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EDITORIALS: Peter Szatmari The causes of autism spectrum disorders BMJ 2003; 326: 173-174 [Full text]

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Explanation of, and Cause of Increase, Autism

James M. Howard   (24 January 2003)

Book for parents and carers

Terri-Anne Simmonds   (24 January 2003)

The Tapestry Model

Lisa C Blakemore-Brown   (25 January 2003)

Abnormal Brain Structure & Autism

Alan Challoner   (25 January 2003)

My humble opinion

M Freeman   (26 January 2003)

Dietary intervention

Edwin J van Beek   (26 January 2003)

Re: My humble opinion

Alan Challoner   (27 January 2003)

Asphyxia at Birth Merits Investigation as the Cause of Autism in Some Children

[Eileen] Nicole Simon   (27 January 2003)

A Differing view

Linda S. Carlton, Mary Helen Brauninger   (27 January 2003)

Remaining doubts about autism spectrum.

Thomas David Simpson   (1 February 2003)

Autism as a 'genetic' condition

Robert A Jensen, None   (2 February 2003)

Re: Remaining doubts about autism spectrum.

Alan Challoner   (2 February 2003)

There are indeed knowns: "The causes of autism spectrum disorders"

Kathleen M. Dickson   (7 May 2003)

The causes of autism and schizophrenia

Silvio Loddo   (29 June 2003)

Explanation of, and Cause of Increase, Autism 24 January 2003
James M. Howard, independent biologist 1037 North Woolsey Avenue, Fayetteville, Arkansas 72701-2046, U.S.A. Send response to journal: Re: Explanation of, and Cause of Increase, Autism	The increase in autism, in California and elsewhere, may be caused by the same mechanism that causes the "secular trend," the increase in size and earlier puberty currently ongoing in the U.S. My work suggests the secular trend is produced by an increase in percentage of individuals of higher testosterone in society. (Some say the secular trend is due to better nutrition; better nutrition simply accelerates the reproductive rate of individuals of higher testosterone.) The increase in percentage of individuals of higher testosterone increases their characteristics in society; as they increase we begin to perceive these characteristics over time. These characteristics include pathologies such as increased breast cancer, obesity, small birth weight, decreased ability to learn English and mathematics, etc. As they increase their percentage, they increase the incidence of these pathologies. Of interest here, of course, is the increase in autism. I contend the characteristics, above and of autism, are due to the effects of increased testosterone reducing the availability of the hormone, dehydroepiandrosterone (DHEA). In the case of autism, Manning, et al., have already suggested that increased testosterone may be involved in autism (Dev Med Child Neurol 2001 Mar;43(3):160-4). Therefore, I suggest that the increase in testosterone, and the other characteristics listed above, are the result of the increase in individuals of higher testosterone and pathologies associated with this group. (The mechanism is simple. Individuals of higher testosterone are more sexual and aggressive, they reproduce faster. Women of higher testosterone expose their fetuses to higher testosterone levels, which may be the source of these increased pathologies.) A simple, single mechanism may account for all of these problems. This may be why these are occurring simultaneously. Increasing autism may be due to an increase in the percentage of individuals of higher testosterone in our society. Competing interests:   None declared
Book for parents and carers 24 January 2003
Terri-Anne Simmonds, Communications Coordinator 2902 Send response to journal: Re: Book for parents and carers	The Australian Early Childhood Association (AECA) has released an excellent publication, Autism Spectrum Disorder and Young Children, written by Diana Roe. The book identifies the different types of Autism Spectrum Disorders and how a child is assessed for Autism Spectrum Disorder. The book also provides wonderful suggestions for carers and parents in understanding and communicating with children with an Autism Spectrum Disorder. For order information, please contact Terri-Anne Simmonds from AECA at tsimmonds@aeca.org.au Competing interests:   None declared
The Tapestry Model 25 January 2003
Lisa C Blakemore-Brown, Independent Psychologist/Specialist in Autistic and ADHD Spectrum Disorders UK Send response to journal: Re: The Tapestry Model	Peter Szatmari writes ' Modelling studies have shown that multiple genes in interaction probably account for the genetic complexity underlying the disorder.w2 5 These data do not exclude an environmental risk factor as well; as long as it is understood that "environmental" in this context can include any event after fertilisation.' For some years now I have proposed using the `tapestry` model to understand the complexity of autism in its varied contexts and the co- morbid disorders mentioned by Peter Szatmari. (1) There is no single explanation but we must push at the edges to find the interacting variables whose interweave results in autism. I am very pleased to see reference to the erroneous mother blame but it is not the case that this is no longer happening. Indeed, after decades of better understanding about the inherited `threads` of autism, Munchausen Syndrome by Proxy ensured that we stepped back not just decades but centuries. As developmental disorders increased and/or we recognised them more, we reverted to the easy method of blaming mothers for making them up or causing them. Mother blame has dramatically increased over the last decade or so and irrespective of whether the MMR vaccine or any other is implicated as part of the causal autism tapestry, my greatest concern has been the vilification of parents, particularly women, especially whose children have regressive autism. The cross they bear weighs heavy from the moment their child changes from a normal child to one sinking into autism and virtually unreachable. The hearts and souls of loving parents are forever branded, the impressions deeper with every visit to a professional who denies their child's regression or their autistic behaviour, especially when the progression or presentation may not appear to precisely meet current sets of criteria - but may, in fact, meet multiple aspects of many in a strangulating tapestry which no-one will acknowledge. I maintain that these lost children are the most at risk, most likely form the largest goup and I propose the tapestry model as a respectful model to explore causality, presentation, efficacious treatment and evaluation for all children with developmental disorders. 1. Reweaving the Autistic Tapestry. Blakemore-Brown. Jessica Kingsley 2002 Competing interests:   None declared
Abnormal Brain Structure & Autism 25 January 2003
Alan Challoner, Retired LL18 5UR Send response to journal: Re: Abnormal Brain Structure & Autism	Abnormal Brain Structure & Autism Professor Peter Szatmari in his Editorial [1], misses important aetiology of autism spectrum disorders. Although he includes a brief note on environmental risk factors, he omits toxic considerations. He goes on to write that the measles, mumps and rubella vaccine is not an environmental risk factor, but omits any reference to the diphtheria, pertussis and tetanus (whole cell) vaccine. It is now accepted that constituents of the whole cell DPT vaccine can pass the blood/brain barrier. If they do so, they then can cause sporadic damage to the brain. Abnormal brain structure has been put forward by researchers looking for a cause for autism. These have involved the amygdala, the hippocampus, the cerebellum and the caudate nucleus. Eric Courchesne et al have shown that neo-cerebellar damage impairs the ability to rapidly and accurately change attentional maps during shifts of attention between auditory and visual information as well as between perceptual domains within the visual modality. During recent studies they have attempted to reveal the underlying causes of autism using a variety of techniques. Particular emphasis was placed on techniques that have been used by a number of different laboratories, including structural magnetic resonance imaging and post-mortem studies of neuro-anatomy. Neuro-biological and neuropsychological data from individuals across a wide age range were examined from a neuro-developmental perspective. From these recent advances they have developed a growth dysregulation hypothesis of autism. [2] In an earlier study, Courchesne et al, in reinforcing the view that autism involves abnormal regulation of brain growth during early life, show that there is an unusual developmental neuro-anatomic phenotype characterised by hyperplasia of cerebellar white matter, neocortical grey matter, and cerebral white matter at the youngest ages with slowed growth thereafter; slowed growth in the cerebellar hemispheres; and a smaller vermis at all ages examined. [3] They hypothesised the genetic factors most likely underlie this growth abnormality, and suggest that future genetic research might usefully explore linkage between autism and genes that are known to alter white matter development. One example of such a gene is p27, which regulates proliferation of glial and neural cells and affects myelin formation by oligodendrocytes. Loss of the p27 gene may lead to additional glial and neuronal cell divisions before withdrawal from cell proliferation cycles. In mice with this gene knocked out, there was a 250% increase in glial fibrillary acid protein–staining glia cells in the cerebellum and a 30% increase in numbers of neurons in CA1 of the hippocampus. [4] Another important aetiology is excitotoxicity, an involvement that may allow the brain to discard useless connections or reduce poorly functioning neurons. If neurons are stimulated by toxins, lack of oxygen or are affected by genetic programmes, they release glutamate. This process may be involved in stroke, Alzheimer’s disease, and other neuro-degenerative conditions, possibly including schizophrenia. Alternatively, one pathology could trigger the second; although it is unclear how Purkinje neuron loss could trigger excessive axonal or glial/myelin growth in cerebellar white matter, excessive proliferation of excitatory axonal projections might be speculated to lead to pathologic excitotoxicity and Purkinje death. Excitotoxicity as a patho-physiologic factor in autism has previously been proposed. [5] The coexistence of both cerebral and cerebellar maldevelopment may explain why the impairments in higher cognitive functions in autism are pervasive and persistent across the life span. A postnatal period of extreme maldevelopment of these two major brain structures will almost certainly be manifest in aberrant behavioural expression, and it is during this early period (typically 12 to 24 months) that parents most often first express concern about their child’s development. [6] During this developmental period, the human brain undergoes rapid synaptogenesis, expansion of dendritic and axon arbors, and selection of which neuronal elements to keep or eliminate. [7-10] In the normally developing brain, shaping of neural architecture and connectivity is theorised to be significantly influenced or directed by functional neural activity driven by learning and experience. [11-12] In the autistic brain, however, the researchers speculated that growth and elaboration of neural architecture and connectivity occurs prematurely and without being guided by functional experiences and adaptive learning; that is, in early life the autistic brain exhibits premature “growth without guidance.” In addition, the cerebellum and certain cerebral regions may perform analogous, possibly complementary, functions. For instance, in the normal brain, cerebellar cortex is activated by tasks that commonly activate frontal cortex, such as tasks involving working memory, attention, or semantic association. [13-15] Adults with cerebellar lesions show impaired performance on similar frontal lobe tasks, including tests of source memory and executive functions (e.g., shifting attention, cognitive planning, working memory). [16-17] So, the presence of both cerebral and cerebellar defects from the earliest stages of cognitive development would likely result in severe and persistent functional deficits. Abnormally elevated brain neurotrophins and neuropeptides (brain-derived neurotrophic factor, neurotrophin-4, vasoactive intestinal peptide, calcitonin-related gene peptide) have been found in neonatal blood spots of individuals who later developed autism and mental retardation. [18] These brain growth factors play roles in neural proliferation, migration, differentiation, growth, and circuit organisation, and it was hypothesised that abnormal elevations may result in unusual regional growth abnormalities (e.g., overgrowth in the cerebrum due to excessive sparing of neurons and stimulation of growth of neural elements, but, paradoxically, loss of Purkinje cells in the cerebellum [19]). Eric Courchesne et al (idem), further hypothesise that in autism there is a relationship between abnormally elevated brain growth factors at birth and the abnormal brain growth patterns described above. From: Alan Challoner MA (Phil.) MChS 24 January 2003 REFERENCES [1] Szatmari, P. The causes of autism spectrum disorders. BMJ 2003;326:173-174 [2] Akshoomoff N, Pierce K, Courchesne E. The neurobiological basis of autism from a developmental perspective. Dev Psychopathol 2002 Summer 14:613-34 [3] Courchesne, E.; Karns, C.M.; Davis, H.R.; Ziccardi, R.; Carper, R.A.; Tigue, Z.D.; Chisum, H.J.; Moses, P.; Pierce, K.; Lord, C.; Lincoln, A.J.; Pizzo, S.; Schreibman, L.; Haas, R.H.; Akshoomoff, N.A.; & Courchesne, R.Y. Unusual brain growth patterns in early life in patients with autistic disorder An MRI study. Neurology 2001;57:245–254. [4]Casaccia-Bonnefil P, Tikoo R, Kiyokawa H, Friedrich J, Chao M, Koff A. Oligodendrocite precurser differentiation is perturbed in the absence of the cyclin-dependent kinase inhibitor p27kip1. Genes Dev 1997;11:2335–2346.. [5] Gordon WP. Neurotoxic theory of autism. In: Naruse H, Ornitz EM, eds. Neurobiology of infantile autism: proceedings of the International Symposium on Neurobiology of Infantile Autism, Tokyo, 10–11 November 1990: satellite meeting of thejoint convention of the 5th International Child Neurology Congress and the 3rd Asian and Oceanian Congress of Child Neurology.New York: Elsevier Science, 1992:373–376 [6]Cox A, Charman T, Baron-Cohen S, et al. Autism spectrum disorders at 20 and 42 months of age: stability of clinical and ADI-R diagnosis. J Child Psychol Psychiatry 1999;5:719–732. [7] Schade JP, van Groenigen WB. Structural organization of the human cerebral cortex. I. Maturation of the middle frontal gyrus. Acta Anat 1961;47:72–111. [8] Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997; 387:167–178. [9] Quartz SR, Sejnowski TJ. The neural basis of cognitive development: a constructivist manifesto. Behav Brain Sci 1998;20: 537–596. [10]Courchesne E, Chisum H, Townsend J. Neural activity-dependent brain changes in development: implications for psychopathology. Dev Psychopathol 1994;6:697–722. [11] Quartz SR, Sejnowski TJ. The neural basis of cognitive development: a constructivist manifesto. Behav Brain Sci 1998;20: 537–596. [12]Courchesne E, Chisum H, Townsend J. Neural activitydependent brain changes in development: implications for psychopathology. Dev Psychopathol 1994;6:697–722. [13] Allen G, Buxton RB, Wong EC, Courchesne E. Attentional activation of the cerebellum independent of motor involvement. Science 1997;275:1940–1943. [14] Desmond JE, Gabrieli JD, Wagner AD, Ginier BL, Glover GH. Lobular patterns of cerebellar activation in verbal working memory and finger-tapping tasks as revealed by functional MRI. J Neurosci 1997;17:9675–9685. [15] Raichle ME, Fiez JA, Videen TO, et al. Practice-related changes in human brain functional anatomy during nonmotor learning. Cereb Cortex 1994; 4:8–26. [16] Akshoomoff NA. Intramodality shifting attention in children with damage to the cerebellum. J Cogn Neurosci 1994; 6:388– 399. [17] Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998; 121:561–579. [18] Nelson KB, Grether JK, Croen LA, et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol 2001;49:597–606. [19] Morrison ME, Mason CA. Granule neuron regulation of Purkinje cell development: striking a balance between neurotrophin and glutamate signaling. J Neurosci 1998;18:3563–3573. Competing interests:   None declared
My humble opinion 26 January 2003
M Freeman, GP Hawarden Health Centre CH Send response to journal: Re: My humble opinion	Far be it from me as a lowly GP to suggest that autistic spectrum disorder may be a result of sensitive children expressing their humanity (ie. vulnerability) in an increasingly inhuman environment.Also, would not plugging my book count as a competing interest? Competing interests:   None declared
Dietary intervention 26 January 2003
Edwin J van Beek, Senior Clinical Lecturer Radiology RHH, Floor C, Glossop Road, Sheffield S10 2JF Send response to journal: Re: Dietary intervention	I read with interest the editorial on causes of autism. One of the potential causes, allergy induced autism, was not mentioned. As a parent with an autistic child, I have experienced the effects of dietary intervention (as can be confirmed by health professionals and teachers). Although this may be controversial, there are many parents with similar empirical evidence, who have seen amazing behavioural changes following the introduction of restrictive diets (e.g. gluten free, casein free). Given the multifactorial genetic background suggested in the editorial, it may be worthy to investigate metabolic errors of metabolism as a causative factor. Urine samples in our situation revealed abnormal glutomorfines for instance. In this context, a dietary intervention would make sense and the empirical evidence could (partly) be explained. A study into these effects seems warranted. Competing interests:   None declared
Re: My humble opinion 27 January 2003
Alan Challoner, Retired LL18 5UR Send response to journal: Re: Re: My humble opinion	Is it not just such scepticism and unwillingness to search for the truth, that has allowed many autistic children to remain locked into their coping strategies? Further, that such coping strategies are often labelled psychoses and treated with inhuman medication in this “inhuman environment”? Competing interests:   None declared
Asphyxia at Birth Merits Investigation as the Cause of Autism in Some Children 27 January 2003
[Eileen] Nicole Simon, Parent / private researcher ConradSimon.org/ 11 Hayes Avenue, Lexington, MA 02420-3521 Send response to journal: Re: Asphyxia at Birth Merits Investigation as the Cause of Autism in Some Children	The brain abnormalities reported in some cases of autism can be viewed as a variant of Wernicke’s encephalopathy: a bilaterally symmetric pattern of damage involving subcortical nuclei and the cerebellum [1]. Wernicke’s encephalopathy is found in cases of chronic alcohol intoxication and factors, like thiamine (vitamin B1) deficiency that interfere with aerobic metabolism [2]. Prenatal exposure to alcohol is one of the co-morbid conditions associated with autistic disorder [3]. Maternal use of alcohol during pregnancy should be investigated in every case of autism, as should use of all other drugs, like the anti-seizure medication valproic acid [4]. Asphyxia at birth of 8 minutes or more produces a variant of Wernicke’s encephalopathy with prominent damage of the inferior colliculi in the midbrain auditory pathway [5]; asphyxia was inflicted experimentally in monkeys by preventing pulmonary respiration then clamping the umbilical cord. Monkeys allowed to survive several years following asphyxia of even shorter duration developed a “transneuronal”.pattern of pathology involving the cerebellum, hippocampus, amygdala, mammillary bodies, corpus callosum, and temporal and frontal lobe radiations [6] – areas of the brain affected in some cases of autism [7]. Monkeys subjected to umbilical cord clamping and prevented from breathing displayed a transient “hypotonic cerebral palsy;” they recovered normal motor functions but remained hypoactive and were impaired in tasks of short-to-long term memory function [8]. Spastic cerebral palsy was later produced in monkeys subjected to prolonged partial hypoxia during gestation, which produced damage of the motor cortex long associated with cerebral palsy [9]. Meconium aspiration was found associated with autism by Matsuishi et al. [10]. Meconium aspiration is suggestive of an asphyxic insult with increased buildup of carbon dioxide stimulating respiratory attempts in utero. Bodier et al. found autism associated most strongly with complications at birth in cases without other co-morbid causes [11]. Complications at birth are associated with autism and merit as much attention as genetic or other environmental causes [12]. Immediate clamping of the umbilical cord has become a standard practice [13]. Could this explain the increased incidence of autism? Hypovolemia and several minutes of asphyxia can result if the cord is cut before an infant is breathing on his own. The auditory system of the brain is prominently affected by asphyxia at birth, and this deserves investigation as cause of echolalic speech, hyperacusis, verbal auditory agnosia[14], and the auditory attention deficit disorder of children with autism [15]. 1. Torvik A. Topographic distribution and severity of brain lesions in Wernicke's encephalopathy. Clin Neuropathol. 1987 Jan-Feb;6(1):25-9. 2. Vortmeyer AO, Hagel C, Laas R. Haemorrhagic thiamine deficient encephalopathy following prolonged parenteral nutrition. J Neurol Neurosurg Psychiatry. 1992 Sep;55(9):826-9. 3. Nanson JL. Autism in fetal alcohol syndrome: a report of six cases. Alcohol Clin Exp Res. 1992 Jun;16(3):558-65. 4. Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol. 2001 Mar;43(3):202-6. 5. Windle WF. Brain damage by asphyxia at birth. Sci Am. 1969 Oct;221(4):76-84. 6. Faro MD, Windle WF. Transneuronal degeneration in brains of monkeys asphyxiated at birth. Exp Neurol. 1969 May;24(1):38-53. 7. Kemper TL, Bauman M. Neuropathology of infantile autism. J Neuropathol Exp Neurol. 1998 Jul;57(7):645-52. 8. Sechzer JA, Faro MD, Windle WF. Studies of monkeys asphyxiated at birth: implications for minimal cerebral dysfunction. Semin Psychiatry. 1973 Feb;5(1):19-34. 9. Myers RE. Two patterns of perinatal brain damage and their conditions of occurrence. Am J Obstet Gynecol. 1972 Jan 15;112(2):246-76. 10. Matsuishi T, Yamashita Y, Ohtani Y, Ornitz E, Kuriya N, Murakami Y, Fukuda S, Hashimoto T, Yamashita F. Brief report: incidence of and risk factors for autistic disorder in neonatal intensive care unit survivors. J Autism Dev Disord. 1999 Apr;29(2):161-6. 11. Bodier C, Lenoir P, Malvy J, Barthelemy C, Wiss M, Sauvage D. Autisme et pathologies associées. Étude clinique de 295 cas de troubles envahissants du developpment. [Autism and associated pathologies. Clinical study of 295 cases involving development disorders] Presse Med. 2001 Sep 1;30(24 Pt 1):1199-203. 12. Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology. 2002 Jul;13(4):417-23. 13. [No authors listed] Utility of umbilical cord blood acid-base assessment. ACOG Committee Opinion: Committee on Obstetric Practice. Number 138--April 1994. Int J Gynaecol Obstet. 1994 Jun;45(3):303-4. 14. Rapin I. Autism. N Engl J Med. 1997 Jul 10;337(2):97-104. 15. Simon N. Echolalic speech in childhood autism. Consideration of possible underlying loci of brain damage. Arch Gen Psychiatry. 1975 Nov;32(11):1439-46. Competing interests:   None declared
A Differing view 27 January 2003
Linda S. Carlton, Independent Researcher/parent 29414, Mary Helen Brauninger Send response to journal: Re: A Differing view	Heat-killed bacteria’s role in inducing an innate immune response and its possible link to Autism Carlton L Brauninger M Introduction Autism, a childhood disorder whose behavioral symptoms usually manifest within the first few months of life, has been recently linked to environmental causes. This paper presents a hypothesis that autism maybe the result of a 'man-created disease'. History and Today The first known cases of autism seemed to have appeared around the 1940's in America. There were several programs of change happening during those years: the chlorination of water, the pasteurization of milk, and newly established immunizations to protect the health of the public, children and adults alike. (Marr and Malloy 1996) All three of the above mentioned programs were initiated for public safety in the control of bacterial and viral diseases. Many new methods employed today to eliminate or control bacterial growth include low or high temperatures, chemicals, gases, microfiltration, bactofugation, sanitation, and flavors. (Champagne et al 1994) Pasteurization is a process that stops fermentation in which the medium is brought to heat levels sufficient enough to cease the fermentation and kill the bacteria. Vaccine programs also use this method of heat-killing the bacteria and viruses to induce an immune response or tolerance to the disease without infecting the patient. It is commonly known that raw milk will sour, but pasteurized milk will putrefy. The idea that putrefaction of the stools causes disease, i.e. intestinal autointoxication, originated with physicians in ancient Egypt. (Chen and Chen 1989) The toxic process, however, was reversed by the consumption of lactic acid-producing bacteria that changed the colonic microflora and prevented proteolysis. (Chen and Chen 1989) Autointoxication is an ancient theory, based on the belief that intestinal waste products can poison the body and are a major contributor to many, if not all, diseases. (Ernst 1997) By ancient tradition lactic acid bacteria (LAB) are involved in the production of fermented foods. German scientists found that foods rich in (LAB) constitute one quarter of the German diet and are characterized by a safe history, certain beneficial health effects, and an extended shelf life when compared with raw materials. (Hammes and Tichaczek 1994) Microflora - 'early life studies' In Finland, a double blind study showed that when pregnant and lactating mothers and their babies were administered (LAB), the immunoprotective potential of the mother's breast milk was increased. (Rautava et al 2002) The study found that the amount of anti-inflammatory transforming growth factor beta2 (TGF-beta2) in the milk of mothers receiving (LAB) as compared to mothers receiving a placebo was significantly higher. (Rautava et al 2002) It documented that breast-fed babies, unlike bottle-fed babies, have a microbic intestinal flora characterized by a marked predominance of bifidobacteria and (LAB). (Coppa 2002) A breast-fed, full-term baby has a preferred intestinal microbiota in which bifidobacteria predominate over potentially harmful bacteria, whereas, in formula-fed babies, coliforms, enterococci, and bacteroides predominate. (Dai and Walker 1999) It is unlikely, however, that a lower ability to ferment carbohydrates is a major cause of increased risk of diarrhea in formula-fed babies, but individual SCFA production may be important. (Parrett and Edwards 1997) What happens is that the formula-fed baby develops a much different microflora than that of a healthy, full-term, breast-fed baby. Autism & Ammonia- 'behavioral symptoms' In 1989 there appears to be the first documented case of a patient with autistic-like symptoms found to also have abnormal blood ammonia. (Drukker 1989) Dr.Drukker's patient had symptoms of dementia, amnesia, and cognitive disorders. (Drukker 1989) The adult was supposably misdiagnosed as autistic. (Drukker 1989) Later in 2002, Cohen found that by an approximate one-third reduction of GABA and ammonia levels for an autistic patient that there was noticeable improvement of verbal/language skills and a reduction of repetitious, ritualistic, self-stimulatory behavior (stimming). (Cohen 2002) Lactic acid bacteria, lactitol, and lactulose have been clinically shown to reduce blood ammonia. (Loguercio et al 1987)(Vince and Burridge 1980) Ammonia is produced by intestinal-bacteria. (Vince and Burridge 1980) The largest amounts of ammonia is generated by gram-negative anaerobes, clostridia, enterobacteria, and Bacillus spp.. (Vince and Burridge 1980) Gram-positive non-sporing anaerobes, streptococci, and micrococci formed modest amounts, and lactobacilli and yeasts formed very little ammonia; and that ammonia may be formed from bacterial cells in the colon. (Vince and Burridge 1980) Gluten & Casein Laboratory studies have provided evidence that casein, gliadins, and glutenins are hydrolyzed or degraded by fermentation with (LAB), providing better digestibility and cereal tolerance. Dietary lipids influence the gastrointestinal microbiota and specifically, the population of (LAB). (Bomba et al 2002) The favorable protein utilization and body mass increment on fermented milk diets are attributed to a better digestibility of proteins in these products. (Vass et al 1984)(Chebbi et al 1977) Much may depend on the dough acidification or quality of specific (LAB) species, live or heat-killed during processing, whether bleached or unbleached flour is used, pasteurized or raw milk in the making of consumer goods. Several autism studies have hypothesized that the behavioral symptoms in autism occur due to opiate-like activity. Opiates are sleep-inducing drugs, and opioids are natural occurring peptides with similar effects. An example would be that warm milk could induce sleep through a natural release of peptides into the system. In autism there are characteristic symptoms of sleeping disorders. The children were found to have increased urinary peptides. (Whiteley and Shattock 2002) These specific peptides were derived from dietary sources, in particular, foods that contain gluten and casein and are known to produce opiate-like affects. (Whiteley and Shattock 2002) Studies preformed on the effects of beta-casomorphin-7 indicate they activate a histamine release in vitro in the presence of copper (II). (Lodyga-Chruscinska et al 2000) Skin tests with opioid peptides naturally occurring in cow's milk (such as beta-casomorphin-7 and alpha-casein) showed wheal and flare reactions similar to histamine and codeine that were observed in all children. (Kurek et al 1995)(Kurek et al 1992) Beta-casomorphin-7 and alpha-casein are noncytotoxic histamine releasers in humans. (Kurek et al 1995)(Kurek et al 1992) The bioactivities of peptides encrypted in major milk proteins are latent until released and activated by enzymatic proteolysis, e.g. during gastrointestinal digestion or food processing. (Meisel H, Bockelmann 1999) The proteolytic system of lactic acid bacteria can contribute to the liberation of bioactive peptides. ((Meisel H, Bockelmann 1999) Lactic acid bacteria were shown to liberate oligopeptides from beta- and alpha-caseins that contain amino acid sequences present in casomorphins, casokinines, and immunopeptides. (Meisel H, Bockelmann 1999) The further degradation of these peptides by endopeptidases and exopeptidases of lactic acid bacteria could lead to the liberation of bioactive peptides in fermented milk products. (Meisel H, Bockelmann 1999) Autism Microflora According to recent laboratory findings some cases of late, onset (regressive) autism may involve abnormal flora. (Finegold et al 2002) The fecal flora of children with regressive autism showed much higher clostridial counts than that of control children, not unlike those studies done on breast-fed and infant formula-fed babies. (Finegold et al 2002) The more popular among diet choices recommended for autistic children is the casein-free and gluten-free diet. While an elimination diet may avoid the offending proteins, it also removes all dietary sources of lactic acid bacteria. Elimination diets (just as in infant formulas replacing mother’s milk) have inherent gaps that create a need for supplementation of vitamins, minerals, and amino acids; but, it is also the absence of any lactic acid bacteria that makes these diets problematic. In 1983, Siegenthaler suggested that under certain conditions cultured milk, rather than fluid milk, can be used for infant formula and child nutrition as well as for school milk programs.(Siegenthaler 1983) Inappropriate handling of pasteurized milk very often is responsible for a high bacterial count and organoleptic defects.(Siegenthaler 1983) The advantages are the low pH caused by the high lactic acid content that detrimentally affects food spoilage and pathogenic organisms in milk. (Siegenthaler 1983) There is a longer shelf life of the fermented product at ambient temperatures. (Siegenthaler 1983) Fermented milk products contain the enzyme lactase that facilitates digestion of residual lactose even after ingestion. (Siegenthaler 1983) Proinflammatory cytokines Jyonouchi tested innate and adaptive immune responses in children with developmental regression and autism spectrum disorders. (Jyonouchi et al 2001) She found that autistic children produced higher levels of proinflammatory and counter-regulatory cytokines without stimuli than controls. (Jyonouchi et al 2001) Her results indicate excessive innate immune responses in a number of autistic children that may be most evident in TNF-alpha production. (Jyonouchi et al 2001) A fermented-milk, kefir, contains a substance that enhances IFN-beta secretion, the active substance that was identified to be sphingomyelin. (Osada et al 1993-94) The gastrointestinal system is continually subjected to foreign antigenic stimuli from food and microbes. (Schley and Field 2002) Intestinal epithelial cells respond to lipopolysaccharides from gram-negative bacteria. (Vidal et al 2002) Observations suggest that gram-positive organisms from lactic acid bacteria temper this reaction and prevent an exaggerated inflammatory response.(Vidal et al 2002) Summary Sixty-plus years have passed, and autism still remains a mystery. Through the efforts made by modern technology to control bacteria and disease the destruction of non-pathogenic bacteria has disabled our ability to battle disease. The attempt to artificially replace mother's milk has created a flawed and harmful bacterial ecosystem in our offspring. Many rural societies provide a diet that contains sufficient quantities of non-pathogenic bacteria. Dietary proteins are broken down through a process of fermentation with non-pathogenic bacteria. A feasible solution would be to ferment foods as has been practiced for many centuries rather than elimination. Scientific studies have found that the use of antibiotics were futile in the attempt to control harmful fecal bacteria;however, non-pathogenic bacteria has been clinically shown to be effective in studies done on other diseases with far worse conditions. Autism is a behavioral disorder defined by characteristic symptoms that we must better compare with other diseases or conditions to lead us to a stronger association. Heat-killed bacteria induce an innate immune response; however, only live bacteria can repair mucosal barriers. References Bomba A, Bomba A, Nemcova R, Gancarcikova S, Herich R, Guba P, Mudronova D.Improvement of the probiotic effect of micro-organisms y their combination with maltodextrins, fructo-oligosaccharides and polyunsaturated fatty acids.Br J Nutr 2002 Sep;88 Suppl 1:S95-9 Champagne CP, Laing RR, Roy D, Mafu AA, Griffiths MW.Psychrotrophs in dairy products: their effects and their control.Crit Rev Food Sci Nutr 34(1):1-301994 Chebbi NB, Chander H, Ranganathan B.Casein degradation and amino acid liberation in milk by two highly proteolytic strains of lactic acid bacteria.Acta Microbiol Pol 1977;26(3):281-4 Chen TS, Chen PS.Intestinal autointoxication: a medical leitmotif.J Clin Gastroenterol 11(4):434-41,1989 Cohen B.Use of a GABA-transaminase agonist for treatment of infantile autism.Med Hypotheses 2002 Jul;59(1):115 Coppa GV, Bruni S, Zampini L, Galeazzi T, Gabrielli O. Prebiotics in infant formulas: biochemical characterisation by thin layer chromatography and high performance anion exchange chromatography.Dig Liver Dis 2002 Sep;34 Suppl 2:S124-8 Dai D, Walker WA.Protective nutrients and bacterial colonization in the immature human gut.Adv Pediatr 1999;46:353-82 Drukker J.Mother was right; a misdiagnosed syndromeNed Tijdschr Geneeskd 1989 Feb 4;133(5):195-8 Ernst E.Colonic irrigation and the theory of autointoxication: a triumph of ignorance over science.J Clin Gastroenterol 1997 Jun;24(4):196-8 Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson PA, Summanen P, Baysallar M, Tomzynski TJ, Read E, Johnson E, Rolfe R, Nasir P, Shah H, Haake DA, Manning P, Kaul A.Gastrointestinal microflora studies in late-onset autism.Clin Infect Dis 2002 Sep 1;35(Suppl 1):S6-S16 Hammes WP, Tichaczek PS.The potential of lactic acid bacteria for the production of safe and wholesome food.Z Lebensm Unters Forsch 1994 Mar;198(3):193-201 Jyonouchi H, Sun S, Le H.Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression.J Neuroimmunol 2001 Nov 1;120(1-2):170-9 Kurek M, Przybilla B, Hermann K, Ring J.A naturally occurring opioid peptide from cow's milk, beta-casomorphine-7, is a direct histamine releaser in man.Int Arch Allergy Immunol 1992;97(2):115-20 Kurek M, Czerwionka-Szaflarska M, Doroszewska G.Pseudoallergic skin reactions to opiate sequences of bovine casein in healthy children.Rocz Akad Med Bialymst 1995;40(3):480-5 Lodyga-Chruscinska E, Brzezinska-Blaszczyk E, Micera G, Sanna D, Kozlowski H, Olczak J, Zabrocki J, Olejnik AK.Can the 1,5-disubstituted tetrazole ring modify the co-ordinating ability and biological activity of opiate-like peptides?J Inorg Biochem 2000 Mar;78(4):283-91 Loguercio C, Del Vecchio Blanco C, Coltorti M.Enterococcus lactic acid bacteria strain SF68 and lactulose in hepatic encephalopathy: a controlled study.J Int Med Res 1987 Nov-Dec;15(6):335-43 Marr JS, Malloy CD. A brief history and inventory of immunizations. J Public Health Manag Pract 2(1):82-6,1996 Meisel H, Bockelmann W.Bioactive peptides encrypted in milk proteins: proteolytic activation and thropho-functional properties.Antonie Van Leeuwenhoek 1999 Jul-Nov;76(1-4):207-15 Osada K, Nagira K, Teruya K, Tachibana H, Shirahata S, Murakami H.Enhancement of interferon-beta production with sphingomyelin from fermented milk.Biotherapy 1993-94;7(2):115-23 Parrett AM, Edwards CA.In vitro fermentation of carbohydrate by breast fed and formula fed infants.Arch Dis Child 1997 Mar;76(3):249-53 Rautava S, Kalliomaki M, Isolauri E.Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant.J Allergy Clin Immunol 2002 Jan;109(1):119-21 Schley PD, Field CJ.The immune-enhancing effects of dietary fibres and prebiotics.Br J Nutr 2002 May;87 Suppl 2:S221-30 Siegenthaler EJ.The potential value of cultured dairy products for child nutrition.Arch Latinoam Nutr 1983 Jun;33(2):247-56 Vass A, Szakaly S, Schmidt P.Experimental study of the nutritional biological characters of fermented milks.Acta Med Hung 1984;41(2-3):157-61 Vidal K, Donnet-Hughes A, Granato D.Lipoteichoic acids from Lactobacillus johnsonii strain La1 and Lactobacillus acidophilus strain La10 antagonize the responsiveness of human intestinal epithelial HT29 cells to lipopolysaccharide and gram-negative bacteria.Infect Immun 2002 Apr;70(4):2057-64 Vince AJ, Burridge SM.Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose.J Med Microbiol 1980 May;13(2):177-91 Whiteley P, Shattock P.Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention.Expert Opin Ther Targets 2002 Apr;6(2):175-83 Copyright © 2002 COPYRIGHT Carlton L Brauninger M. All rights reserved. Competing interests:   None declared
Remaining doubts about autism spectrum. 1 February 2003
Thomas David Simpson, Consultant child &adolescent psychiatrist Tavistock Clinic London NW3 5BA Send response to journal: Re: Remaining doubts about autism spectrum.	Dear Sir, I am concerned that Professor Szatmari’s editorial ‘The causes of autism spectrum disorder’ is misleading in that it suggests more certainty about the existence of an autism spectrum and about causes of autism that is currently warranted. In fact there remains considerable debate about the validity and usefulness of a broad definition of autism (Volkmar and Klin, 2000). Autism and Asperger’s syndrome, the main contenders for inclusion are distinct conditions and although they share common features, namely difficulties in social relatedness and obsessiveness, they can be distinguished in regard to these. In autism, children are socially withdrawn, while in Asperger’s syndrome they usually desire social contact but cannot negotiate social rules. Furthermore in autism, which unlike Asperger’s syndrome is frequently associated with mental retardation, obsessiveness commonly revolves around routine behaviours and physical objects while those with Asperger’s syndrome frequently display idiosyncratic and often highly intellectual interests. The distinction between autism and Asperger’s syndrome is comparable to that between schizophrenia and schizoid personality disorder. Like autism and Asperger’s syndrome they share common features and genetic loading, however from a clinical point of view their distinction is crucial. The danger of confusing Asperger’s syndrome with autism in a broad definition is that not only that it might hamper research but that it risks over diagnosis. This is an increasing problem in child psychiatry where worried parents of troubled children increasingly demand diagnostic certainty at the risk of error. Professor Szatmari’s categorical statement that autism is a neuro- psychiatric disorder is not only misleading but risks playing into this latter problem. Although neurological problems have a bearing on autism, the relationship remains obscure and the implied claim that autism results from a primary neurological disorder is based on slim evidence. A strong genetic link does not necessary imply neurological damage. Although Professor Szatmari acknowledges environmental influences, he makes no references to the social and emotional environment in which children are raised. Although there is considerable evidence to support the importance of these influences on children’s psychological and brain development, he does not consider that these may play a part in the development of autism. In fact there is evidence for the role of these factors in autism from the studies of Romanian adoptees. (Rutter et al, 1999) Professor Szatmari believes that research findings that support organic causation help temper parental guilt when children have these conditions. From a clinical point of view, it is my experience that helping parents understand and come to terms with their unwarranted feelings of blame about having children with these disorders is more productive than trying to allay their anxiety with premature certainty about causation. References 1. Rutter, M et al. Quasi-autistic patterns following severe early global privation in Journal of Child Psychology and Psychiatry. 40, 537 – 549. (1999) Cambridge University Press. 2. Volkmar, F. R. and Klin, A. Diagnostic Issues in Asperger’s syndrome in Klin, A and Volkmar, F. R. and Sparrow, S. S. (2000) Asperger’s syndrome. New York. London – The Guildford Press.. Dr. David Simpson Consultant Child & Adolescent Psychiatrist Tavistock Clinic, 120 Belsize Lane, London NW3 5BA dsimpson@tavi-port.nhs.uk Competing interests:   None declared
Autism as a 'genetic' condition 2 February 2003
Robert A Jensen, None 08863, None Send response to journal: Re: Autism as a 'genetic' condition	The acceptance of the majority of autism researchers that autism is a strongly genetic condition is puzzling. Most rely on Twin studies and prevelance rates. No doubt genetic susceptability applies to autism related conditions as they do to many conditions that aren't thought to be genetic conditions. The International Registry of HIV infected twins reported a significantly higher concordance in MZ twin pairs compared to DZ twin pairs (1). The risk of mother to fetus transmission of the HIV-1 virus has been reported to be approximetly 25% before treatment regimes were available to pregnant women (2). Maternal HIV research could easily persuade rational investigators that HIV infection is a strongly genetic condition as evidenced by the higher rate of concordance in MZ twins compared to DZ twins and the approximate 25% risk of mother to fetus infection suggests an autosomal recessive method of transmission. Some investigators, including the present author, believe that research into non genetic contributing factors of autism causation (3) is under researched despite such research having the potential to be of more immediate fruition (prevention) than current vast overfunding of genetic research into autism. 1: Goedert JJ, Duliege AM, Amos CI, Felton S, Biggar RJ. High risk of HIV-1 infection for first-born twins. The International Registry of HIV-exposed Twins. Lancet 1991 Dec 14;338(8781):14711. 2.Fowler MG, Mofenson L. Progress in prevention of perinatal HIV-1. National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA. Acta Paediatr Suppl 1997 Jun;421:97-103 3. Jensen RA Autism and the chemical connection. J Autism Dev Disord. 1994 Dec;24(6):785-7. Competing interests:   None declared
Re: Remaining doubts about autism spectrum. 2 February 2003
Alan Challoner, Retired LL18 5UR Send response to journal: Re: Re: Remaining doubts about autism spectrum.	Dr Thomas David Simpson, states that, “Although neurological problems have a bearing on autism, the relationship remains obscure and the implied claim that autism results from a primary neurological disorder is based on slim evidence.” This seems to fly in the face of the evidence, which I posted earlier. There is not doubt in my mind that neurological damage from the DPT (whole cell) vaccination (pertussis element) has a bearing on subsequently diagnosed autism. Toxins passing the blood/brain barrier from other sources also may not be blameless. Competing interests:   None declared
There are indeed knowns: "The causes of autism spectrum disorders" 7 May 2003
Kathleen M. Dickson, Founder and Moderator, ActionLyme Pfizer, Inc (Disabled) Send response to journal: Re: There are indeed knowns: "The causes of autism spectrum disorders"	"No causative factors have been found to differentiate children with autism from children with other disorders on the spectrum such as Asperger syndrome." It's not premature to state that there are genetic differences between Autism and Aspergers. There most certainly are identifiable genetic correlates, and even the molecules identified, and the mutations in the genes in specific types and related phenotypes. Mutations on just Chromosome 15 are pretty *specific* for various types of Autism, yet there are few for Aspergers. We know there is a difference from birth, and in skills differences. Do the research. It's harmful to make uneducated statements. http://www.actionlyme.com/Autism_HFA.htm Autism (High Functioning, Angelman's and Prader-Willi) vs. Aspergers are definitely, identifiably, genetically different. Competing interests:   None declared
The causes of autism and schizophrenia 29 June 2003
Silvio Loddo, Child and Adolescent Psychiatryst Neuropsichiatria dell'età evolutiva, AUSL n.5 Oristano, 09170 Oristano Send response to journal: Re: The causes of autism and schizophrenia	I respect the scientific cautiousness of professor Szatmari, who probably did not want to mention unwarranted hypothesis on the pathophysiology of autism in his recent article on the causes of autistic spectrum disorders [1]. However, I think that a certain number of results from the literature on autism and schizophrenia allow some inferences which might be of interest for the readers of this journal. 1) In autism, as in schizophrenia, the ability of selecting, filtering, giving priority to perceptual data and to organize contextually appropriate answers to those inputs, an ability very often referred to as "executive function(s)" [2], is especially compromised, in a way that qualitatively and quantitatively seems to distinguish these two disorders from other psychiatric disorders. 2) There are surprising analogies between the neuropathological findings in the two disorders: the function and/or the neuroanatomy of the cerebellum, the amygdala, the limbic system, the frontal and the temporal lobes, the thalamus are supposed to be compromised by many authors. Statements by Andreasen [3] on schizophrenia and Riva and Giorgi [4] on autism, amongst others, are strikingly similar and support this assertion. 3) In both autism and schizophrenia there is a specific reduction of the ability to infer other persons' mental states, which has been referred to as a "lack of theory of mind". Interpersonal data are the richest, the most fluid and most complex data to be processed by the human brain. As such, they probably require both dedicated cortical areas and a spacious integrative system, charged with the task of smoothly addressing neural energies toward the source of the stimulus while coordinating other brain functions. Included amongst these other functions are appropriate emotional, verbal and physical answers to inputs and "stand-by" activities (both routinary and emergency ones). To give an example, while we are speaking with an interlocutor we are able to monitor his reactions to our communications and readjust these latter to the level of interest and understanding he demonstrates with his facial expressions and body gestures. We often emphasize the content of our speech through the use of a particular prosody and body language. We keep in an neurally activated state alternative cognitive and behavioral programs, not last amongst them purposeful "fight-or-flight" reactions, should we appreciate the intrusion of an unexpected danger. All these activities are at fault, distorted or less easily accessible in autism and schizophrenia. 4) The main symptomatological difference between autism and schizophrenia, namely the absence of prominent delusions in autism, could be explained by the fact that the two disorders hit the brain at two very different stages of neural development. Schizophrenia manifests itself when ideas and thoughts are already present, well formed and integrated into a centrally coherent, meaningful whole. A failure of the integrative function mentioned above could explain why the affected individual a) detects the presence of those thoughts, b) fails to (fully) appreciate their anarchic endogenous origin and c) is unable to check them for reality testing by matching them with other stored and contextual data. Autism starts when ideas and thoughts are still under construction, so to say. A reduction in the integrative power of the same areas supposed to be dysfunctional in schizophrenia could cause a disorder of meaning, but not the emergence of full-blown delusions, in autism. The home of autism and schizophrenia in the brain is probably not to be searched in a single area, but in a distributed system. In normality, this system could be easily identified as a coordinator of mental functions, possibly the main agency of what has been described as "the self". A single or multiple causes could interfere with the correct development and functioning of this system, by acting in one, or more than one, area of its circuits. In our abilitative experience, early educative interventions seem to contrast this negative effect, to reduce autistic core deficits and secondary symptoms. From: Silvio Loddo, MD, Oristano, Italy, June 29th, 2003 REFERENCES [1] Szatmari, P. The causes of autism spectrum disorders. BMJ 2003;326:173-174 2. [2] Ozonoff, S. (1995). Executive functions in autism. In E. Schopler & G. Mesibov (Eds.), Learning and cognition in autism, New York: Plenum Press. [3] Andreasen, N. C: A Unitary Model of Schizophrenia. Bleuler's "Fragmented Phrene" as Schizencephaly. Arch Gen Psychiatry 1999; 56: 781-787. [4]. Riva D, Giorgi C: The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain 2000; 123: 1051-61. Competing interests:   None declared