981 2 Suppl 2 7-16

Dermorphin and deltorphin are opioid-like substances which elicit acute and chronic activation of of mu- and delta-opioid receptors, thereby affecting the functional activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, both in basal conditions and in response to acute stress.

Acute administration of dermorphin (a mu-receptor agonist) increases basal and stress induced plasma levels of corticosterone and beta-endorphin. These effects are antagonized by pretreatment with naloxone, a specific mu-opioid receptor antagonist, but not by naltrindole, a delta-opioid receptor antagonist. Long-term administration of dermorphin does not alter resting plasma levels of corticosterone and beta-endorphan, but does reduce stress-induced increases of these hormones.

Both the acute and chronic administration of the delta-opioid receptors agonist, failed to modify resting and stress induced hormone levels. Thus, mu-opioid receptors, but not delta-opioid receptors modulate the response of the hypothalamic-pituitary-adrenal axis to acute stress.

Reference:  Degli Uberti EC, Petraglia F, Bondanelli M, Guo AL, Valentini A, Salvadori S, Criscuolo M, Nappi RE, Genazzani AR Involvement of Mu-Opioid Receptors in the Modulation of Pituitary-Adrenal Axis in Normal and Stressed rats. J Endocrinol Invest 1995 Jan 18:1 1-7

Intravenous dermorphin injection decreases the levels of thryotropin releasing hormone in the hypothalamus. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min after the injection. The plasma thyroid hormone levels were not changed significantly. The plasma TRH and TSH responses to cold were inhibited by dermorphin, but the plasma TSH response to TRH was not.

Naloxone partially blocked the inhibitory effect of dermorphin on TSH levels. In the para-chlorophenylalanine or pimozide pretreated groups the inhibitory effect of dermorphin on TSH levels was prevented, but not in the groups pretreated with 5-hydroxytryptophan or L-DOPA. These drugs alone did not affect plasma TSH levels in the dose used. Dermorphin is thought to act on the hypothalamus to inhibit TRH release, its effects being mediated through mu-opioid receptors and modified by central nervous system amines.

Reference:  Mitsuma T, Nogimori T, Chaya M Dermorphin Inhibits Basal and Cold Induced Thyrotropin Ssecretion in Rats. Endocrinol Exp 1985 Jun 19:2 83-90

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Opioids and Secretin:

Opioids decrease gastric acid secretion. One theory as to the apparent "secretin deficiency" seen in many autistic patients is that the pH of the contents in the upper duodenum never gets low enough to cause the mucosal cells to release secretin.

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Opioids have been shown to decrease hepatic glutathione. Low levels of glutathione have been demonstrated in autism.

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Opioids and immunosuppression:

Many autistic people demonstrate a mild immunosuppression which could be accounted for by the actions of opioids on T-cells. Opioids decrease T-cell proliferation via the mu-receptors.

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Gluten/Casein Theories and Relation to Celiac Disease

Dr. Paul Shattock, of Sunderland,England is doing work on the casein free/gluten free diet connections to autism and is studying the development of caso-morphine and gluteo-morphine in autistic children. In some individuals who cannot metabolize gluten, a-gliadin is produced. The body cannot metabolize A-gliadin, which binds to opiod receptors C & D. These receptors are associated with mood and behavior disturbances. A strict gluten and casein-free diet does appear to reduce the level of opioid peptides and improve autism for some people. The earlier the implementation of the diet, the better the chance of recovery.

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Opioid receptors:

There are at least 3 different opioid receptors - mu, delta, and kappa. When an opioid molecule attaches to a receptor in which it"fits", adenylate cyclase is inactivated, leading to a decrease in intracellular cAMP. Cyclic AMP (cAMP) is an important messenger system in the brain and body. Opioid theory. In keeping with the opioid theory of autism, some children are given naltrexone (an opioid antagonist) with reported benefit. An example would be a small dose of 10 mg every 2-3 days

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Urinary IAG:

The increase in urinary IAG levels among autistic people observed by Paul Shattock may be explained in this manner. Tryptophan hydroxylase (the rate-limiting step in the conversion of tryptophan to serotonin) must be phosphorylated in order to be active. Cyclic AMP is required for phosphorylation. If intracellular cAMP levels have been lowered because of constant (inappropriate) stimulation of opioid receptors on the cell surface, less tryptophan hydroxylase is phosphorylated, and therefore more of the enzyme is inactive. When this happens, tryptophan is not converted into serotonin, but is shunted down alternate pathways, eventually leading to urinary IAG and 3-indoleacetate.

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Fatty Acids:

Another abnormality observed in autism is the accumulation of long-chainand very-long-chain fatty acids in cell membranes. Carnitine palmitolytransferase is essential in the steps responsible for the transport of Long Chain Fatty Acids (LCFA) and Very Long Chain Fatty Acids (VLCFA) across the mitochondrial membrane so these fatty acids can be broken down and metabolized. Carnitine palmitoyltransferase synthesis and half-life are dependent on the presence of cAMP.

There is evidence that cAMP levels may be reduced in autism (see other sections). One theory for the action of secretin is that it raises cAMP levels. Carnitine has also helped some autistic children,and, in fact, there is a glycogen storage disease that is a carnitine deficiency syndrome which presents like autism.

There are 12 types of glycogen storage disease, including carnitine deficiency syndrome, and defects of Acyl-CoA dehydrogenase.

The Cincinnati Children's Hospital Medical Center’s Department of Enzymology has identified two patients with the"carbohydrate deficient glycoprotein syndrome" through alpha-1-antitrypsin phenotyping. The carbohydrate deficient glycoprotein in the serum of these patients produces a band on polyacrylamide gel isoelectric focusing that moves cathodally of the Z-band. In the area of carnitine deficiency, there is, for example, less than 5% of normal muscle carnitine concentration. After carnitine supplementation, patients unable to talk or walk, with hypotonic musculature and symptoms of autism, can became able to walk with the help of a walker, can stand alone for short periods, and can acquired an interest in their surroundings. The common findings of carnitine deficiency were an impaired ability to walk, muscular hypotonia, reduced muscle carnitine concentration and an improvement in locomotion while on carnitine.

Among a family with recessive X-linked cardiomyopathy, affected patients used to die before age 2 yrs. Early carnitine supplementation has greater improved survival. The clinical picture of this disease resembles Barth Syndrome, the gene for which has a location near the marker DXS52 on the X chromosome (Bolhuis et al., 1991). This carnitine deficiency syndrome is also related to the DXS52 marker (Bione, et al., 1996). The banding pattern of cDNA from a patient's liver differs from that of normal liver and that sequencing of cDNA from a patient's heart shows that exon 7 has been eliminated.

Vitamin B12 therapy is based in part upon the role of vitamin B12 in synthesizing essential fatty acids.

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Gamma Interferon Theory

Dr. Vijendra Singh has found elevated levels of interleukin-12 and gamma interferon in autistic patients. Opioids can increase levels of gamma interferon.

[More information on this topic coming soon!]

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Free Sulphate Theory

Dr. Rosemary Waring has demonstrated low levels of free sulfate in the plasma of autistic people. Free sulfate homeostasis is regulated by reabsorption in renal tubules primarily. Opioids change sodium, bicarbonate, and chloride reabsorption in the kidney, but no work has been done on sulfate reabsorption.

Waring (1993) has demonstrated deficiencies in the sulphur-transferase capabilities of people with autism. This inadequacy is not the consequence of a missing enzyme (sulphur transferase) but of insufficient sulphate ions for the sulphation to be accomplished.

Sulphur transferase activity is important for many biological reactions in the body, some of which may be relevant to autism. These reactions include the breakdown of bilirubin and biliverdin, which are the breakdown products of haemoglobin; as well as the breakdown and removal of phenolic compounds. The tests used to estimate sulphur-transferase activity rely upon the conversion of paracetamol to its sulphate.

An inadequately functioning sulphur-transferase system will also affect the metabolism of some neurotransmitters. Serotonin (5-HT) metabolism will be affected, and the appearance of unusual metabolites (such as the hallucinogen bufotenin) could be predicted. Himwich (1972) has reported this, but the significance is uncertain.

Foods with high phenolic content should exacerbate symptoms since the overtax the available sulphur resources of the body. Anecdotal reports abound about the adverse effects of apples, oranges and other citrus fruits, chocolate (possibly on account of the phenol flavoring vanillin) and other phenolic foods on behavior in children with autism. Interestingly, two parents (who must remain anonymous). Cranberry juice has been anecdotally reported to reduce or even eliminate these effects. Whether this due to the sulphur content of the juice or some other mechanism including placebo remains to be determined.

Sulphate ions are not absorbed from the gut so this route is not a possibility for replenishment. The main source of free sulphate in the body is the amino acid "cysteine" which is obtained from the breakdown of protein. Some parents have attempted to combat this by feeding their children large doses of cysteine in tablet or powder form with mixed results reported. Other parents have introduced other sulphur containing amino-acids and claim this therapy beneficial. One of the sulphur containing amino-acids used for this purpose is "taurine," which is reported to have an anti-opioid effect (Braverman 1987).

Parents have also been experimenting with alternative routes of administration. One popular route is percutaneous, in which magnesium sulphate (Epsom Salts) are placed in the bath water in the hope that the sulphate will enter the body through the skin. Anecdotal benefits are claimed from this therapy, though increased irritability has also been reported.

Similar sulphate deficiencies have been reported in people with migraine, rheumatoid arthritis, jaundice and other allergic conditions all of which are anecdotally reported as common in the families of people with autism.

More information on Rosemary Waring’s work is available at the Autism, Intolerance & Allergy Network (AIA).

Dr. Robert Sinaiko has also written an interesting paper, The Biochemistry of Attentional/Behavioral Problems, in this area.

Also, see Paul Shattock's discussion of Waring's work, Back to The Future: An assessment of some of the unorthodox forms of biomedical intervention currently being applied to autism, at The Autism Research Unit's Website.

Sulfated glycosoaminoglycans are critical to the formation of the neuromuscular junction and the development of appropriate motor control and function.

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Other Sulfation Problems in Autism

®Sulfation problems have been described by Rosemary Waring at the University of Birmingham in autism which could lead to an inability to handle virus infections, with a disruption of cell-mediated immunity® as well as an impairment of natural killer cell function.® Unlike the situation with type I interferons, which are released by infected cells, interferon gamma (a type II interferon) is released by T lymphocytes and natural killer cells, but that happens not when they themselves have been activated, but rather, when they are alerted to the presence of infection by other immune cells or by a superantigen or a chemical mitogen.

Sulfate also plays an important role in initiating interferon gamma's signal.® [ Reference:® Benito A. Yard, Christian P. Lorentz, Dieter Herr, Fokko Van Der Woude.® Sulfation-dependent Down-Regulation of Interferon-gamma-induced Major Histocompatibility Complex I and II Intercellular Adhesion Molecule-1 Expression on Tubular and Endothelial Cells by Glycosaminoglycans.® Transplantation Vol.66(9), November 15, 1998, pp. 1244-1250]. Glycosaminoglycans (GAG) are sulfated sugars, involved with great deal of the action on the cell surface.® They also have activity in their "shed" form, where they act in the extracellular matrix, external to the cell.® All cells make GAGs, and shed GAGs continuously, but to properly assemble these sulfated GAGs, each cell has to be supplied with adequate sulfate, which is low in autism.® When these sugars are not sufficiently populated with sulfate, they will not behave normally, and their interaction with other chemistry can be hampered.® If sulfated GAGs are required for the proper action of interferon gamma, then a problem with sulfation may indeed be able to explain why so many autistic children have a hampered cell-mediated immunity and poor natural killer cell function.

Sulfated GAGs on the cell surface appear necessary for interferon gamma to generate a signal through its receptors on the cell surface.® More highly sulfated GAGs do indeed bind interferon and prevent it from binding to its receptors and generating its signal into the cell.® This varies in a dose-dependent manner.

Sulfated cell surface GAGs are required to dimerize, or assemble, two different components of receptors. Also, in the extracellular matrix around the cell, sulfated GAGs have been found to provide an escort for the GAG-binding chemical to get to the cell surface, actually protecting it from degradation as it wends its way to its cell-bound GAG/receptor complex.® Another example of this process is seen in chylomicron metabolism, where sulfated GAGs in most pathways are necessary for helping the cells in the liver to "eat" and process cholesterol-laden fatty particles.

There is another article from the May 1994 Scientific American: "How Interferons Fight Disease", by Howard M. Johnson et al., that gives a particularly valuable review of what a problem with the interferon gamma signal would be expected to produce.® Even though this article does not even mention GAGs, it does say that in order to activate its receptor, some part of the interferon gamma molecule which is coming from the outside of the cell has to associate with a part of its receptor that is actually underneath the cell membrane and in the cytosol, so the authors speculate that the whole complex has to at least be partially endocytosed (taken inside the cell) before this could happen.® That may be where these GAGs are functioning, as they are recognized in the liver also as being involved with the endocytosis of ligand/receptor complexes.

But, if this process were inhibited by poor sulfation what would be the consequences?

[Exerpts from the article in Scientific American]:

"Interferons activate pathways that cause cells to transcribe, or copy, certain genes into molecules of messenger RNA.® The RNA transcripts, in turn are translated into proteins that interfere with viral replication or produce other effects...

Interference with viral protein translation:

For example, one of the best-studied proteins (the eIF-2-alpha protein kinase) interferes with the cellular machinery that viruses exploit in order to reproduce themselves.® Viruses trick the protein-making machinery of host cells into translating viral messenger RNA into the proteins needed to make new infectious particles.® Messenger RNA, viral or otherwise, is translated by ribosomes.® These structures travel down the length of the RNA strand, linking one specified amino after another to a growing protein chain. First, however, each ribosome has to be built.® Several molecules join together to form the smaller of two ribosomal subunits, and then the larger subunit comes on board.

All three interferons can precipitate the production of the eIF-2-alpha protein kinase, the active form of which phosphorylates one component required for forming the smaller ribosomal unit.® Such phosphorylation blocks further construction of the subunit and thus stalls protein synthesis.® The newly made kinase becomes active only when it encounters double-stranded RNA.® Such RNA appears in a cell only when a virus replicates its genetic material.® Consequently, the enzyme blocks protein synthesis in infected cells but not in healthy ones.

Destruction of viral RNA:

Among other groups of proteins induced by both type I and type II interferons is the family consisting of the 2',5'-oligo (A) synthetases. These enzymes, too, interfere with the production of viral proteins, but they do so by activating enzymes that break down RNA before it can be translated into protein. ...

Enhancement of macrophage function:

Interferon gamma can induce macrophages to kill tumor cells and cells infected by parasites, bacteria or viruses.® It can also prod macrophages ot destroy pathogens that have colonized the scavengers themselves.® And interferon gamma stimulates macrophages to produce what are called class II MHC (major histocompatibility complex) molecules.® After macrophages ingest pathogens, they break up several of the microbes and fit the fragments into grooves on the MHC molecules, which are then transported to the cell surface.® There they display the antigenic fragments to what are called CD4 T cells.® (These lymphocytes can "see" antigens only if the foreign fragments are complexed with a class II MHC molecule.)® Having recognized particular antigens, the CD4 cells proliferate and release chemicals that help other immune system cells to fight off infection..

Interferon gamma...serves as a kind of immunologic switch.® The protein helps to turn on the cell-mediated arm of the immune system, consisting of macrophages, various kinds of T cells and other cells that respond to microbes inside the cells of other tissues.® At the same time, interferon gamma may dampen the production of antibodies.® Antibodies are better suited to eradicating pathogens that establish colonies outside of cells."

The article does not really talk about natural killer cells, but it would make sense if they are the other cell type besides macrophages that release interferon gamma, that their effectiveness would be greatly reduced if their signal from interferon was lost because of poor reception by the recipient cell.

All in all, these two articles go far in explaining the possible cause of the particular weaknesses we've found in some children's immune system with both poor cell-mediated immunity and impaired function of natural killer cells that go along with their sulfation problems.

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Cholecystokinin and Autism

Rats born without a functional CCKA receptor developed a type II (adult onset) like diabetes (insulin resistant type). Insulin and insulin-like growth factor, can both engage each other’s receptors, so a process affecting the function of one, may influence the other. IGF (insulin-like growth factor) is important for cell growth. IGF also regulates the sulfate uptake in glycosaminoglycans in cartilage and potentially other tissues.

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Oxytocin and Vasopressin in Autism

Oxytocin is produced through the influence of the cholecystokinin-A (CCKA) receptor, which requires its substrate, cholecystokinin, to be sulfated (see the free sulfate theory of autism). If there is insufficient ability to sulfate compounds (a finding in some autistic people), the receptor will not work well, and many CCKA mediated functions will be afffected.

There is an argument that pitocin (oxytocin) might cause some cases of autism since so many mothers of autistic children had to have pitocin to induce labor. Others have suggested that the association was more likely caused by the mother/childunit having sulfation problems which made it difficult for mom's oxytocin to be produced in sufficient quantity to move labor along, necessitating a jumpstart with exogenous oxytocin (pitocin). The theory is that mothers with sulfation problems would have a higher likelihood for delayed or desultory labor.

A literature is developing to support a role for oxytocin in autism 4.

Coexisting with oxytocin or vasopressin in the cell bodies and nerve terminals of the hypothalamic-neurohypophysial system are smaller amounts of other peptides 5. For a number of these ''copeptides'' there is strong evidence of corelease with the major magnocellular hormones. The effects on secretion of oxytocin and vasopressin of three copeptides, dynorphin, cholecystokinin (CCK), and corticotropin releasing hormone (CRH), has been studied. Dynorphin is coreleased with vasopressin from neural lobe nerve terminals and acts on neural lobe kappa-opiate receptors to inhibit the electrically stimulated secretion of oxytocin. Naloxone augments oxytocin release from the neural lobe in a manner directly proportional to the amount of vasopressin (and presumably dynorphin) released.

Cholecystokinin, coreleased with oxytocin by neural lobe (NL) terminals, has been shown to have high-affinity receptors located in the NL and to stimulate secretion of both oxytocin and vasopressin. CCK's secretagogue effect is independent of electrical stimulation and extracellular Ca2+ and is blocked by an inhibitor of protein kinase C.

CRH, coreleased with oxytocin from the neural lobe, has receptors in the intermediate lobe of the pituitary, but not in the neural lobe itself. CRH stimulates the secretion of oxytocin and vasopressin from combined neurointermediate lobes but not from isolated neural lobes. Intermediate lobe peptides, alpha and gamma melanocyte stimulating hormone, induces secretion of oxytocin and vasopressin from isolated neural lobes. Their effect is, like that of CCK, independent of electrical stimulation and extracellular Ca2+ and is blocked by an inhibitor of protein kinase C.

Among the CRH-producing parvocellular neurons of the paraventricular nucleus, in the normal rat, approximately half also produce and store vasopressin. After removal of glucocorticoid influence by adrenalectomy, virtually all of the CRH neurons contain vasopressin.

The two subtypes of CRH neurosecretory cells found in the normal rat possess different topographical distributions in the paraventricular nucleus, suggesting the possibility of differential innervation. Stress selectively activates the vasopressin containing subpopulation of CRH neurons, indicating that there are separate channels of regulatory input controlling the two components of the parvocellular CRH neurosecretory system.

The presence of opioid peptides and opiate receptors in the hypothalamo-neurohypophysial system, as well as the inhibitory effects of enkephalins and beta-endorphin on release of oxytocin and vasopressin has been well documented 6. Opioid peptides inhibit oxytocin release and thereby promote the preferential secretion of vasopressin when it is of functional importance to maintain homeostasis during dehydration and hemorrhage. Both neuromodulators and a neurohormones co-exist in the same neuron, as demonstrated for vasopressin with dynorphin or leucine-enkephalin, which serves to regulate the differential release of two biologically different, yet evolutionarily-related, neurohormones, e.g. oxytocin and vasopressin, from the same neuroendocrine system.

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Autism and Amino Acids

Many autistic people have low levels of specific amino acids, despite a diet sufficient to support normal levels. DPP IV is found on epithelial cells in the kidney and is responsible for breaking down peptides into amino acids which are then reabsorbed. An absent or non-functioning enzyme could explain lowered levels of amino acids.

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Methylation Theory of Autism

Methylation is an important metabolic process, possibly defective in autism, and pertaining to the control of histamine excess, protection of DNA, promotion of serotonin production, and other brain functions. A number of experiments have suggested a relationship between methyl group metabolism and the exocrine secretion of the pancreas 32.

These included nutritional studies which showed that ethionine, the ethyl analog of methionine which inhibits cellular methylation reactions, is a specific pancreatic toxin. Other studies indicated that protein carboxymethylation might be involved. Capdevila, et al. 32 showed that in vivo ethionine inhibits amylase secretion from freshly isolated rat pancreatic acini, while in vitro ethionine inhibits amylase secretion from the AR42J pancreatic cell line.

S-Adenosylhomocysteine (SAH) is an inhibitor of all methyltransferase reactions involving S-adenosylmethionine (SAMe). Treatments that elevate cellular levels of SAH such as inhibition of S-adenosylhomocysteine hydrolase and the in vitro addition of adenosine and homocysteine result in the inhibition of amylase secretion in both isolated pancreatic acini and AR42J cells. Measurement of SAMe and SAH levels in AR42J cells shows that inhibition of secretion is more closely related to elevation of SAH levels than to a decrease in the SAMe/SAH ratio.

Small G-proteins are carboxymethylated on the C-terminal byprenylcysteine, and inhibitors of membrane-associated prenylcysteine methyltransferase, N-acetylfarnesylcysteine, N-acetylgeranylgeranylcysteine, and farnesylthioacetic acid (FTA), block secretion in AR42J cells. N-Acetylgeranylcysteine is not an inhibitor of the methyltransferase and does not inhibit amylase secretion. FTA inhibits membrane-associated prenylcysteine methyltransferase from AR42J cells.

These results suggest that a methylation event is needed for pancreatic exocrine secretion which may be the reversible methylation of a G-protein involved in signal transduction or membrane trafficking. One theory of action of secretin revolves around restoration of normal methylation in the pancreas, and thereby normalizing pancreatic exocrine secretion. Pancreatic exocrine secretion is blocked by inhibitors of methylation.

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Stress and Immunity

The experience of stress affects cellular immunity, an important aspect of many medical problems, including controlling/curing cancer and the immunobiology of autism. Treating disease with immunological components means also treating and managing psychological stress.

Human immune function is mediated by the release of cytokines, nonantibody messenger molecules, from a variety of cells of the immune system, and from other cells, such as endothelial cells. There are Th1 and Th2 cytokines. Autoimmune and allergic diseases involve a shift in the balance of cytokines toward Th2. The autoimmune aspect of autism has been related to excessive Th2 cytokines resulting, in part, from vaccination. Gulf War syndrome and asthma have been similarly linked to excess immunization in the presence of increased environmental toxins and pollutants (high antigenic load).

Cytokines stimulate cellular release of specific compounds involved in the inflammatory response. Stress-induced activation of the sympathetic nervous system and the sympathetic-adrenal medullary and hypothalamic-pituitary adrenal axes lead to the release of cytokines 1. Blocking the response of the sympathetic nervous system by pre-treating subjects in stressful experiments with adrenergic antagonists can reduce this release of cytokines and decrease the resulting inflammatory response 2, 3. Discrete areas of the brain (for example, the hypothalamus and the locus coeruleus) regulate the sympathetic nervous system and therefore the levels of circulating adrenergic stress hormones, thereby influencing the activity of the immune system 4, 5. Adrenergic stress hormones alter the synthesis and release of cytokines by white blood cells (leukocytes).

The effects of stress on immunity has been experimentally studied in animals. The stress of crowding prior to and following tuberculosis infection affects the outcome of the infection in mice 6. Social disruption in mice causes reactivation of latent herpes simplex virus 7. Stress enhances the reactivation of latent herpes viruses including the Epstein-Barr virus in humans 8.

Psychological stress inhibits many aspects of the immune response including innate immunity (eg, natural killer cell lysis), T-cell responses, and antibody production [1]. Caregivers of parents with Alzheimers disease along with matched noncaregivers received influenza vaccine. All subjects had similar vaccine histories, rates of chronic illnesses, and medication usage, but caregivers showed poorer cellular and humoral immune responses to the vaccine than controls 9 - 12. Their less robust response was thought to relate to the chronic stress of caregiving.

Acute stress can suppress the virus-specific antibody and T-cell responses to hepatitis B vaccine 2, 13-15. People who show poorer responses to vaccines have higher rates of clinical illness including influenza virus infections 16, so these findings are clinically relevent.

Stress influences host resistance to upper respiratory tract infections produced by exposure to five different strains of rhinovirus, to a strain of coronavirus, and to respiratory syncytial virus. After inoculation, subjects were quarantined and monitored for 5 or more days to assess whether they developed infections and cold symptoms. Approximately one third of those subjects exposed to one of these viruses developed a serologically verified clinical illness 17. Higher scores on a questionnaire for stressful life events, higher perceptions of stress, and more negative emotional experiences were associated with a greater likelihood of developing a clinical illness defined as cold symptoms concomitant with isolating an infectious virus or developing a 4-fold increase in antibody titers 18.

In a second study, a life-stress interview replaced the questionnaire. This technique allowed the specification of the types of stressful events that increase risk. These included chronic events (lasting a month or longer), especially chronic social conflicts and underemployment or unemployment 18. Other plausible factors that might be the cause of both changes in stress and greater susceptibility to disease, such as age, sex, education, and personality characteristics including self-esteem and personal control, were unable to account for these results. The results demonstrated a relationship between psychological stress and susceptibility to several cold viruses.

Attempts to find an association between stress and disease progression in patients with acquired immunodeficiency syndrome (AIDS) have met with conflicting results 19. Among a cohort of San Francisco AIDS patients, depression predicted CD4+ T-lymphocyte decline 20 and mortality 21. Analysis of the Multicenter AIDS Cohort Study failed to observe an association between depression and the decline of CD4+ T lymphocytes, disease progression, or death 22, but others have found significant associations between immunological parameters reflective of HIV progression and psychosocial factors, particularly denial and distress 23 and concealment of homosexual identity 24.

Outside of proven clinical interventions, there is reason to think that certain changes in lifestyle might increase host resistance to infectious diseases. These include broadening one's social involvements (eg, joining social or spiritual groups, having a confidant, spending time with supportive friends) and being more careful to maintain healthful practices such as proper diet, exercise, and sleep, especially under stressful conditions 26.


1. Rabin BS. Stress, Immune Function, and Health: The Connection. New York, NY: Wiley-Liss & Sons Inc; 1999.

2. Bachen EA, Manuck SB, Cohen S, et al. Adrenergic blockade ameliorates cellular immune responses to mental stress in humans. Psychosom Med. 1995;57:366-372. MEDLINE

3. Benschop RJ, Nieuwenhuis EES, Tromp EAM, Godaert GLR, Ballieux RE, van Doornen LJP. Effects of beta-adrenergic blockade on immunologic and cardiovascular changes induced by mental stress. Circulation. 1994;89:762-769. MEDLINE

4. Wetmore L, Nance DM. Differential and sex-specific effects of kainic acid and domoic acid lesions in the lateral septal area of rats on immune function and body weight regulation. Exp Neurol. 1991;113:226-236. MEDLINE

5. Rassnick S, Sved AF, Rabin BS. Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses. J Neurosci. 1994;14:6033-6040. MEDLINE

6. Tobach E, Bloch H. Effect of stress by crowding prior to and following tuberculosis infection. Am J Physiol. 1956;187:399-402.

7. Padgett DA, Sheridan JF, Dorne J, Berntson GG, Candelora J, Glaser R. Social stress and the reactivation of latent herpes simplex virus-type 1. Proc Natl Acad Sci U S A. 1998;9:7231-7235.

8. Glaser R, Kiecolt-Glaser JK. Stress-associated immune modulation and its implications for reactivation of latent herpesviruses. In: Glaser R, Jones J, eds. Human Herpesvirus Infections. New York, NY: Marcel Dekker Inc; 1994:245-270.

9. Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan J. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci U S A. 1996;93:3043-3047. MEDLINE

10. Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R. Slowing of wound healing by psychological stress. Lancet. 1995;346:1194-1196. MEDLINE

11. Kiecolt-Glaser JK, Page GG, Marucha PT, MacCallum RC, Glaser R. Psychological influences on surgical recovery: perspectives from psychoneuroimmunology. Am Psychol. 1998;53:1209-1218. MEDLINE

12. Vedhara K, Cox NKM, Wilcock GK, et al. Chronic stress in elderly caregivers of dementia patients and antibody response to influenza vaccination. Lancet.1999;353:627-631. MEDLINE

13. Glaser R, Kiecolt-Glaser JK, Bonneau RH, Malarkey WB, Kennedy S, Hughes J. Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom Med 1992;54:22-29. MEDLINE

14. Jabaaij L, Grosheide RA, Heijtink RA, Duivenvoorden HJ, Ballieux RE, Vingerhoets AJ. Influence of perceived psychological stress and distress antibody response to low dose rDNA hepatitis B vaccine. J Psychosom Res. 1993;37:361-369. MEDLINE

15. Glaser R, Kiecolt-Glaser JK, Malarkey WB, Sheridan JF. The influence of psychological stress on the immune response to vaccines. Ann N Y Acad Sci. 1998;840:649-655. MEDLINE

16. Gravenstein S, Drinka P, Duthie EH, et al. Efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak. J Am Geriatr Soc. 1994;42:245-251. MEDLINE

17. Cohen S, Tyrrell DAJ, Smith AP. Psychological stress in humans and susceptibility to the common cold. N Engl J Med. 1991;325:606-612. MEDLINE

18. Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney Jr JM. Types of stressors that increase susceptibility to the common cold in adults. Health Psychol. 1998;17:214-223. MEDLINE

19. Solomon GF, Kemeny ME, Temoshok LT. Psychoneuroimmunologic aspects of human immunodeficiency virus infection. In: Ader R, Felten D, Cohen N, eds. Psychoneuroimmunology. San Diego, Calif: Academic Press; 1991:1081-1114.

20. Burack JH, Barrett DC, Stall RD, Chesney MA, Ekstrand ML, Coates TC. Depressive symptoms and CD4 lymphocyte decline among HIV-infected men. JAMA. 1993;270:2568-2573. MEDLINE

21. Mayne TJ, Vittinghoff E, Chesney MA, Barrett DC, Coates TJ. Depressive affect and survival among gay and bisexual men infected with HIV. Arch Intern Med. 1996;156:2233-2238. MEDLINE

22. Lyketsos CG, Hoover DR, Guccione M, et al. Depressive symptoms as predictors of medical outcomes in HIV infection. JAMA. 1993;270:2563-2567. MEDLINE

23. Ironson G, Friedman A, Klimas N, et al. Distress, denial and low adherence to behavioral interventions predict faster disease progression in gay men infected with human immunodeficiency virus. Int J Behav Med. 1994;1:90-105.

24. Cole S, Kemeny M, Taylor S, Visscher B, Fahey J. Accelerated course of HIV infection in gay men who conceal their homosexuality. Psychosom Med. 1996;58:219-231. MEDLINE

25. Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med. 1993;55:364-379. MEDLINE

26. Cohen S, Doyle WJ, Skoner DP, Rabin BS, Gwaltney Jr JM. Social ties and susceptibility to the common cold. JAMA.1997;277:1940-1944.

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Autoimmune Theories

One possible cause of autism may involve faulty immune regulation, in particular, autoimmunity 7.

Brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children 8. Among 33 autistic children (less than or equal to 10 years of age) compared to 18 age-matched normal children, antibodies to myelin basic protein were found in 19 of 33 ( 58%) sera from autistic children as compared to only 7 of 50 ( 7% ) sera from control children 9. The diagnosis of autism was made by at least one pediatric psychiatrist and one clinical child psychologist using the DSM-III-R guidelines of the American Psychiatric Association, Washington, D.C. Since nearly 60% of autistic children show mental retardation ( MR ) (IQ of 70 or lower ), 20 children with MR due to unknown causes and 12 children with Down syndrome ( DS ) were also studied as the disease controls. The testing for serum antibodies to MBP was performed with the technique of protein-immunoblotting. This result indicated that the autistic children have about 8.3 times greater incidence of antibodies to MBP than the control children. Since none of the 12 DS children and only 3 of 20 MR children showed this antibody- positive reaction, the authors concluded that the mental retardation in autistic children was not related to the production of antibodies to MBP.

Singh, et al. (1998), examined the 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. They found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but did not significantly differ from normal controls. They 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. Their study was the first to report an association between virus serology and brain autoantibody in autism. They authors believed that their data supported the hypothesis that a virus-induced autoimmune response may play a causal role in autism.

Immunological testing of autistic children has shown certain features that are also found in patients with autoimmune diseases such as systemic lupus erythematosus ( SLE ), thyroid disease ( TD ), ankylosing spondylitis ( AS), rheumatoid arthritis (RA ), insulin-dependent diabetes ( IDD ), and multiple sclerosis ( MS ). These are: ( a ) genetic predisposition -- autism shows a greater concordance rate in monozygotic twins than in the normal population; ( b ) gender factor -- autism is 4 or 5 times more common in boys than in girls; ( c ) triggering by microorganisms -- rubella virus and cytomegalovirus infections have been indirectly linked to autism; ( d ) maternal factors --maternal antibodies in autism were detected 10; (e ) major histocompatibility ( MHC ) association -- autism displays genetic linkage with immunogenetic factors located on chromosome six 11; and ( f ) immune activation 12.

The parallels between autism and other autoimmune diseases suggest that autoimmunity may be a critical factor in the cause of autism. An essential part of the autoimmune mechanism should involve antibody-mediated immune response or antibodies against brain, the affected organ in autism. In this respect, a few recent studies in autism have found evidence of antibodies to brain tissue antigens, e.g., MBP, neurofilament proteins, and serotonin receptor 13. Antibodies to MBP may have some pathological relevance since abnormal cell-mediated immune response ( involving a soluble factor but not antibodies ) to this protein was previously detected, suggesting that autistic children somehow develop inappropriate immune responses to this brain protein 14. Brain-reactive antibodies and the increased serum levels of IgG3 antibody, which selectively activates complement function via classical pathway ( another type of immunity ), could be an important first step in the activation of complement-mediated nerve cell damage, thereby altering their ability to perform normal function of nerve impulse transmission 15.

Despite numerous behavioral problems, research into the brains of autistic children has been hampered by the lack of available brain biopsies or autopsies. Based on a very limited number of case studies, anatomical abnormalities in certain parts of the brain have been found, but the findings are not suffiently consistent to permit any firm conclusion. While the pathological data are scarce, we know virtually nothing about the neurochemistry ( neurotransmitter function ) of the autistic brain. Whatever the pathological abnormalities might be, it is generally believed that the anatomical defects are the results of abnormal development rather than damage following full development of the brain in autistic children 16. At present, the relationship between antibodies to MBP and autism is not understood. However, the development of this immune response may be the basis of autoimmune pathogenesis in some cases of autism. At birth, there is very little myelin in the brain, and the synthesis of myelin may not be complete until the age of 10 years or older in the normal child 17. Moreover, it has been suggested that some children with learning disabilities ( LD ) may have delayed or incomplete myelin development 18. In light of the above, it is conceivable that if an immunological assault were to occur before birth or during infancy or childhood, it could lead to poor myelin development or abnormal function of the nerve fiber myelin. This line of thinking may be an important step in the future understanding of the pathological basis of autism.

For more information about immunology and autism see the following sites:


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Antibodies to Myelin Basic Protein found in Autistic Children:

The theory of an autoimmune cause for autism rests upon studies that find antibodies to myelin basic protein (anti-MBP) in the sera of children with autism. A study of children under age 11, reported in Brain, Behavior, and Immunity (Volume 7, pp 97-103, 1993) compared 33 autistic children, with 18 normal children, 20 children with idiopathic mental retardation, 12 children with Down's syndrome, and - as a separate control - 38 normal adults in the age range of 20 to 40 years.

Anti-MBP antibodies were found in 19 of 33 (58%) autistic children, but only in 8 of 88 (9%) control subjects. Among the controls, 15% were positive among mentally retarded children, 22% among normal children, less than 3% among normal adults, and none among Down's syndrome children.

Neither seizure activity nor antipsychotic drugs were related to the production of anti-MBP since there was neither the history of seizures nor the intake of antipsychotic drugs among autistic or retarded children.

Immunological studies of autistic patients have revealed features also found in patients with other autoimmune diseases. Autoimmune diseases, including Grave's thyroid disease, rheumatoid arthritis, and insulin-dependant diabetes, show some genetic predisposition. Similarly, autism shows a greater concordance rate in monozygotic twins than in the normal population. Autism is four to five times more prevalent in boys than in girls Ä a gender factor also found in systemic lupus erythematosus, Grave‚s disease, and ankylosing spondylitis.

Autoimmune disease may be triggered by infections with bacteria or viruses. In autism, coincidental findings indicate infections with congenital rubella and cytomegalovirus. Certain soluble antigens of immunocyte activation are elevated in the sera of autistic children, similar to findings in other autoimmune diseases, like lupus and multiple sclerosis.

Lymphocyte proliferation by phytohemagglutinin, concanavalin A, and pokeweed mitogens are generally depressed in 40 to 50% of autistic patients. The blood proportions of CD4+ T helper cells and a suppresor-inducer (CD4CD45RA+) subset are significantly depressed in autistic patients.

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Viral Infection Theory

The viral theory of autism relies upon a relative immunosuppression, often thought to be in the intestinal tract, and a viral infection to produce the central nervous system symptoms of autism. Secretory immunoglobulin A (SIgA) is an important defense in the intestines against viral infections and is often postulated to be deficient in autism.

Viral encephalitis is known to give rise to autistic-like disorders, particularly when it occurs early in life.30  31  

Among the viruses that can invade the gastrointestinal tract is herpes simplex (HSV), which has been shown in the human enteric nervous system, from which it can migrate into the CNS, including into the central amygdala (RM Gesser at al, series of studies). Other studies have shown that HSV (i) tends to migrate towards the cerebellum and temporal lobe, (ii) is capable of affecting language, (iii) can migrate intra-neuronally without causing encephalitis, and (iv) once within the CNS can remain hidden from view for long periods of time (ie, no peripheral signs, no detectable CSF markers (Dr. Snyder; Myron Levin et al).

Some investigators speculate about an autism-spectrum subgroup wherein the infant or child's gastrointestinal pathology provides the route by which herpes simplex virus migrates into the central nervous system to produce the autistic symptoms.

The major immunoglobulin (Ig) present in human secretions is a dimeric IgA covalently bound to an epithelial glycoprotein of about 80 kD, now called the secretory component (SC). IgA protects against viral infection from the gut. Secretory IgA and secretory IgM are the products of two cell types: plasma cells synthesise IgA dimers and IgM pentamers which, by non-covalent association, become complexed with the secretory component (SC) which is synthesized by serous-type glandular cells. The adsorption of the Ig polymers to the SC-expressing epithelial cells depends on J-chain-determined binding sites. This fact gives biological significance to the striking J chain expression shown by mucosal immunocytes regardless of the Ig class they produce. The immunocytes populating the gut mucosa apparently belong to relatively early memory B cell clones. The obvious functional goal of J chain expression at this stage of clonal differentiation is local generation of SC-binding IgA and IgM polymers. In various gut diseases, altered immune regulation results in a disproportionately increased number of J chain-negative IgG-producing cells in the mucosa. Such altered immunological homeostasis may contribute to perpetuation of inflammatory bowel diseases.

Pentameric IgM is likewise actively enriched in most exocrine fluids (like gut excretions) and is associated with SC, although not in a covalently stabilized complex.

Three findings explain the selective translocation of polymeric Ig (pIg) into exocrine fluids: (1) preferential local production; (2) J-chain-expressing capacity of pIg-producing immunocytes; and (3) SC-mediated epithelial transport.

The J chain of pIg and the epithelial SC represent the "lock and key" in the glandular transport of secretory IgA (SIgA) and SIgM.

It has recently been shown that SC is synthesized as a transmembrane protein of about 95 kD and constitutes the actual pIg surface receptor. Complexing between ligand and receptor in the plasma membrane is followed by endocytosis. The completed SIgA and SIgM molecules are then translocated in cytoplasmic vesicles through the epithelial cell to the gland lumen along with an excess of free SC.

The main function of SIgA is to exert immune exclusion; that is, by intimate cooperation with innate nonspecific defense factors it decreases penetration of soluble antigens and inhibits epithelial colonization of bacteria and viruses. Especially in selective IgA deficiency, SIgM may exert a similar protective function since its synthesis is markedly increased in the intestinal mucosa, especially in selective IgA deficiency.

IgG should not be considered a secretory immunoglobulin because its external translocation depends on passive intercellular diffusion. By activating complement, antibodies of this isotype may cause increased mucosal permeability and tissue damage. By activating complement, IgG antibodies may at the same time be phlogistic and accelerate mucosal penetration of antigens. IgG may thus contribute to persistent immunopathology in mucosal disease. The same is true for IgE antibodies which, in atopic individuals, may be carried into the gut mucosa by mast cells and cause their degranulation with histamine release.

Leakage of IgG into exocrine fluids is enhanced by mucosal irritation. Although IgG should not be considered as a SIg, it may contribute to immune exclusion. This is seen especially in the respiratory tract where IgG is less easily subjected to proteolytic degradation than in the intestinal juice.

Traces of IgD may likewise be found in the secretions but without obvious biologic significance. Regulation of secretory immunity takes place both in organized lymphoepithelial structures in the gut, such as the Peyer's patches, and adjacent to the glands in the lamina propria of the gut 19  20.

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Vaccinations and Autism

Dr. Andrew Wakefield, a Gastroenterologist at the Royal Free

Hospital in London, England, discovered a possible connection between autism and viral infection associated with the MMR vaccination. The damage from autism is thought to be provoked by the an allergic type reaction initiated by the body’s reaction to the vaccine. This auto-immine response could also affect DPP-IV, reducing its levels, thereby connecting vaccines to the opioid theory of autism.

For more information, please see The Mechanism of Encephalitic Damage from Vaccines by Val Valerian.

Myelination is an essential part of human brain development. Nerves can only conduct pulses of energy efficiently if it is covered with myelin. Like insulation on an electric wire, the fatty coating of myelin helps keep the pulses confined and maintains the integrity of the electrical signal so that it has a high signal-to-noise ratio. When the insulation on a wire is damaged or destroyed, the flow of electrical current may be interrupted and a short-circuit occurs. See Colorado Health Net's MS Definitions, Facts, and Statistics for more information.

Oligodendrocyte cells give white matter its color by manufacturing myelin. If myelin falls into disrepair, nerve axons cease to function, even though they themselves aren't damaged. Protecting oligodendrocytes after brain or spinal cord injury might keep nerve cells intact." See Washington University in St. Louis School of Medicine's article on new findings on nervous system damage for more information.

At birth, relatively few pathways have myelin insulation. Myelination in the human brain continues from before birth until at least 20 years of age. Up until the age of 10 or so, vast areas of the cortex are not yet myelinated, and up to the age of 20, large areas of the frontal lobes are not yet myelinated 21.

Myelination begins in the developmentally oldest parts of the brain, like the brain stem, moving to the areas of the nervous system that have developed more recently, like the prefrontal lobe and cortex. Myelin spreads throughout the nervous system in stages which vary slightly in each individual. Impairment of myelination can alter neural communication without necessarily causing severe CNS damage.

The prefrontal portions of the cerebrum have a profound influence on human behavior 22. If an individual is injected with vaccines,most of which have adjuvants like mercury and aluminum compounds, as well as foreign proteins (some from other species in which the vaccines were grown) and biological organisms, unprotected nerves may be impacted. The argument for a role of vaccines in the development of autistic disorders hinges on these biological effects upon nerves, damaging them in a way that influences behavior and learning patterns.

The history of studies on vaccines began in 1922 when a smallpox vaccination program caused an outbreak of encephalitis, with a secondary result of Guillain-Barre Syndrome, an ascending paralysis ending in death. The polio virus produces a breakdown of the myelin shealth, called poliomyelitis, which results in paralysis. Encephalitis, whether caused through disease or as a result of vaccination, can cause demyelination of the nerves. For more information, see again The Mechanism of Encephalitic Damage from Vaccines. "In regions in which there is no organized vaccination of the population, general paralysis is rare. It is impossible to deny a connection between vaccination and the encephalitis which follows it. 23"

In 1935, Thomas Rivers discovered "experimental allergic encephalomyelitis," or (EAE). Until then, it was assumed that encephalitis was caused by a viral or bacterial infection of the nervous system. Rivers was able to produce brain inflammation in laboratory monkeys by injecting them repeatedly with extracts of sterile normal rabbit brain and spinal cord material, which made it apparent that encephalitis was an allergic reaction. EAE can explain the association of allergies and autoimmune states with encephalitis.

In 1947, Isaac Karlin suggested that stuttering was caused by "delay in the myelinization of the cortical areas in the brain concerned with speech." In 1988, research by Dietrich and others using MRI imaging of the brains of infants and children from four days old to 36 months of age have found that those who were developmentally delayed had immature patterns of myelination.

In 1953 it was realized that some children's diseases, measles in particular, showed an increased propensity to attack the central nervous system. This indicated a growing allergic reaction in the population to both the diseases and the vaccinations for the diseases.

In 1978, British researcher, Roger Bannister, observed that the demyelinating diseases were getting more serious "because of some abnormal process of sensitization of the nervous system."

Some investigators believe that this increased sensitization of the population is being enhanced by vaccination programs.

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DPT and Brain Damage:

In 1948, Randolph Byers and Frederick Moll , of Harvard Medical School and the Federal Drug Administration carried out tests on DPT vaccines at Children's Hospital in Boston and concluded that severe neurological problems could follow the administration of DPT vaccines. The results of the tests were published in Pediatrics.

In 1976, Dr. Charles Manclark, an FDA scientist, remarked that "the DPT vaccine had one of the worst failure rates of any product submitted to the Division of Biologics for testing."

According to the testimony of the Assistant Secretary of Health, Edward Grant, Jr., before a U.S. Senate Committee on May 3rd, 1985, every year, 35,000 children suffer neurological damage related to the DTP vaccine. See "Vaccinations", by Alex Logia, for more information.

In 1992, the Institute of Medicine concluded that "the evidence is consistent with a causal relation between DPT vaccine and acute encephalopathy, defined in the studies reviewed as encephalopathy, encephalitis, or encephalomyelitis, and the evidence indicates a causal relation between DPT vaccine and anaphylaxis, between the pertussis component of DPT vaccine and protracted, inconsolable crying." For more information, see the Leading Edge Master Analysis of the Vaccination Paradigm.

Like the material used to produce experimental allergic encephalitis, vaccines contain substances which qualify as "adjuvants." These substances initiate reactionary antibody formation. Common adjuvants used in vaccines are aluminum hydroxide and aluminum potassium sulfate. In the body, formalin coating around the injected material dissolves, releasing all bacterial and viral particles from animal culture sources. Substances such as thimerosal and these adjuvant chemicals irritate body tissues and increase the action of accompanying bacteria and viruses, as well as the reaction of the immune system to the foreign protein antigens, potentially damaging neurological membranes where the myelin sheath has only partially protected the nervous system. This can result in mild to severe neurological damage, leading to learning disabilities and other nervous system disorders, or death, especially upon subsequent injections, since body has already been sensitized, promoting allergic reactions of increasingly severe nature. For more information, see again the Leading Edge Master Analysis of the Vaccination Paradigm.

Dr. Charles M Poser has drawn the link between the vaccines and demyelination: "Almost any... vaccine can lead to a non infectious inflammatory reaction involving the nervous system 24. The common denominator consists of a vasculopathy that is often... associated with demyelination." For more information, see the Society For The Autistically Handicapped (S.F.T.A.H.)'s Vaccines: Fact Sheet.

Jonas Salk, the developer of the vaccine, wrote in 1975, "Live virus vaccines against influenza or poliomyelitis may in each instance produce the disease it intended to prevent . . . . the live virus against measles and mumps may produce such side effects as encephalitis 25. "

Post-vaccinal pathology of the central nervous system (CNS) is a topic deserving further investigation (An Italian Study Finding Biochemical Markers of Vaccine Damage, © 1996, Harris L. Coulter, Ph.D.). Observation of 30 patients of Italian nationality, observed between April, 1994, and October, 1995, showed that clinical signs of CNS pathology, along with associated dermatitis, food allergies, constipation, and leaking from the anus, emerged concomitantly or immediately after vaccination with the Salk or Sabin polio vaccine, DT, measles, DPT, anti-tuberculosis, or Hepatitis-B vaccines 26.

These 30 patients from various regions of Italy, all presented with a clinical history of convulsions concomitant with, or immediately after, vaccinations. Patients whose clinical history was not referable to a vaccination were excluded from the study. Accepted patients received tissue typing for HLA (A, B, C) and HLA DR-DQ. Various immune functions: were also studied, including lymphocyte subpopulations, serum immunoglobulin content, and presence of antibodies to specific viruses (CMV, EBV, HSV-1 and HSV-2, VZV).

Patients had earlier been diagnosed with epilepsy, myoclonic epilepsy, evoving epilepsy, epileptigenic encephalopathy, autism, West Syndrome, and Angelman's Syndrome. All the patients had presented with the first symptoms shortly after receiving a vaccination.

The first symptoms were convulsions, high fever, or diarrhea immediately following vaccination. The parents had told their physicians about this; then, after taking EEGs and visiting neuropsychiatric specialists or pediatricians without conclusion, the physicians had administered the recall shots of the vaccines leading to stabilization of the condition with progressive clinical deterioration.

Children were 3 to 9 months old. All patients were studied for the presence of metabolic diseases with negative results; then chromosomal mapping was done, also with negative results; encephalic TAC and RMN were performed at first appearance of the symptomatology, also with negative results.

The EEG performed at first appearance of the symptomatology gave a negative result in 92% of the patients. Serologic investigations for herpetic virus (IgG and IgM) were positive in all for IgG and negative for all for IgM, leading to an estimate of seropositivity (IgG) for Epstein-Barr virus of 73.8%; for cytomegalovirus, of 71.4%; for Herpes Simplex virus, of 47.6%; and for Varicella-Zoster Virus of 21.4%. In all the patients they observed diminished sideremia and a deficit of IgA and IgG with a slight increase of SGOT and SGPT. None of the patients had maternally transmitted viral encephalopathy, and in all the patients the vegetative and relational life was quite normal prior to administration of the first dose of vaccine. Again, see An Italian Study Finding Biochemical Markers of Vaccine Damage, for more information.

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MMR Vaccine and Autism:

The following news release appeared in the popular media in 1998, and was a major television news item:

Cleveland, Ohio, Posted 4:00 p.m. November 20, 1998:

"Studies Suggest the Measles-Mumps-Rubella
Vaccine Is a Possible Cause of Autism"

NewsChannel5 reports hundreds of thousands of children receive the MMR vaccine every year, but now studies show a tiny percentage of cases may cause autism. Since the MMR vaccine was introduced about 35 years ago,the incidents of autism in children have increased by 1,000 percent, from two or three in 10,000 to one in 500.

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Pro & Con Research on MMR, Autism Connection Compared:

The publications of Dr. Andrew Wakefield in March 1998 and of Dr. Brent Taylor in June 1999 share only two important features, they both originated from The Royal Free Hospital in London, and they both appeared in Lancet. Andrew Wakefield did his first colonoscopy on an autistic child, because the anguished mother begged him to find the reason why her son had such terrible gastro-intestinal problems. When he found some very specific pathology, Dr. Wakefield proceeded to investigate several more autistic children, identifying and documenting, again and again, the same very unusual findings.

A particular aspect of the history intrigued Dr. Wakefield. Many parents adamantly stated that their children's autistic symptoms appeared shortly after they received the MMR vaccine. One ten year old boy's story was probably the most striking This child was fine, and absolutely normal in every respect, as per his doctor, parents, and teachers. Shortly after he received the MMR vaccine, he started exhibiting symptoms of autistic behavior, and within three months, he was severely damaged.

Dr. Wakefield, in his very professionally written article, described each case carefully, history, blood work, colonoscopy findings, and histo-pathological reports, etc. He went on to review the work of several distinguished researchers in different fields, who were also looking at the causes of Autism, and had developed tests, or suggested therapies.

Dr. Wakefield had no choice but to mention that many parents reported some temporal relationship between the MMR vaccine administration, and the onset of their children's autistic symptoms. As an ethical researcher he could not in all conscience, "bury" such a frequently reported association, and he urged other disciplines to study the problem. Although full of medical terms, Dr. Wakefield's paper was clear, and easy to understand, even by a lay person. Findings were factual, and all conclusions were justified, logical, and fully supported by the evidence presented.

The immediate result of Dr.Wakefield's paper was a vitriolic attack from every front. A flood of opposing articles appeared in the same issue of Lancet, and systematic criticism, nearing persecution, of this decent researcher began, and is still going on.

Distraught parents of affected children have become even more confused, because no one has been able to prove conclusively to them yet, that an MMR vaccine-Autism connection does not really exist. There have been no safety follow-up studies looking beyond four weeks post vaccination, and many studies quoted, have been partially funded by vaccine manufacturers, with obvious commercial interests.

Indeed, no serious researcher has looked at a large sample, three to nine months post MMR vaccination, when auto-immune diseases usually would occur. When some parents in England became vocal, the pro-vaccine authorities in the UK reacted forcefully, to protect their MMR vaccination program. The single measles, mumps and rubella vaccines effectively became unavailable, and every effort was made to prove Dr. Wakefield wrong.

The Medicines Control Agency and The Public Health Laboratory Service supported a study, to be carried out by the Department of Community Child Health Royal Free, Dr. Wakefield's own institution, and University College Medical School, London.

Again, it is important to repeat here, that Dr. Wakefield never said there was a causal relationship between the MMR vaccine and autism. The just published study by Taylor et al was hailed by everyone as the definitive work on the subject, .......but is it?. I personally believe it has raised more questions than it has answered.

Dr. Taylor's paper seems difficult to read and understand. The summary findings are confusing, and the whole report is full of statistics, symbols and figures, clearly for the purpose of proving that the conclusions are unquestionably true. Case series analysis is a very weak statistical approach, and can only reliably suggest or refute relationships in very large samples. The samples in this case are small. The methodology used is therefore of marginal quality, and the authors readily acknowledge its limitations.

Dr. Taylor and associates also present some data as graphs, without text support. This makes it impossible for the reader to check said graph data for accuracy, and tends to disguise the very small sample size used. It is customary that study results are written as a text, and then, a chart or a graph can be added, to emphasize a point. The authors report numbers clearly indicating a massive and persistent increase in autism over the years. They then do not offer any sensible cause for that increase to negate an MMR connection, and choose to conclude simply that their study fails to prove any causal relationship.

Elsewhere, Dr. Taylor and associates, state that the age of diagnosis was the same before and after the introduction of the MMR vaccine, and then go on to deduct, that this is proof that the MMR vaccine therefore does not have a causative role, a conclusion I have difficulty with.

On page 6, Dr. Taylor states in his discussion, in the last paragraph, that "There is uncertainty about whether the prevalence of autism is increasing". This totally contradicts all what he reported through the article, and particularly the statement which immediately followed, "Our study is consistent with an increase in autism in recent birth cohorts." It also contradicts the most impressive California report to the legislature. and my own, Autism 99, A National Emergency, in which I have clearly demonstrated a four to seven fold increase in the incidence of Autism in the last seven years.

On page 7, third paragraph, Dr. Taylor states: "For age at first parental concern, no significant temporal clustering was seen for cases of core autism and atypical autism, with the exception of a single interval within six months of MMR vaccine associated with a peak in reported age of parental concern at 18 months." In the next paragraph, Dr. Taylor states, " Our results do not support the hypothesis that MMR vaccination is causally related to autism ". I am personally unable to understand how he can make such a deduction after he himself reported a peak.

But by far, the most serious problem I have with this study, is the case selection, ie the very data on which the paper is based. The MMR vaccination was started in the UK in 1988. The vaccine was originally administered around age fifteen months to avoid its neutralization by maternal antibodies. ( Lately, this has been changed to twelve months of age.) By selecting children born "after 1987", Dr. Taylor does not include in the post- MMR series, all children born in 1986 and 1987, who reached the age of 15 months in 1988, and received the vaccine at some time that year or later. Also not included were the 2, 3 and 4 year old children, whose parents had not immunized pre 88, and who received the MMR vaccine when it became available, or when the requirement was enforced.

Finally, also excluded from the sample were many children who had received one of the single vaccines (Measles, Mumps or Rubella) from 1983 on, and who were given a booster of MMR in 88 or later. By excluding ALL these children, Dr. Taylor not only removes them from the after 1988 group, but indeed adds them to the pre-1988 statistics. I believe this flaw alone may compromise the whole study.

In the first paragraph, Dr. Taylor and associates state that "we undertook the study to investigate whether the MMR vaccine may be causally associated with autism". It rather seems to me that this study was undertaken to prove that there was no causal association between the two. Similarly, Dr. Taylor states in the last paragraph that his results "will reassure parents and others, who have been concerned about the possibility that the MMR vaccine is likely to cause Autism, and that they will help restore confidence in MMR vaccine".

To my knowledge no one has ever said that the MMR vaccine is "likely" to cause autism. Concerned parents have only requested that independent researchers investigate why certain somehow predisposed children exhibit autistic symptoms shortly after they receive the MMR vaccine. It also seems unlikely to me, that Dr. Taylor's work has helped restore the confidence of those parents in this vaccine. It may soon be apparent that in spite of all the publicity that surrounded the publication of this study, it somehow "has missed the mark". I do not believe Dr. Taylor and associates have significantly changed the picture.

The following facts remain:

  • The incidence of Autism has increased significantly in the last decade.
  • There is every reason to believe that this trend will continue.
  • No one has proved that MMR vaccine plays a role in autism.
  • No one has proved conclusively that it does not.
  • Serious studies by independent researchers are desperately needed, to look into all aspects of this dreadful disease.
  - F. Edward Yazbak, MD, FAAP

[Note: Dr. Yazbak is one of the collaborating physicians of the Autism Autoimmunity Project.]

The above article originally appeared in the June 24, 1999 issue of the FEAT Daily Online Newsletter.

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Elevated Rubeola Titers in Autistic Children and MMR vaccine:

T. Zecca , et al. at the New Jersey Medical School's Children's Hospital of New Jersey in Newark compared rubeola virus in autistic and normal children. Among 16 children diagnosed with autism followed in their clinical practice, they found a 3-fold increase in rubeola titers over expected normal range. A Wilcoxon Kruskal Wallas test comparing 13 rubeola titers from normal children revealed a statistically significant p-value of 0.005.

Subjectively, parents have stated that their children's developmental milestones deteriorated following MMR vaccination. Neurological sequelae following MMR are widely reported. The authors suggested that elevated titers of anti-measles antibodies in autistic children could signify a chronic activation of the immune system against this neurotropic virus, which may play a role in the pathogenic sequences of events leading to autism. They emphasized the need for further studies.

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Vaccination During Pregnancy and Risk for Autism:

F. Yazbak describes six mothers who received live virus vaccines and one received a Hepatitis B vaccine during pregnancy after having received an MMR booster five months prior to conception. All the children who resulted from these pregnancies have had developmental problems, six out seven (85%) were diagnosed with autism, and the seventh seems to exhibit symptoms often associated with autistic spectrum disorders. Since we do not know from this data how many women received vaccines during pregnancy and had entirely normal children, Yazbak's observations may be spurious. Nevertheless, the observation could be important. For a copy of this observation, see: Autism: Is There a Vaccine Connection? Part I: Vaccination after Delivery and Autism: Is There a Vaccine Connection? Part II: Vaccination During Pregnancy.

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Vaccination and the Risk for Autism:

Do vaccines contribute to autism?

A February 28, 1998, report in The Lancet suggested an association among inflammatory bowel disease, autism, and measles-mumps-rubella (MMR) vaccine based on 12 cases. Dozens of heart-rending anecdotal accounts link permanent neurologic disability or death to vaccine use. One of the leading sites in the anti-immunization field is the National Vaccine Information Centre (NVIC).

Some information about the risks and side effects of vaccines on the NVIC site is accurate in spite of its overwhelming emphasis on the risks of vaccination. Nevertheless, as the site states,

"Vaccination is a medical procedure which carries a risk of injury or death. As a parent, it is your responsibility to become educated about the benefits and risks of vaccines in order to make the most informed, responsible vaccination decisions."
A similar statement can be made about any medical procedure.

There area also possible, but unproven links between MMR vaccine and juvenile diabetes, multiple vaccines and autism, and OPV and Gulf War syndrome. Time and further research will tell if these proposed relationships are real.

In the Lancet report, Dr. Wakefield and team from Royal Free Hospital and School of Medicine in London reported a case series of 12 children, referred to their pediatric gastroenterology clinic with a diagnosis of pervasive developmental disorder and intestinal symptoms. These children had lost acquired skills, including communication, after a period of apparent normality. Among eight of the children, the onset of behavioral problems had been linked, either by the parents or the child's physician, with MMR vaccination.

Five had an early adverse reaction to immunization (rash, fever, delirium, and seizures in 3). The average interval from exposure to first behavioral symptom was 6.3 days (range 1-14). Among the remaining 4 children, one received monovalent measles vaccine at 15 months, after which his development slowed. A striking deterioration then occurred in his behavior at age 4.5 years, the day after he received an MMR vaccine.

A second child received the MMR vaccine at 16 months, developing at 18 months a combination of recurrent, antibiotic resistant, otitis media, along with his first behavioral symptoms (lack of interest in siblings and lack of play). A third child received an MMR at 15 months, experienced recurrent "viral pneumonia" for the next 8 weeks, and developed behavioral symptoms 4 weeks after the MMR ( loss of speech development and deterioration in language skills). The fourth child developed self- injurious behavior 2 month after the MMR. Urinary methylmalonic - acid excretion was significantly raised in all children tested (8 of the 12). Ten of the twelve children showed lymphoid nodular hyperplasia of the terminal ileum on endoscopy. The eleventh child had prominent luteal lymph nodes and the ileum was not reached in the twelfth (who had an ulcer in the rectum along with chronic colitis).

Other studies have suggested a link between autism and vaccination. H.H.Fudenberg reported that the first symptoms of autism among 15 of 20 children developed within a week of vaccination. S.Gupta commented on the striking association between MMR vaccination and the onset of behavioral symptoms in all the children he investigated for regressive autism. The MMR vaccine is all live virus. Disintegrative psychosis is recognized as a sequela of measles encephalitis. Viral encephalitis can give rise to autistic disorders, particularly when it occurs early in life.

A genetic association for autism is represented by a null allele of the complement C4B gene located in the class III region of the major histocompatibility complex. The C4B-gene is also crucial for protection against viruses. Affected individuals may not handle certain viruses appropriately; even the attenuated ones used in vaccines. In an addendum to the paper, the authors noted that their sample size had increased to 40 children by Jan 28,1998, with 39 of those showing similar findings.

These studies raise an important provocative point. MMR vaccine may trigger a cascade of events leading to autism in genetically susceptible children. The possibility must be further studied. Unfortunately vaccination among public health and medical practitioners has become almost sacred. Questioning the wisdom of vaccination for certain children is seen as professional heresy. Nevertheless, the possibility cannot be ignored. Could killed MMR accomplish the same task? Should measles be administered separately from mumps? We know that the combination of chicken pox and measles dramatically increases the risk for subacute sclerosing panencephalitis. Perhaps other mixed viral infections are also clinically significant.

More important is the science we must use to explore this. Simply correlation analysis and comparison studies will not suffice. If autism is linked to MMR vaccine in genetically susceptible individuals, unless these individuals are selected from the larger pool, the statistical significance will cancel out. Medical research suffers from a failure to consider interactions and synergy in the disease process. Simple epidemiology will not suffice, since we are not even sure what the potential genetic defect is in autism or if autism is one syndrome or many.

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Action of Secretin Theories

The improvement of some autistic people on secretin has been dramatic. No one knows how secretin brings about behavioral changes. A good review of Secretin can be found at The National Alliance for Autism Research (NAAR) Website

Secretin and cAMP:

Secretin stimulates pituitary adenylate cyclase (via PACAP) which increases intracellular cAMP in certain brain regions. One thought is that secretin administration reverses the lowering of cAMP brought about by opioids.

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Lectins and Secretin:

Lectins are able to bind to cholecystokinin (CCK) receptors and other glycosylated membrane proteins 27. The lectins, wheat germ agglutinin (WGA) and Ulex europaeus agglutinin (UEA-I), are used for affinity chromatography to isolate the highly glycosylated CCK-A receptor of pancreatic acinar cells. In vitro both lectins showed a dosage-dependent inhibition of CCK-8-induced alpha-amylase secretion of acini over 60 min. WGA showed a strong inhibitory effect on amylase secretion, approximately 40%, in vitro. UEA-I caused a smaller, but significant decrease, approximately 20%, in enzyme secretion of isolated acini. Additionally, both lectins inhibited cerulein/secretin- or cerulein-induced pancreatic secretion of rats in vivo, but not after secretin alone. The results are discussed with respect to a possible influence of both lectins on the interaction of CCK or cerulein with the CCK-A receptor.

There are two divergent opinions on secretin--one that high dose secretin is necessary to obtain CNS binding of secretin to receptors in the brain as opposed to the concept that secretin is a neuropeptide and only small concentrations are required (as per oral secretin administration).

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The Concept of Increased Intestinal Permeability

The concept of increased intestinal permeability is key to many theories of autism. Just how important is the integrity of the intestine's mucosal lining to good health? In children in remote tropical regions without access to adequate medical care, progressive damage to the gut's barrier function can eventually lead to life-threatening conditions, requiring them to be airlifted for emergency medical treatment.

Aboriginal children in Australia, for example, have high rates of severe intestinal diseases, or enteropathies, that cause chronic diarrhea. These conditions can lead to dehydration, acidosis, and hypokalaemia - serious complications associated with central nervous system damage and even death.

To shed more light on how these conditions develop, researchers from Australia evaluated intestinal permeability (IP) in Aboriginal children, measuring the rate that two nondigestible sugars are excreted in urine after ingesting a challenge drink. This noninvasive test indicates the gut's ability to absorb nutrients and to block toxins, bacteria, allergens, and other potentially harmful molecules from penetrating into the systemic circulation.

The IP ratio for Aboriginal children with diarrhea was, on average, more than twice as high as that found in their healthy Aboriginal peers. When compared with healthy non-Aboriginal children, these Aboriginal children with diarrhea showed an IP ratio over three times higher than normal. An elevated ratio of larger molecules such as lactuolose to smaller sugar molecules such as mannitol or rhamnose, recovered in the urine sample, indicates increased permeability and mucosal damage. This value is known as the IP ratio.

Surprisingly, a higher IP ratio was found even in healthy Aboriginal children without diarrhea. Researchers speculated that this increased permeability - double that normally found in healthy non-Aboriginal children - was "consistent with an underlying partial villous atrophy," a wearing down of the finger-like projections on the intestine's mucosal layer, caused by environmental factors. For this reason, the Aboriginal children were more susceptible to gastrointestinal diseases and their complications.

How does this all happen? One possible mechanism involves the body's digestion of milk products. Increased IP may reflect damage to the microvilli, which can reduce levels of lactase, the enzyme needed to digest milk sugar, eventually triggering osmotic diarrhea. Once this disease process starts, small bowel mucosal damage, indicated by higher IP ratios, remains "an important factor" associated with increased acidosis, hypokalaemia, iron deficiency, dehydration, and parasitic infection.

Great Smokies Diagnostic Laboratory offers an Intestinal Permeability Assessment. This test is a noninvasive and convenient way to evaluate gut mucosal barrier function in patients with chronic gastrointestinal disorders or in those individuals with a higher likelihood of developing such problems, including patients with chronic inflammatory conditions, especially those using NSAIDS. I use it with my autistic children and monitor the effectivenes of my treatment to reduce intestinal permeability.

Two physicians have written articles that are posted on the Great Smokies' web site: Inflammatory Conditions and the Gastrointestinal Tract, by Myron Lezak. M.D., and Leaky Gut Syndrome: A Modern Epidemic, by Jake Paul Fratkin, O.M.D. Both discuss aspects of intestinal permeability and the conditions related to impaired mucosal function.

I suspect intestinal permeability is very important for autistic children, and that the assay should be routinely used as a means of following the success of therapies for autism.

Reference: Kukuruzovic RH, Haase A, Dunn K, Bright A, Brewster DR. Intestinal Permeability and Diarrhoeal Disease in Aboriginal Australians. Arch Dis Child 1999;81:304-308.

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Gastrointestinal Abnormalities Among Children with Autism

Horvath, et al. (1999)29 evaluated the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. 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. 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.

The authors concluded that unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggested an upregulation of secretin receptors in the pancreas and liver.

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Binstock's Anterior Insular Cortex Hypothesis for Linkage Between Gut and Brain.

Binstock ( has developed a hypothesis to explain the gut-brain relationships for autistic children.

The anterior insular cortex (aIC) links visceral sensation from the gastrointestinal tract with the amygdala and the hypothalamus (1-6). The anterior insular cortex also participates in oral phenomena, object recognition, and naming (5) along with "apraxia of speech" (7,8).

Twenty-five stroke patients with articulatory deficits all had a lesion within "a discrete region of the left precentral gyrus of the insula", whereas this area was "completely spared" in 19 stroke patients without these deficits (7).

Autism-spectrum children with atypical oral habits and/or disorders of naming and of language (9-10) also tend to have a typical gastrointestinal symptoms (11-12). There is also a growing volume of anecdotal data that a small subgroup of autism-spectrum children experiences improved sound production and language use in response to treatments whose focus and effects are gastrointestinal. These treatments include gluten-free and casein-free diets, anti-Candida therapies, anti-viral therapies, and antibiotic therapies (13-19,31,32) suggesting that the underlying neuronal circuitry is intact.

Binstock suggests that the aIC and associated nuclei could become disrupted by at least two mechanisms: (I) intraneuronal migration of a neurotropic virus and/or (II) chronic hyperstimulation of the gastrointestinal tract.

Gesser and colleagues have documented (I) the translocation of HSV from the gastrointestinal tract into the mesenteric nervous system (rats and humans), and (II) the migration of mesenteric HSV as far as theamygdaloid nuclei in rats (20-23). In this theory, viruses could migrate from the gastrointestinal tract through neural pathways into the central nervous system.

Given a high rate of stimulation of neuron pathways reporting gastrointestinalconditions to limbic regions and cortex, neurotransmitter or intracellular-messenger use in excess of their production or recirculation could occur, thereby inducing a change of function of neurons within the aIC.

This hypothesis provides a basis for helping autistic children through treating their gastrointestinal disturbances.


  1. Krushel LA, van der Kooy D. Visceral cortex: integration of the mucosal senses with limbic information in the rat agranular insular cortex. J Comp Neurol 270.39-54 1988.
  2. Mesulam MM, Mufson EJ. Insula of the Old World Monkey. I. Architectonics of the insulo-orbito-temporal component of the paralimbic brain. J Comp Neurol 212.1-22 1982.
  3. Mesulam MM, Mufson EJ. Insula of the Old World Monkey. II. Afferent cortical inputs and comments on the claustrum. J Comp Neurol 212.23-37 1982.
  4. Mesulam MM, Mufson EJ. Insula of the Old World Monkey. III. Efferent cortical output and comments on function.
  5. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev 22.229-44 1996.
  6. Morecraft RJ, Geula C, Mesulam MM. Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. J Comp Neurol 323.341-58 1992.
  7. Dronkers NF. A new brain region for coordinating speech articulation. Nature 384.159-61 1996.
  8. Donnan GA et al. Indentification of brain region for coordinating speech articulation. Lancet 349.221-2 1997.
  9. Peeters T, Gillberg C. Autism: Medical and Educational Aspects. Whurr Pub Ltd 1999.
  10. [Additional Citation]
  11. D'Eufemia PD et al. Abnormal intestinal permeability in children with autism. Acta Paediatrica 85.1076-9 1996.
  12. Horvath K et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999 135.5.559-63 1999.
  13. Bolte ER, personal communication; see also Sandler RH, Bolte ER et al. Possible gut-brain interaction contributing to delayed onset autism symptomatology. Abstract #18, Fourth Int Symp on Brain-Gut Interactions; Neurogastroenterol Mot 10.363 1998.
  14. BR..., Ph.D., Personal communication.
  15. Jane El-Dahr, MD, Personal communication.
  16. Ray Kopp, Personal communication based upon his internet experience with hundreds of parents of autism-spectrum and/or gfcf children.
  17. WM..., MD, Personal communication.
  18. PS..., Ph.D., Personal communication.
  19. Amy Holmes, MD, Personal communication.
  20. Gesser RM et al. Oral-oesophageal inoculation of mice with herpes simplex virus type 1 causes latent infection of the vagal sensory ganglia (nodose ganglia). J Gen Virol 1994 Sep;75 ( Pt 9):2379-86.
  21. Gesser RM et al. Oral inoculation of SCID mice with an attenuated herpes simplex virus-1 strain causes persistent enteric nervous system infection and gastric ulcers without direct mucosal infection. Lab Invest1995 Dec;73(6):880-9.
  22. Gesser RM, Koo SC. Oral inoculation with herpes simplex virus type 1 infects enteric neuron and mucosal nerve fibers within the gastrointestinal tract in mice. J Virol 1996 Jun;70(6):4097-102.
  23. Gesser RM, Koo SC. Latent herpes simplex virus type 1 gene expressionin ganglia innervating the human gastrointestinal tract. J Virol 1997 May;71(5):4103-6.
  24. Bourdois PS, McCandless DL, MacIntosh FC. A prolonged after-effect of intense synaptic activity on acetylcholine in a sympathetic ganglion. CanJ Physiol Pharmacol 1975 Feb;53(1):155-65.
  25. Michael Goldberg, MD, NeuroImmune Dysfunction conference; Bethesda,Maryland, 1999.
  26. Sid Baker, MD, Defeat Autism Now! conference; Cherry Hills, New Jersey,1999.

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Prenatal Aspartamate Exposure

Some parents suspect that prenatal aspartame (NutraSweet) can trigger the auto-immune response that leads eventually to autism. Controversy exists about the potential effects of this artificial sweetener, and about whether or not it has an effect on the developing brain. We agree that there is absolutely no reason for its use. Nancy Markle (1120197) lectured at the World Environmental Council in 1999 on Aspartame, also marketed as Equal and Spoonful.

When the temperature of Aspartame exceeds 86 degrees F, the wood alcohol in Aspartame coverts to formaldehyde and then to formic acid, which in turn causes metabolic acidosis. The methanol toxicity is thought to mimic the symptoms of multiple sclerosis.

Some believe that systemic lupus erythematosis may be triggered by Aspartame. Other practitioners report that lupus improves when diet soda consumption is stopped.

Symptoms of fibromyalgia, spasms, shooting pains, numbness in the legs, cramps, vertigo, dizziness, headaches, tinnitus, joint pain, depression, anxiety, slurred speech, blurred vision, or memory loss have been attributed to Aspartame.

It is thought that the methanol in the aspartame converts to formaldehyde in the retina of the eye, causing blindness.

Aspartame changes the dopamine level in the brain, affecting Parkinson's Disease.

This drug is thought by some to cause Birth Defects. In the Congressional record, Dr. Roberts stated, "It makes you crave carbohydrates, and will make you gain weight." He reported that when he got patients off aspartame, their average weight loss was 19 pounds per person. The formaldehyde stores in the fat cells, particularly in the hips and thighs.

Aspartame is thought to make diabetic control especially problematic.

Memory loss is thought to be due to aspartic acid and phenylalanine being neurotoxic without the other amino acids found in protein. They may go past the blood brain barrier and deteriorate the neurons of the brain. Dr. Russell Blaylock, neurosurgeon, said, "The ingredients stimulate the neurons of the brain excessively, causing ... damage of varying degrees.

Dr. Blaylock has written a book entitled Excitotoxins: The Taste That Kills (Or, Publisher: Health Press: 1-800-643-2665).

Dr. H.J. Roberts, diabetic specialist, has written a book entitled Defense Against Alzheimer's Disease : A Rational Blueprint for Prevention ( Or, 1-800-814-9800). Dr. Roberts believes that aspartame poisoning is escalating Alzheimer's Disease.

Dr. Roberts says, "consuming aspartame at the time of conception can cause birth defects."

"The phenylalanine concentrates in the placenta, causing mental retardation," according to Dr. Louis Elsas, Pediatrician Professor -Geneticist, at Emory University in testimony before Congress. In the original lab tests, animals developed brain tumors (phenylalanine breaks down into DXP, a brain tumor agent).

We recommend avoiding aspartame, since it has no nutritional value and appears to contribute to weight gain overall, rather than weight loss. While its effects on the developing brain are largely speculative, it clearly has no benefits, is not a food, and should be avoided. Apparently, the term "diet drink," is a misnomer.

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Vitamin A Deficiency and Autism

Research is currently being conducted by Dr. Mary Megson on a connection between Vitamin A deficiency and Autism. Children are receiving either Vitamin A or placebos to study effect on behavioral and biological symptoms. According to the World Health Organization, approximately 250 million children worldwide have Vitamin A deficiency. While these statistics refer to primarily developing nations, researchers are beginning to examine a link between Vitamin A deficiency and Autism.

Autistic children may have a Vitamin A deficiency because of gastrointestinal inflammation caused by Leaky Gut syndrome, allergies or viral infections. Vitamin A deficiency is the leading cause of treatable blindness in the world. This important vitamin is necessary for the health of every organ in the body. It is essential for normal growth and development, cell growth and repair, especially in bones, teeth, collagen and cartilage. Vitamin is known as a natural anti-infective and anti-viral agent.

Vitamin A can be found naturally in animal products like liver and whole milk and cold water fish like salmon and cod. Cod liver oil is an excellent source of Vitamin A. For further information about Vitamin A deficiency and Autism see the links below.

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Orphanin Protein: Orphanin FQ/nociceptin (OFQ/N)

A brain protein may modulate the level of anxiety experienced by those who are exposed to novel or threatening environments.28 The protein has been discovered by researchers at the University of California, Irvine. Mice who lacked the gene required to produce the OFQ/N protein display ''increased anxiety-like behavior when exposed to a novel and threatening environment.'' OFQ/N is concentrated in several areas, including the hypothalamus and amygdala. These brain areas are essential for modulating stress reactions.

The chances that OFQ/N has a similar function in humans is very high (since) the protein is identical between rat, mouse, and human and is made in the same brain regions in all three species.

The protein is relevent to autism in that it might explain the exaggerated anxiety experienced by some developmentally disabled children. Future interventions may develop based upon manipulating the levels of this protein in key brain areas.

[Return to "Quick-Index" of Theories of Autism]

Smoke and Air Pollution May Be Related to Learning and Behavioral Problems

The following appeared in Science Total Environment in January, 1989. While the reference is old, the problem is not:

"The Effect of Ambient Cadmium Air Pollution on the Hair Mineral Content of Children"

Stewart-Pinkham, SM
Neurobehavioral Toxicologist
Columbus, OH 43212.

"Hair analyses of 80 children with learning and behavioral problems were assessed by age, sex, season, place of residence, exposure to passive smoke and excess contact with known cadmium air pollutant sources. All children had been exposed for at least 2 years to air pollution from a refuse-derived fuel incineration plant.

All of the patients had increased hair cadmium compared with a control group, but there was a strong seasonal influence on hair cadmium. Exposure to cadmium was ubiquitous. A neurobehavioral toxic effect was found in children who showed evidence of inhibition of pyrimidine-5'-nucleotidase by low hair phosphorus levels and low zinc levels in whom there was enhanced lead absorption.

Hair analyses appear to be a useful biological monitor for detecting toxic effects from ambient air cadmium levels in subsets of the population at risk for heavy metal toxicity. Air filter measurements appear worthless for detecting environmental contamination with cadmium in air with low levels of lead. Trees, on the other hand, which are more adversely affected by cadmium than other heavy metals, show evidence of inhibition of pyrimidine-5'-nucleosidase by excess seeding. "

Reference: Sci Total Environ 1989 Jan;78:289-96

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1.   Pfeiffer A, Herz A. Endocrine actions of opioids. Horm Metab Res 1984 Aug 16:8 386-97

2.   Drucker DJ, Shi Q, Crivici A, Sumner-Smith M, Tavares W, Hill M DeForest L, Cooper S, Brubaker PL.Intestinal response to growth factors administered alone or in combination with human [Gly2] glucagon-like peptide 2.

Address: Department of Medicine, Toronto Hospital, University of Toronto, Ontario

3.   Drucker DJ. Glucagon-like Peptides. Diabetes 1998 (Feb): 47:159-169

4.   Panksepp J. Commentary on the possible role of oxytocin in autism [letter]. J Autism Dev Disord 1993 Sep 23:3 567-9

Modahl C, Fein D, Waterhouse L, Newton N. Does oxytocin deficiency mediate social deficits in autism? [letter],J Autism Dev Disord 1992 Sep 22:3 449-51

Fein D, Allen D, Dunn M, Feinstein C, Green L, Morris R, Rapin I, Waterhouse L. Pitocin induction and autism [letter]. Am J Psychiatry 1997 Mar 154:3 438-9

5.   Bondy CA, Whitnall MH, Brady LS, Gainer H. Coexisting peptides in hypothalamic neuroendocrine systems: some functional implications. Cell Mol Neurobiol 1989 Dec 9:4 427-46

6.   Summy-Long JY, Miller DS, Rosella-Dampman LM, Hartman RD, Emmert SE. A functional role for opioid peptides in the differential secretion of vasopressin and oxytocin. Brain Res 1984 Sep 10 309:2 362-6

7.   Warren RP, Immune abnormalities in patients with autism.J. Aut. Devlopm. Disord. 16:189-197 (1986)

Singh VK , Immunodiagnosis and immunotherapy in autistic children. Ann. N Y Acad Sci 540:602-604 (1988)

8.   Singh VK, Lin SX, Yang VC. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998 Oct; 89 (1):105-8

9.   Warren RP, et. al. Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiat 29:873-877 (1990)

10.   Warren RP, et. al. Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiat 29:873-877 (1990)

11.   Warren RP, et. al. Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics (1992, in press)

12.   Singh VK, et .al. Changes of soluble interleukin-2, interleukin-2 receptor, t8 antigen, and interleukin-1 in the serum of autistic children. Clin Immunol Immunopathol 61:448-455 (1991)

13.   Todd RD and Ciarnello RD. Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proc. Natl. Acad. Sci., USA 82:612-616 (1985)

14.   Weizman A, et. al. Abnormal immune response to brain tissue antigen in the syndrome of autism. Am. J. Psychiat. 7:1462-1465 (1982)

15.   Singh VK, et. al. Abnormalities of interleukin-2 production and levels of IgG isotypes in autistic patients. The FASEB J. 3:A496 (1989)

16.   Bauman ML. Microscopic neuroanatomic abnormalities in autism. Pediatrics (Suppl.) 87:791-796 (1991)

17.   Trevarthen C. Cerebal embryology and the split brain. In: Hemispheric Disconnection and Cerebral Function ( M. Kinsbourne & W. Smith,eds. ). pp. 208-236 (1974), Charles C. Thomas Publ., Springfield, Ill.

18.   Musiek FE, et. al. Myelination of the corpus callosum and auditory processing problems in children: theoretical and clinical correlates. Seminars in Hearing 5:231-241 (1989)

19.   Brandtzaeg P, et. al. (Institute of Pathology, University of Oslo, Rikshospitalet, Norway). Production and secretion of immunoglobulins in the gastrointestinal tract. Ann Allergy 1987 Nov; 59 (5 Pt 2): 21-39

20.   Brandtzaeg P, et. al. The human gastrointestinal secretory immune system in health and disease. Scand J Gastroenterol Suppl 1985; 114:17-38

21.   Ref: Peter Nathan.The Nervous System, (Philadelphia: J.B. Lippincott, 1969), p.296

Leslie Hart. Human Brain and Human Learning, (New York: Longman Inc., White Plains) Books for Educators, Oak Creek, CA, p. 119

22.   ibid. [Hart, p. 118]

23.   Journal of the American Medical Association. July 3, 1926, p. 45

24.   Poser CM. Neurological syndromes that arise predictably. Consultant; January 1987; pp. 45-46

25.   Science; March 4, 1977

26.   Herroelen, De Keyser J, Ebinger G. CNS demyelination after immunization with recombinant hepatitis-B vaccine. Lancet; 338; November 9, 1991; 1174-1175

Brezin AP, Lautier-Frau M, Hamadani M, Rogeaux O. Loss of Vision and Eosinophilia after Recombinant Hepatitis-B Vaccine. Lancet, Italian Edition, April, 1994

27.   Mikkat U, Damm I, Schroder G, Schmidt K, Wirth C, Weber H, Jonas L. Effect of the lectins wheat germ agglutinin (WGA) and Ulex europaeus agglutinin (UEA-I) on the alpha-amylase secretion of rat pancreas in vitro and in vivo. Pancreas 1998 May; 16(4):529-38

28.   Reinscheid, et al.   Proceedings of the National Academy of Sciences USA 1999; 96:10444-10449

29.   Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. Gastrointestinal abnormalities in children with autistic disorders . J Pediatr 1999;135(5):559-63.

30.   Wing L. The Autistic Spectrum . London: Constable, 1996, pp. 68-71.

31.   Laura J. Ruede, MLS. Reply To: "The ABCs of MMRs and DTPs: Is There an Association Between Vaccination and Autism?", by Eric London . A Bibliographic Essay, rev. 5-17-99 ) .

32.   Capdevila A, Decha-Umphai W, Song KH, Borchardt RT, Wagner C. Arch Biochem Biophys. 1997 Sep 1 345:1 47-55 .

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