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World Community Autism Program

Introduction "Autism is a movement disorder at the cellular level"
    Circadian Rhythm "The relationship of pigment metabolism to circadian and circannual rhythms"
    Transthyretin and xanthophils (lutein)
    Correlates of pathogenesis in autism   "The connection between movement, pigment and known
 scientific data on autism"

Part One:  Autism and Affective disorders: New findings in neurochemistry
    Galanin "Galanin may thus be involved in the manifold functions hitherto ascribed to ascending 5-hydroxytryptamine neurons"
    Kynurenine "A number of neuroactive compounds, the kynurenines, are metabolites of tryptophan"
    Autism a hypoglutamatergic disorder?
    Tetrahydrobiopterin "Severe tetrahydrobiopterin (BH4) deficiency is a naturally occurring model of cerebral catecholamine and serotonin shortage"
    Galanin & Epilepsy "hippocampal galanin acts as an endogenous anticonvulsant via galanin receptors"
    Autism & Anorexia Nervosa "deregulation of the serotonergic neurotransmitter system as a common underlying mechanism"
    Autism, Trichotillomania & Seasonal Affective Disorder (SAD) "Oils and pigments leaving the body through the hair
 and hair follicles may be responsible for the biological responses which result in trichotillomania"

Part Two: Autism - Evolutionary Perspectives "Syndromes with autism show purine synthesis defects and/or pigmentation defects"
    Brain Structure "The size of the brain stem and cerebellar vermis are anatomically altered in autistic children"
     Pellagra "Altered mental status is common in pellagrins"
    The cytochrome P-450 pathway and its relevance to autism "Lutein is an aldehyde and an immune response to lutein
 could produce a similar interference in P450 lipid peroxidation"
    NMDA and NO
    The pterin factor
    Cathepsins

Part Three: Natural pain killers from our immune system "In the autist the substances released back into the body when the macrophage engulfs and removes the pigment can be epoxides, carboxylase and potentially mu opioids."

References
    Introduction
    Part One & Part Two
    Part Three

 Autism is a movement disorder at the cellular level,
 involving the immunomodulation of pigment metabolism. At
 the cellular level pigments are moved about through a
 complex system which explains the relationship of
 pigmentation and movement (1); “both pigment
 aggregation and maintenance of the CPM (central pigment
 mass) are dynein-dependent processes. ” (2) “dynein is
 localized in Purkinje cells of cerebellum and axons of
 central and peripheral nervous systems.” (4)

 “Two of the most consistently observed biological findings
 in autism are increased serotonin levels in the blood and
 immunological abnormalities. A positive relationship was
 observed between elevated serotonin levels and the MHC
 types previously associated with autism.” (10)

 The predominant pathogen that I have identified in my
 research as creating a hapten-type immune response is
lutein, I suggest that  it is  being engulfed and removed
from the body by the cytokine reaction, leading to a
cascade of metabolic responses which is dependent
upon the individual’s genetics, diet and environment (13).
To support this  hypothesis, five years of research has
taken place with  diagnosed autists from around the world
implementing an  individualized lutein free diet. The results
of these efforts  are the basis of this paper.

 As the full potential of an immune response to a pigment
 of this nature is elucidated, it becomes clear that the
 co-occurring disorders associated with autism may or may
 not involve the immune response. However, these
 disorders most often do have a connection to the pigment
 metabolism or pigment genetics. (53)

 Included in either the evaluation criteria or research on
 autism have been behavior, movement, handedness, (29)
 speech pathology, eating disorders(32), hearing
 differences (33), visual anomalies (60) as well as the
 alternative diagnoses of Prader-Willi Syndrome (40), Rett’s
 Syndrome and the co-occurring disorders of
 Hypomelanosis of Ito (34, 35, 36), Angelman Syndrome
 (37,38,39), Anorexia (30, 31), Tuberous Sclerosis (41),
 Usher’s type I and type II, trichothiodystrophy (45), light
 chain storage disorder or Scotopic Sensitivity Syndrome,
 abnormal tryptophan metabolism (46), circadian rhythm
 disturbances as in sleep disorders, Circannual rhythm
 disturbances as in Seasonal Affective Disorder (47),
 trichotillomania (47), blindness and retinal abnormalities
 (48,49), ear discharge (52), vitiligo, adenylosuccinate
 lyase deficiency, xerophthalmia, auto-immunity, Raynaud’s
 phenomena, Hartnup’s Disease (50), Phenolketonuria (59),
 Cytochrome P450 (P for pigment) abnormalities as well as
 diseases with some similar clinical as well as laboratory
 findings such as Xeroderma pigmentosum (42).

Circadian rhythm

 The relationship of pigment metabolism to circadian and
 circannual rhythms was first described in our book (13):
 ‘Many parents of autistic children are now familiar with
 the pineal gland for its role in melatonin secretion. Less
 familiar is the pineal gland’s function as a regulatory gland
 to environmental stimuli, metabolism, immunity, adrenal
 glands, behavior and brain chemistry. The pineal gland
 could be the connecting link in current theories, research
 and treatments for autism. A very important feature to
 note about the pineal gland is that the pineal gland is not
 protected by the blood brain barrier.’ I have mentioned
 that ‘carotenoids are not essential to the human diet’ ref
 (AA) however, the pigments perform regulatory actions
 which can include the role of lutein as the serotonin
 regulator. Serotonin and melatonin are both indoleamines.
 ‘John Panskepp Ph.D. in his article “Melatonin The Sleep
 Master”shares with us the role of melatonin to coordinate
 our “SCN Clock”. “This clock-like control center is situated
 in two small clusters of neurons at the base of the brain
 called the suprachiasmatic nuclei (SCN) which, as the
 name implies, are situated directly above the optic
 chiasm, the place where half the nerves from each of our
 eyes cross over to the opposite halves of our brains. The
 many output pathways from the SCN control practically all
 behavioral rhythms that have been studied, from feeding
 to sleep. When both nuclei are destroyed, animals scatter
 their behavior haphazardly throughout the day instead of
 maintaining a well-patterned routine of daily activities.”’
 (55)

 ‘An unrecognized type of receptor in the eye's retina must
 detect light and help set the body's circadian rhythm
 clock.(BB) Two proteins found in the retina may be those
 previously unknown receptors, which help regulate daily
 rhythms of sleep and activity, hormone release, appetite,
 and other functions. A team of researchers report in two
 papers published that mice lacking normal rods and cones,
 types of light-sensitive receptors on the retina, are still
 able to use light to reset their circadian clocks. (CC)
 ‘Researchers led by Dr. Gijsbertus T.J. van der Horst of
 Erasmus University in Rotterdam, the Netherlands, began
 their research by studying two retinal proteins, the
 “cryptochromes”Cry1 and Cry2. These proteins are very
 similar to proteins that regulate the day/night cycle of
 plants. The team theorized that they might also play a
 role in establishing circadian rhythm in animals. Mice
 deficient in both Cry1 and Cry2 displayed a complete loss
 of normal daily rhythm, according to the investigators.’ “In
 mammals the retina contains photoactive molecules
 responsible for both vision and circadian photoresponse
 systems. CRY1 is expressed at high level in the SCN and
 oscillates in this tissue in a circadian manner. These data,
 in conjunction with the established role of CRY2 in
 photoperiodism in plants, lead us to propose that
 mammals have a vitamin A-based photopigment (opsin)
 for vision and a vitamin B2-based pigment (cryptochrome)
 for entrainment of the circadian clock.” (61)

Transthyretin and xanthophils (lutein)

 "Transthyretin (TTR) in plasma is associated with yellow
 compounds. Their properties differ, and in the chicken
 protein a major yellow compound has recently been
 identified as a carotenoid, lutein, also called xanthophyll.
 The human TTR derivative has chromatographic and
 spectral properties identical to a yellow photochemical
 degradation product of biopterin and a spectrum like that
 of the pterin aldehyde.”(62)

 “Histologic, biochemical, and spectral absorption data
 suggest that the yellow color is due to a xanthophyllic
 pigment, lutein, that is distributed in all retinal layers
 internal to the outer nuclear layer, with greatest
 concentration in the outer and inner plexiform layers.
 Clinically absent in newborns, the pigment gradually
 accumulates from dietary sources and appears to serve
 both as an optical filter, by absorbing blue light and
 reducing chromatic aberration, and in a protective
 capacity, preventing actinic damage.” (64)

 “Transthyretin, a protein synthesized and secreted by the
 choroid plexus and liver, binds thyroid hormones in
 extracellular compartments. This binding prevents
 accumulation of thyroid hormones in the lipids of
 membranes, establishing extracellular thyroid hormone
 pools for the distribution of the hormones throughout the
 body and brain”. (66) (69)

 “Localization of retinol binding protein (RBP) and
 transthyretin (TTR) may indicate a role in the transport
 and distribution of retinol and thyroid hormone,
 respectively, from yolk to embryo prior to establishment of
 the circulatory system.” “Protein proportions
 (transthyretin and transferrin) increased until about 3
 years of age and decreased from then on.” “Studies
 on the physical-chemical properties of these hybrid TTRs
 will help to understand the pathogenicity associated with
 TTR.” “A low molar ratio of retinol binding protein to
 transthyretin indicates vitamin A deficiency during
 inflammation.”(71-74)

  “Carotenol esters in human skin may be formed by
 reesterification of xanthophylls (lutein) following
 absorption. Also, very small amounts of esters may
 circulate in the blood and subsequently accumulate in
 tissues such as skin."(75)

 Small blister-type eruptions and mosquito bite like bumps
 on the skin have been reported with picture
 documentation from autistic children beginning the lutein
 free individualized dietary protocol. It is my hypothesis
 that these prurigo type eruptions are simply agglutination
 of carotenol fatty esters being removed naturally through
 the skin. That the elimination of the pathogen, lutein,
 allows for the utilization of these same type fatty esters
 which are entering the digestive system with
 non-pathogen containing carbohydrates thus accounting
 for the alleviation of the blister-type skin eruptions
 reported consistently in those who had experienced this
 occurrence.

Correlates of pathogenesis in autism

 As we consider the results of an immune response which
 identifies a pigment such as lutein as non-self and
 produces a cytokine reaction we can follow the
 possibilities for outcome of this reaction to the area of
 the brain referenced in the autism research., “ loss of
 cerebellar Purkinje and granule cells occurring early in
 brain development and an immature development of the
 limbic system.”(14) To fully identify the possibility of this
 immune system response and state that autism is a
 manifestation of symptoms brought about by this reaction
 the connection between movement, pigment and known
 scientific data on autism must be shown. Therefore the
 relationship between the purkinje neuron cells, dynein and
 pigment must exist. “Immunohistochemical experiments
 have demonstrated that dynein is localized in Purkinje
 cells of cerebellum and axons of central and peripheral
 nervous systems.”(4) This coupled with the data which
 ‘show that dynein is involved in the homogeneous
 distribution of dispersed pigment’ (2) should be adequate
 to justify the potential of the hypothesis. “Microtubules
 serve as a rail on which motor proteins, such as kinesin
 and dynein superfamily proteins, convey their
 cargoes.”(15)

 There must also be shown the relationship between these
 factors, purkinje cells and pigment, and their relationship
 to the immune system. “Polypeptide subunits from these
 microtubule-based motility factors were detected on
 phagosomes.”(16)

 This information must fit within the knowledge database
 thus collected in relationship to autism. “Ahlsen says that
 GFAP is elevated in all cases of autism or autistic-like,
 whether child or adolescent. This was 47 out of 47 cases,
 which to me means 100%. In autism the levels remain at
 sometimes three times the normal level.” (13,17,18) “Aryl
 sulfatase works chemically rather opposite PST, and I had
 wondered last year if maybe a problem in aryl sulfatase
 would lead to not enough sulfate around to power the
 PST enzyme, which is the scenario described by Rosemary
 Waring’s study of PST in autism.”(13,18,19,20)

 It has been indicated that neurofilament antibody is a
 consistent marker for autism. The neuroglial cells are of
 three types: astrocytes and oligodendrocytes (astroglia
 and oligodendroglia), which appear to play a role in myelin
 formation, transport of material to neurons, and
 microcytes (microglia), which phagocytize waste products
 of nerve tissue. Called also glia. (21) So, if the types of
 neuroglial cells associated with myelin formation are not
 effected, as can be indicated by CSF testing, then we are
 left with the neuroglial cells which are associated with
 phagocytosis. One type of phagocyte cell is the
 macrophage. In the brain this is called myelinophage, in
 the liver kupffer cells. The primary function of these cells
 are to break down and remove substances the immune
 system marks as ‘non-self’. In studies dating back to 1952
 (22) carotenes, bilirubin, methemoglobin and the levels of
 these and other pigment wastes in amniotic fluid have
 been used as a marker to determine the fetal
 environment. Elevated bilirubin is a consistent marker in
 infants later diagnosed with neurological impairment.(23)
 Bilirubin is said to remain in the brain once it has reached
 this destination. However, I believe that with the autist,
 the immune trigger is pigment and that the phagocytosis
 is the immune system’s attempt to remove the hapten
 from the brain through the Cerebral Spinal Fluid, thus loss
 of granule cells (14). Research into the phagocytosis of
 the pigment metabolites (pterins, carotenoids) and the
 improvement for many using dietary intervention removing
 the pigments from their diet leading to improvement and
 ‘symptom free’ results (13) has produced some of the
 most dramatic case histories available. (24, 39)

 Additional evidence to support the linking of this data can
 be included from further research on autism and the
 co-occurring disorder tuberous sclerosis (25) “Altered
 patterns of gangliosides in the CNS might reflect
 important correlates of pathogenesis in autism.” (27) This
 information also has the potential to elucidate the
 intriguing connections between the known and suspected
 co-occurring genetic disorders and autism, especially
 genetic disorders associated with pigmentation. (44) (28)

Part One: Affective disorders

 More recent reports identifying autism as “an affective
 disorder treatable with antidepressants such as Prozac
 (fluoxetine)”(1) have failed to include the information
 identifying the co-occurring “abnormalities in CSF
 (cerebral spinal fluid) which have been reported in
 OCD.”(2) “The prolactin response to d-fenfluramine was
 significantly increased in OCD patients compared with
 controls. The disparate results of studies of 5-HT
 (serotonin) neuroendocrine function in OCD make it
 unlikely that disturbances of brain 5-HT function play a
 central role in the pathophysiology of OCD.” (3) “Results
 indicate that galanin exerts an inhibitory effect via an
 increase in K+ (potassium) conductance in
 5-hydroxytryptamine neurons by acting on a postsynaptic
 receptor. In addition, galanin at low, possibly physiological
 concentrations enhances the inhibitory effect of
 5-hydroxytryptamine at the cell soma level. Galanin may
 thus be involved in the manifold functions hitherto
 ascribed to ascending 5-hydroxytryptamine neurons, for
 example in mood regulation.”(4) These factors may finally
 be the evidence needed to elucidate autism as an immune
 system regulated response. (5, 26, 51, 53)

Galanin
  “The effects on 5-HT release in vivo are most likely
 mediated by a galanin receptor in the dorsal raphe. The
 implications of these findings are discussed in relation to
 the role of acetylcholine in cognitive functions in the
 forebrain and the role of the raphe 5-HT neurons in
 affective disorders.” “A recent study has shown
 that ventral hippocampal galanin plays a role in spatial
 learning and that it has an inhibitory effect on basal
 acetylcholine release.” “Inhibition of cholinergic
 transmission by cosecreted GAL may be enhanced under
 certain conditions.” “Galanin-like immunoreactivity and
 galanin receptors are found in dorsal root ganglion (DRG)
 cells and in dorsal horn interneurons, suggesting that this
 neuropeptide may have a role in sensory transmission and
 modulation at the spinal level. Expression of galanin or
 galanin receptors in the DRG and spinal cord are altered,
 sometimes in a dramatic fashion, by peripheral nerve
 injury or inflammation.” “Overall, galanin appears to
 have inhibitory effects in the central nervous system,
 causing in most cases a potassium-mediated
 hyperpolarization accompanied by a decrease in input
 resistance. Other actions include a reduction in
 presynaptic excitatory inputs and an interaction with
 other applied neurotransmitters. These effects are robust
 and long lasting in most cases.”(5-10)

 Some studies already have identified: “The effects of
 fenfluramine (hydrochloride) [an SSRI] on the behaviors of
 autistic children. Videotaped data favored the subjects
 while on placebo. The implications of this research make it
 difficult to recommend fenfluramine as a treatment for
 autism.”(11)

 Emotional states and lack of emotional expression in
 autism may be a protective measure which cannot be
 maintained under conditions of extreme stress, most often
 a response to change in routine or environment. Hormones
 synthesized from cholesterol: glucocorticoids (cortisol
 corticosterone); mineralcorticoids (aldosterone );
 androgens (testosterone, estrogens, and progestins).
 Some symptoms of metabolic problems in the adrenal
 glands are: in the medulla - increased secretion of
 catecholamines, hypertension, excessive sweating,
 blanching or flushing of skin, tachycardia, headache,
 weight loss, personality changes, signs of increased
 metabolism, constipation, postural hypotension; in the
 cortex, when increased secretion of cortical hormones
 occurs, one of a variety of syndromes may occur:
 Cushing’s syndrome (buffalo hump/moon face), muscle
 wasting, osteoporosis, decreased glucose tolerance,
 atherosclerosis, and systolic hypertension.

 Inositol, like choline, also exists in cells as a phosphatide.
 Current research indicates that inositol lipids appear to be
 intimately involved in Ca mediated control of cell functions
 by hormones and other ligands, in cell proliferation, and in
 the attachment of enzymes to the plaza membranes.
 Stearic and arachidonic acid esterified represent the
 major fatty acids in phosphatidylinositol of mammalian
 tissues. And, current research indicates that each form of
 inositol may have distinct, unique biologic activity. A list
 has been summarized by Mitchell in “Modern Nutrition in
 Health and Disease”: Stimuli whose major effects are to
 produce rapid physiologic responses include muscarinic,
 cholinergenic, adrenergenic, serotonin, histamine
 receptors, angiotensin, vasopressin, and those that bring
 about long term stimulation of cell proliferation.

Kynurenine
 “Approximately 40% of the kynurenine in brain is
 synthesized there, the remainder having come from
 plasma. Tryptophan loading also increases kynurenine
 formation in the brain and in the periphery. Because of
 the formation of kynurenine, which competes for cerebral
 transport and cellular uptake of L-tryptophan, and
 because of substrate inhibition on tryptophan
 hydroxylase, excessively high doses of tryptophan may
 actually decrease the production of cerebral serotonin
 and 5-hydroxyindoleacetic acid.”(15)

 Protein intake needs to be carefully considered in autism
 just as it is in the co-occurring disorder of PKU
 (phenylketonuria). It has been my observation that
 following the ‘food guide pyramid’ would provide protein at
 3 to 4 times the RDA (recommended daily allowance)
 which is higher than the RDI (recommended daily intake).

 “It can be concluded, that reduction of D2-receptors is
 due to loss of cholinergic and GABA-ergic cell bodies in
 the striatum or may be a response to iron deficiency. Low
 serotonergic and high kynurenergic activity may be of
 pathogenetic importance.”(16)

 “Recent studies have revealed that, in addition to
 serotonin, a number of neuroactive compounds, the
 kynurenines, are metabolites of tryptophan. Of these,
 perhaps the most important is quinolinic acid, a neurotoxin
 that acts at the N-methyl-D-aspartate (NMDA) receptor
 and whose precursor responsiveness to tryptophan far
 exceeds that of serotonin. In the central nervous system,
 kynurenines, and in particular quinolinic acid, may
 modulate excitatory amino acid transmission, and may act
 as neurotoxic agents implicated in the pathogenesis of
 several neurologic diseases.”(18)

 Lab tests often indicate a need for ubiquinone
 supplementation. However, the additional supplementation
 can lead to additional neurotoxins. I have found that
 removing the lutein and balancing the nutrient intake
 results in superior outcomes and is the primary method for
 reducing natural opioid production.

Autism a 'hypoglutamatergic disorder'?
 “Based on 1) neuroanatomical and neuroimaging studies
 indicating aberrations in brain regions that are rich in
 glutamate neurons and 2) similarities between symptoms
 produced by N-methyl-D-aspartate (NMDA) antagonists in
 healthy subjects and those seen in autism, it is proposed
 in the present paper that infantile autism is a
 hypoglutamatergic disorder.” “Increased glutamatemia
 may be dietary in origin or may arise endogenously for
 several reasons, among others, metabolic derrangements
 in glutamate metabolism perhaps involving vitamin B6,
 defects or blockage of the glutamate receptor at the
 neuronal compartment, or alterations in the function of
 the neurotransmitters transporters. Increments of taurine,
 an inhibitor, is likely compensatory and calcium
 dependent.”(19, 23)

Tetrahydrobiopterin
  “6R-L-erythro-5, 6, 7, 8-Tetrahydrobiopterin (6R-BH4) is
 known as a cofactor for the hydroxylases of
 phenylalanine, tyrosine and tryptophan and also as a
 cofactor for nitric oxide synthase. 6R-BH4 acts on specific
 membrane receptors to directly stimulate the release of
 monamine neurotransmitters such as dopamine and
 serotonin, independently of its cofactor activity. In
 addition, it indirectly stimulates the release of
 non-monoamine neurotransmitters such as acetylcholine
 and glutamate, through activation of monoaminergic
 systems. In this paper, we briefly review recent
 experimental data, which provide new insights into the
 role of 6R-BH4 as a regulator of neuronal function. We
 also discuss the possibility of treatment by 6R-BH4 of
 neuropsychiatric diseases such as Parkinson's disease,
 Alzheimer's disease, depression and infantile autism.”(20)

 “Severe tetrahydrobiopterin (BH4) deficiency is a naturally
 occurring model of cerebral catecholamine and serotonin
 shortage. …Our data indicate immense hyperprolactinemia
 but few other hormonal disturbances in severe BH4
 deficiency.” “Defects in tetrahydrobiopterin and a
 deficiency of aromatic L-amino acid decarboxylase,
 tyrosine hydroxylase or dopamine-beta-hydroxylase are
 candidate inborn errors for neurotransmitter metabolites
 screening. This investigation has to be considered in any
 child with motor retardation and extrapyramidal
 signs.”(20-21)

 What percentage of individuals diagnosed with autism
 have been screened for inborn errors? Subtle
 improvements in behavior and decreased anxiety have
 been reported consistently when folic acid
 supplementation has been included in an autism
 intervention regimen.

 “Antidepressant treatment effects differ according to
 many variables, including the pre-existing state of the
 organism (e.g. depressed, stressed or normal), the
 species, the duration of treatment and the particular brain
 or peripheral circuits investigated. These examples
 illustrate the complexity found in attempts to identify a
 unitary mechanism of antidepressant drug action.” (24)

Galanin & Epilepsy
 “Thyroid hormone is required for basal and
 estrogen-induced expression of anterior pituitary
 galanin.” “We examined the role of hippocampal
 galanin in an animal model of status epilepticus (SE). We
 suggest that hippocampal galanin acts as an endogenous
 anticonvulsant via galanin receptors. SE-induced galanin
 depletion in the hippocampus may contribute to the
 maintenance of seizure activity, whereas the increase of
 galanin concentration and the appearance of
 galanin-immunoreactive neurons may favor the cessation
 of SSSE. The seizure-protecting action of galanin SSSE
 opens new perspectives in the treatment of SE.” (12,13,26)

 “An abnormal circadian pattern of melatonin was found in
 a group of young adults with an extreme autism
 syndrome. Although not out of phase, the serum
 melatonin levels differed from normal in amplitude and
 mesor. There appears to be a tendency for various types
 of neuroendocrinological abnormalities in autistics, and
 melatonin, as well as possibly TSH and perhaps prolactin,
 could serve as biochemical variables of the biological
 parameters of the disease.”(30)

  “Growth hormone (GH)-releasing hormone (GHRH)
 stimulates GH and slow wave sleep” “It is now well
 established that the balance between the neuropeptides
 growth hormone-releasing hormone (GHRH) and
 corticotropin-releasing hormone (CRH) plays a key role in
 normal and pathological sleep regulation. In addition to
 GHRH, galanin, growth hormone-releasing peptide, and
 neuropeptide Y also promote sleep, unlike ACTH(4-9),
 which disturbs sleep.”(31-32)

 “Galanin is an important target for regulation by many
 hormones, and we postulate that as a cotransmitter,
 galanin acts presynaptically to modulate the secretion of
 GnRH and GHRH, possibly by altering their pulsatile release
 patterns, which in turn influences the release of the
 gonadotropins and GH from the pituitary.” (35)

 “Changes occur in the GH secretory pattern under
 discrete, pathological conditions, such as abnormal
 growth and dwarfism, diabetes, and acromegaly, as well
 as during inflammatory processes.”(36)

Autism and anorexia nervosa
 “The development of anorexia nervosa in a
 high-functioning, early adolescent, autistic female is
 described. This case raises the issue of co-occurrence of
 childhood-onset disorders sharing the phenomena of
 obsessions and compulsions. The role of deregulation of
 the serotonergic neurotransmitter system as a common
 underlying mechanism in these disorders is
 suggested.” “Because of the increase in public school
 programs for severely handicapped children, teachers are
 more likely than ever to be confronted with serious
 medical or psychological problems like anorexia nervosa. If
 programs are to meet the needs of these children in the
 future, service and resource models for the public school
 settings must be developed.”(37-38)

 “An example of self-administered gastric tube nutrition in
 a boy aged 15 years with infantile autism is presented.
 The boy would neither eat nor drink in the normal manner
 since the age of eight years and has gradually
 administered tube-feeding himself. This patient does not
 fulfill the international criteria for the diagnosis of anorexia
 nervosa.”(39)

 “Most autistic children showed a large variation of total
 sleep time. Forty per cent of subjects showed 10% or
 more on coefficient of variation of total sleep time. In the
 retiring and rising time, many subjects tended to show
 late retiring and early rising.”(41)

Autism, Trichotillomania and Seasonal Affective
Disorder (SAD)
 “Our data indicate that the optical pathway participates
 in prolactin regulation.” “Intraocular pressure and
 prolactin measures in seasonal affective disorder (SAD).
 The SAD women had significantly lower IOP and PRL
 values than the control subjects at all four time points
 measured starting from 4.00 p.m. The authors discuss the
 implications of the finding of lowered IOP in relation to
 opposing roles of dopamine and serotonin in prolactin
 secretion in SAD.”(43-44)

 Both seasonal affective disorder (SAD) and
 trichotillomania are reported as co-occurring in autism.
 (42) Oils and pigments leaving the body through the hair
 and hair follicles may be responsible for the biological
 responses which result in trichotillomania.(45)(46) (47)
 The hairpulling greatly dimishes with changes in diet and
 supplementation. Additionally, changes in hair color and
 structure are noted. Eyelash hairs with thick hairbulbs and
 dark pigmentation as well as course structure can change
 to depigmented hairs. In one instance the symptoms of
 co-occurring aldosterism were alleviated in an adult
 female autist.

Autism - evolutionary perspectives
 Evolution of the autism disorder most probably is a result
 of our own medical breakthroughs. The development of
 the original vaccine placing a live attenuated virus inside
 a lipid filled chloroplast has forced our immune system to
 re-evaluate the potential for a chloroplast (carotenoid
 containing plant structure) to harbor a pathogen.
 Agricultural changes including the widespread use of
 pesticides contributed further to the immune system’s
 alert to chloroplasts and pathogens. As the developing
 fetal immune system produces it’s first cytokines which
 set out to identify a non-self pathogen it is reasonable
 that pigments/pterins such as lutein and beta-carotene
 are readily available and easily cross the placental barrier.
 This would occur at the time of development just past
 neural tube closure. Although neural tube closure has
 been suggested as a time for the developmental
 alterations leading to a diagnosis of autism this slightly
 earlier time frame would likely also produce a significant
 population with autism and co-occurring spina bifida. This
 correlation does not exist. The immune response to a
 pigment pathogen would likely result in co-occurring
 disorders of purine, pyrimidine, and pigment metabolism.
 This correlation does exist.

 “Syndromes with autism show purine synthesis defects
 (PSDs) and/or pigmentation defects (PDs)” . (48) (49) By
 continuing to diagnose autism solely on the basis of the
 behavioral characteristics we continue to be deprived of
 the information which could become available should
 screening tests such as that provided to determine PKU
 at birth be implemented. This type of diagnostic tool
 would further increase the database of information
 necessary to establish the connection between autism
 and those diseases, disorders and conditions which lead
 to inevitable miscarriage, fetal distress and early infant
 death. “Disorders in purine and pyrimidine metabolism may
 be difficult to recognize because their recent description
 means many are little known. These disorders should be
 suspected, particularly where the history involves siblings,
 in anaemia, susceptibility to infection, or neurological
 deficits including autism, delayed development, epilepsy,
 self-mutilation, muscle weakness and - unusual in children
 and adolescents - gout.”(50) “Autism is caused by very
 lengthy expansions of (CAG)n, (CGG)n and (GAA)n
 repeats, while schizophrenia results from much smaller
 (CAG)n and (CGG)n repeat expansions.”(48)

Brain Structure abnormalities
 “The neuropeptide galanin (GAL) has been shown to be
 located in the pituitary gland and to modulate the
 secretion of several pituitary hormones. In the human
 pituitary, GAL is almost exclusively located within
 corticotrophs. The possibility exists that GAL produced by
 corticotrophs exerts its action principally through a locally
 mediated paracrine or autocrine mechanism without being
 secreted into the bloodstream.” “Galanin gene
 expression may represent a useful marker for
 differentiating the anterior and posterior cerebellar
 lobes.”(51) (52) (53) (54) (55) (56)

 “Autism may be one of the first developmental
 neuropsychiatric disorders for which substantial
 concordance exists among several independent
 microscopic and macroscopic studies as to the location
 and type of neuroanatomic maldevelopment. Onset might
 be as early as the second trimester. Discovery of the
 etiologies underlying cerebellar maldevelopment may be
 the key to uncovering some of the causes of infantile
 autism.” “The rapid maturation of the pro-dynorphin
 system in the substantia nigra is in contrast to the
 development of the pro-dynorphin system in the posterior
 pituitary where adult-like processing patterns are not
 observed until neonatal day 21”. “The brain stem
 and cerebellar vermis lobules VIII to X were found to be
 significantly smaller in autistic children. This suggests that
 the size of the brain stem and cerebellar vermis are
 anatomically altered in autistic children and that growth
 of the brain stem and cerebellar vermis in autistic children
 is different from normal children.”(11, 58-60)

 “Nerve growth factor inhibits sympathetic neurons'
 response to an injury cytokine: …recent evidence
 suggests that galanin plays a role in peripheral nerve
 regeneration.” “…results suggest that autism may
 involve a type of structural brain impairment different from
 MR.” “These results suggested that significant
 anatomical changes took place in the posterior fossa brain
 structures in the prenatal period in autistic children, but
 were not progressive.” “Results suggest that
 brainstem and vermian abnormalities in autism were due to
 an early insult and hypoplasia rather than to a progressive
 degenerative process.” “Fewer than 35 brains have
 been examined pathologically, none with modern
 techniques. The findings thus far suggest subtle prenatal
 neuronal maldevelopment in the cerebellum and certain
 limbic structures. Abnormalities in distributed networks
 involving serotonin and perhaps other neurotransmitters
 require further documentation.”(62-67)

Pellagra
 “The data suggested that ascorbic acid was rapidly (iron
 accelerated) metabolized to monodehydroascorbate, a
 compound that rapidly reacts with tissue (NADPH) to form
 (NADP). This mechanism could reduce tissue levels of
 (NADPH) such that the feed-back control of tryptophan
 pyrrolase enzyme was depressed. The change in control
 level of the pyrrolase enzyme permitted large quantities of
 tryptophan to be converted into the kynurenine pathway
 products, and a smaller quantity for the serotonin
 pathway. This mechanism could contribute to the
 abnormal tryptophan metabolism found in chronic
 pellagrins with dementia.”(70)

 “Serotonin metabolism is pellagra: Altered mental status is
 common in pellagrins.” “Particular features of clinical
 pellagra: The follow-up of an important number of
 patients during the last three decades has shown a
 substantial difference between the clinical description of
 pellagra in the 40's (the triad: dermatitis, diarrhea,
 dementia) and its clinical aspects today: sun-exposed
 teguments revealing erythema and rapidly becoming
 pigmented and parchment like, dried, parched lips, angular
 stomatitis, lead like sclera fine cornea vascularization;
 gastro-intestinal disturbances: constipation, unjustified
 diarrhea, strange migratory abdominal feelings
 accompanied by ubiquitous dysesthesias. Other
 characteristics of this form of disease are: unexpressive
 look, continuously concerned, thoughtful, anxious or
 frowning, labile mind, headaches, insomnia.” (71-72)

 “Metabolic photodermatoses are diseases in which
 photosensitization reactions, often revealing, are due to
 the accumulation in the skin of an endogenous
 chromophore as a result of a congenital (porphyria) or
 acquired (pellagra) enzymatic disorder.” (73)

 “Pellagra was once a major cause of three behaviorally
 different mental disorders - schizophreniform,
 manic-depressive-like, and phobic neurotic
 - plus drying dermatoses, autonomic
 neuropathies, tinnitus, and fatigue. In this preliminary
 study all three of the corresponding present-day mental
 diseases are found to exhibit, statistically, the same
 pellagraform physical disorders but to ameliorate not so
 much with vitamins as with supplements of a newly
 discovered trace omega-3 essential fatty acid (w3-EFA),
 which provides the substrate upon which niacin and other
 B vitamin holoenzymes act uniquely to form the
 prostaglandin 3 series tissue hormones regulating
 neurocircuits en block. Since present-day refining and
 food selection patterns, as well as pure corn diets,
 deplete both the B vitamins and W3-EFA, the existence of
 therapeutically cross-reacting homologous catalyst and
 substrate deficiency forms of pellagra are postulated, the
 first contributing to the B vitamin deficiency epidemics of
 50-100 years ago, the second to the more recent
 endemic ‘Diseases of Western Civilization’ which express in
 certain genetic subgroups as the major mental illnesses of
 today.”(74)

 “About 1900, modern food selection and processing
 caused widespread epidemics of the B vitamin deficiency
 diseases of beriberi and pellagra which, for genetic
 reasons, often expressed as different diseases ranging
 from bowel and heart disease to dermatoses and
 psychoses. But the B vitamins merely help convert
 essential fatty acids (EFA) into the prostaglandin (PG)
 tissue regulators and it now turns out that, through
 hydrogenation, milling and selection of w3-poor southern
 foods, we have also been systematically depleting, by as
 much as 90%, a newly discovered trace Nordic EFA (w3)
 of special importance to primates and sole precursor of
 the PG3(4) series, even as a concurrent fiber deficiency
 increases body demand for EFA. Since substrate EFA is
 processed by many B vitamin catalysts, an EFA deficiency
 will mimic a panhypovitaminosis B, i.e., a mixture of
 substrate beriberi and substrate pellagra resembling
 vitamin beriberi and pellagra but exhibiting as even more
 diverse endemic disease. It is an assumption that our
 dominant diseases are unrelated to each other.” (75)

 “Although one of the first biological treatments of a major
 psychiatric disorder was the dietary treatment of pellagra,
 the use of diet and dietary components in the study of
 psychopathology has not aroused much interest. …data
 indicate that low serotonin levels alone cannot cause
 depression. Folic acid deficiency causes a lowering of
 brain serotonin in rats, and of cerebrospinal fluid
 5-hydroxyindoleacetic acid in humans. There is a high
 incidence of folate deficiency in depression, and there are
 indications in the literature that some depressed patients
 who are folate deficient respond to folate administration.
 Folate deficiency is known to lower levels of
 S-adenosylmethionine, and S-adenosylmethionine is an
 antidepressant that raises brain serotonin levels. These
 data suggest that low levels of serotonin in some
 depressed patients may be a secondary consequence of
 low levels of S-adenosylmethionine.”(76)

 “A 9-year-old girl presented with a red scaly rash
 confined to sun-exposed areas which started at 2 years
 of age and had the appearance of pellagra. Investigation
 of urinary tryptophan metabolites following an oral
 tryptophan load, showed increased excretion of
 kynurenine and kynurenic acid but reduced excretion of
 3-hydroxy-kynurenine, xanthurenic acid and N1-methyl
 nicotinamide. These results indicated a defect in the
 hydroxylation of kynurenine, an important reaction in the
 synthesis of the nicotinamide nucleotide coenzymes, NAD
 and NADP, from tryptophan. The patient went on to
 develop severe colitis and psychological changes. All her
 symptoms responded to treatment with nicotinamide.” (77)

The  Cytochrome P (Pigment)-450 pathway and its relevance to autism
 Ascorbic acid is a requisite in the diet of man. It may act
 as a reducing agent in enzymatic reactions, particularly
 those catalysed by hydroxylases. Vitamin C is a water
 soluble vitamin crucial for the maintenance of connective
 tissue, wound healing and scar formation. Deficiency is
 known as scurvy and symptoms include dry skin, bleeding
 and swollen gums, bone pains, dental cavities and mouth
 sores.

 The effects of scurvy are due to a failure of the
 hydroxylation of proline residues in collagen synthesis and
 the consequent failure of fibroblasts to produce mature
 collagen. Problems with collagen synthesis are not
 associated with autism or the primary conditions
 co-occurring with autism. This absence of problems with
collagen synthesis is likely a result of certain advantages
which may be afforded the autistic population based on
the immune diversity which results after the immune error
(lutein reaction) occurs. Other advantages may include that
autists do not present with the manifestation of specific
conditions or diseases for which they have been identified
as 'at risk' based on current genetic studies. How the pigment
pathways are altered individually and for the population
have resulted in need for identifying supplements which
can improve outcome. Common supplements such as
ascorbic acid and niacin may result in unexpected adverse
reactions for this 'abnormal' population. Closer study should
reveal that supplements designed to address the specific
needs of this population may include NADH, SAMe and
some hormones (VIP, galanin), enzymes and medications
(oral tiaconazole) not yet available.

“At all concentrations of ADP and collagen used the
 autistic children consistently exhibited diminished platelet
 aggregability; the differences, however, did not reach
 statistical significance.”(78)

 “To determine the role of major chromophores of the
 human retinal pigment epithelium (RPE) in photooxidation
 of ascorbate, we monitored spectrophotometrically rates
 of ascorbate depletion, induced by blue light, in
 suspensions of human RPE melanin, melanolipofuscin and
 lipofuscin and in preparation of pigmented and
 nonpigmented bovine RPE cells. The results clearly show
 that melanin is the key retinal pigment responsible for the
 photosensitized oxidation of exogenous ascorbate.
 Because in the absence of oxygen, no measurable
 oxidation of ascorbate is observed, it can be concluded
 that melanin acts as an electron transfer agent. Biological
 implications of this study remain unclear; however, the
 formation of oxygen-reactive species that accompany
 melanin-mediated photooxidation of ascorbate may
 represent a potential risk to the RPE that should be
 minimized by yet unknown cellular mechanisms.” (80)

  “The role of NADPH--cytochrome P450 reductase and
 cytochrome P450 in NADPH- and ADP--Fe3(+)-dependent
 lipid peroxidation was investigated. The results suggest
 that NADPH- and ADP--Fe3(+)-dependent lipid
 peroxidation involves both NADPH--cytochrome P450
 reductase and cytochrome P450.”(81)

 “polyunsaturated fatty acids are initially reduced to form
 alkoxyl radicals, which then undergo intramolecular
 rearrangement to form epoxyalkyl radicals.” (82)

 “The inactivation of cytochrome P450 2B4 by aldehydes in
 a reconstituted enzyme system requires molecular oxygen
 and NADPH and is not prevented by the addition of
 catalase, superoxide dismutase, epoxide hydrolase,
 glutathione, or ascorbic acid. We conclude that
 inactivation of P450 by aldehydes occurs via homolytic
 cleavage of a peroxyhemiacetal intermediate to give an
 alkyl radical that reacts with the heme.” “Using a
 reconstituted system comprised of purified NADPH-P450
 reductase, P450 and isolated microsomal lipid or pure
 L-alpha-phosphatidylcholine diarachidoyl, a mechanism
 has been proposed for the iron-independent microsomal
 lipid peroxidation and its prevention by ascorbic acid.
 Apparently, ascorbic acid prevents initiation of lipid
 peroxidation by interacting with P450 Fe3+.O2.-.” (84)

 “SOD activity has increased in the mammals which is
 accompanied by a decrease in the L-gulonolactone
 oxidase LGO activity. In fact, there has been an inverse
 relationship between LGO and SOD in the progress of
 evolution. SOD activity is markedly high in the guinea pig,
 flying mammal, monkey and man, the species those lack
 LGO. The inverse relationship between LGO and SOD is
 also observed in rats during postnatal development, that
 is when the new born rats are exposed to high
 concentration of atmospheric oxygen. Recent results from
 our laboratory indicate that ascorbic acid is specifically
 needed for protection of microsomal membranes against
 cytochrome P450-mediated lipid peroxidation and protein
 oxidation, where SOD is ineffective. Data presented in this
 paper also indicate an apparent tissue-specific correlation
 among LGO activity, P450 level and O2.- production
 during phylogenetic evolution.”(85)

 Lutein is an aldehyde and an immune response to lutein
 could produce a similar interference in P450 lipid
 peroxidation thus identifying the need for the minimal
 intake of vitamin C in the autist and the abnormal or
 detrimental effects of megadosing with vitamin C.

 "Human cytochrome P (pigment)450's are pro-oxidants in
 iron/ascorbate-initiated microsomal lipid peroxidation.” (86)

 “Excessive cystine and histidine increased serum
 cholesterol and alpha-tocopherol. Excessive cystine and
 methionine increased liver and kidney alpha-tocopherol
 and ascorbic acid. Excessive tyrosine and phenylalanine
 caused a marked increase in serum copper and
 ceruloplasmin activity, whereas excessive cystine,
 methionine, and histidine caused a decrease in the
 ceruloplasmin activity. Excessive histidine increased liver
 cytochrome P-450, whereas excessive tyrosine markedly
 decreased liver cytochrome P-450.”(87)

 Recent investigations into the use of diet as a therapy for
 autism has resulted in high numbers of children with
 autism being placed on restrictive diets. Abnormal levels
 of cystine and histidine are common in their lab profiles
 prior to implementing the lutein free diet.

 “There are extreme contradictions in the question of an
 optimum intake of vitamin C. Ideal RDA should be based
 on studies with increasing vitamin C doses in which the
 efficiency of the ascorbate-dependent systems would be
 correlated with the vitamin C concentration in the target
 tissues. On the basis of correlations of the hepatic
 vitamin C levels in guinea pigs with the rate of cholesterol
 degradation and the activity of microsomal detoxification
 systems, it is suggested that such intake of ascorbic acid
 is optimum that ensures a maximum body pool and
 maximum steady-state levels of vitamin C in the tissues.
 It is probable that in healthy adults, such a dose ranges
 from 100 to 200mg and that in stress conditions, it
 exceeds 200mg per day.”(88)

 “Long-term or high-dosage consumption of vitamin C may
 play a role in calcium oxalate kidney stone formation. …
 Oxalate excretion increased by about 350% during
 ascorbate ingestion before haematuria. Ascorbate
 concentrations also increased dramatically but appeared
 to reach a plateau maximum. Increasing calcium excretion
 was accompanied by decreasing potassium and phosphate
 values. Clinicians need to be alerted to the potential
 dangers of large dose ingestion of vitamin C in some
 individuals.”(92)

 "Ascorbic acid inhibits lipid peroxidation but enhances DNA
 damage in rat liver nuclei incubated with iron ions: In this
 report we studied DNA damage and lipid peroxidation in rat
 liver nuclei incubated with iron ions for up to 2 hrs in order
 to examine whether nuclear DNA damage was dependent
 on membrane lipid peroxidation. The chain-breaking
 antioxidants butylated hydroxytoluene and diphenylamine
 (an alkoxyl radical scavenger) did not inhibit DNA damage.
 Hence, this study demonstrated that ascorbic acid
 enhanced Fe(II)-induced DNA base modification which
 was not dependent on lipid peroxidation in rat liver
 nuclei.”(93)

 It has been my experience with the implementation of
 individualized dietary intervention and autism that
 excesses are equally as deregulating as deficiencies.
 Some individuals do require higher intake and/or
 supplementation of specific nutrients based on lab work
 and testing identifying individual exposures to toxins, such
 as heavy metals. From the case files, a significant
 regression has been observed with an excessive
 consumption of vitamin C. In one instance an 8 year old
 male child reached symptom free status and was
 declassified. Almost 2 years later symptoms returned. The
 only change identified was an increased intake of dietary
 vitamin C. With a return to the RDI levels of vitamin C (up
 to 60 mg supplementation with additional dietary intake of
 50 to 150 mg) his symptoms were once again alleviated.
 (22)

NMDA and NO
 “Cytokines and NO production could play a role in
 regulation of the blood-ocular barrier function and of the
 development of ocular inflammation.”(94)

 “The data from purification, ligand binding, reconstitution
 and immunochemical studies indicate that there is a group
 of small molecular size proteins (30 to 70 kDa) that form
 what appear to be NMDA receptor complexes. Based on
 cell biological studies of the expression and localization of
 one of the subunits of this complex, the
 glutamate-binding subunit, it appears that this putative
 NMDA receptor plays a key role in neuronal sensitivity to
 NMDA and in neuronal survival in early development.
 However, brain neurons quite clearly express another
 family of proteins which have all functional characteristics
 of an NMDA receptor plus a great degree of variability
 that can account for the varieties of NMDA receptors
 found in brain. If brain neurons are indeed expressing two
 very diverse families of proteins that function as
 glutamate/NMDA receptors, this must be an indication
 that either there is a very selective expression of one of
 these forms in specific neurons or neuronal compartments,
 or that one of these forms of the receptor plays an
 important role in unique functions of the cell, such as
 synaptic plasticity or neurodegeneration.” (95)

 “This study determined if hippocampal AMPA and NMDA
 subunit immunoreactivity (IR) in temporal lobe epilepsy
 patients was increased compared with nonseizure
 autopsies. In humans, these findings support the
 hypothesis that glutamate receptor subunits are
 increased in association with chronic temporal lobe
 seizures, which may enhance excitatory neurotransmission
 and seizure susceptibility.”(96)

 “N-methyl-D-aspartate (NMDA)-activated glutamate
 receptor subunits are invariably expressed in neurons,
 although NMDA-activated currents have been recently
 described in Bergmann glia. To date, the NMDA receptor
 subunit 2B (NMDAR2B) was thought not to be expressed
 in adult cerebellum. Our findings suggest that Bergmann
 glial cells contain the molecular machinary to synthesize
 the NMDA receptor 2B subunit. The role of physiological
 NMDA receptors in the interaction between Bergmann glia
 and Purkinje neurons is not yet known.” (97)

 “Our findings suggest a common mechanism for galanin
 and NOS (NADPH-diaphorase activity) expression.”
 “When galanin (10(-8) M) and the cholinergic agonists
 muscarine and nicotine (10(-6) M) were tested on the
 same astrocyte, all three compounds induced a
 hyperpolarization, suggesting a colocalization of functional
 galanin and cholinergic receptors on the glial
 membrane.”(98-99)

 “NMDA induces NO release from primary cell cultures of
 human fetal cerebral cortex: We and others have
 previously reported that N-methyl-D-aspartate (NMDA)
 induces nitric oxide (NO) release from the rat cerebral
 cortex in vivo. It is crucial to determine if this
 phenomenon also exists in human brain tissue. This is the
 first time, to our knowledge, that extracellular NO
 concentration evoked by exogenous NMDA has been
 directly measured from the fetal human cortical
 neurons.”(100)

 The behavior associated with NO production in the autist
 is maniacal laughter. This symptom can be understood as
 the protective mechanism in a metabolism with elevated
 levels of free radicals. (101) (102) (103)

The pterin factor
 The combination of elements which make up the simplest
 pterin and simplest amino acids are nearly the same.
 When we consider the additional carbons and hydrogens
 (isoprenoids, oil residues, PUFA fats) which are part of the
 metabolites of the fruits and vegetables, then the
 complexity of the plant storage system and the response
 of the human immune system to these foods becomes
 more clearly understood. The most understood immune
 system responses are to amino acids. Recently there have
 been carbohydrate receptors identified. (105). The
 carbohydrate receptor is located on the C5a amino acid
 chain cytokine present on cell walls which is an immune
 component which can trigger many immune system
 responses. It may be significant that serine has been
 identified as part of the cytokine amino acid chain. It is
 possible that the similarities between the identified pterin
 [of which there are many i.e. biopterin, neopterin: pterin
 is the simplest] and the structure of the cytokine could
 provoke an immune system glitch (like a computer virus).
 The immune system is needed to identify ‘self’ or ‘not self’
 and ‘not self’ is then removed. By identifying a substance
 which is nearly identical to the amino acids contained in
 the cytokine there could be the consequence that the
 immune system determines “Self is not self”and this could
 lead to an immune compromised host.

 In August of 1996, lutein pigment was finally identified as
 a pterin (pigment) in Stockholm, Sweden. The pterin
 connection has been elucidated through the research into
 PKU, a disorder of tetrahydrobiopterinhydrofolic acid
 metabolism which is listed as one of 5 conditions likely to
 precede an autism diagnosis. Viral exposure and vaccine
 reactions are additional factors associated with or
 possibly leading to an autism diagnosis. High levels of
 cytokines (immune components which identify non-self
 pathogens) leads to an increase in production of
 macrophage cells (the immune components which engulf
 and remove pathogens) which produce antibodies to
 antigens. So an increased reaction to vaccines and
 viruses could be a result of elevated levels of
 macrophages, and identifying the reason for the elevated
 levels of macrophages (cytokine reaction to a hapten)
 and the knowledge that pterins can act as haptens (106)
 leads to a scientific theory with supportable evidence for
 the removal of specific dietary components to determine
 outcome.

 The lutein pigment is a carotenoid pigment widely
 distributed in fruits, vegetables, meat fats and some
 grains. ‘Biopterin is a hapten without antigenicity’ (107)
 The disorders of pterin metabolism most scientifically
 investigated to date are PKU, Senile dementia of the
 Alzheimer’s type, Methylene tetrahydrofolate deficiency,
 Down’s syndrome, Parkinson’s disease, some types of
 depression, aluminum and dialysis dementia.

Cathepsins
 Just as our gastrointestinal system relies on digestive
 enzymes to perform its functions so the immune system
 components utilize their own special digestive enzymes
 called cathepsins. “Cathepsin B: A lysosomal cysteine
 proteinase which hydrolyzes proteins, with a specificity
 resembling that of papain. The enzyme is present in a
 variety of tissues and is important in many physiological
 and pathological processes. In pathology, cathepsin b has
 been found to be involved in demyelination, emphysema,
 rheumatoid arthritis, and neoplastic infiltration.” (108)

 “The existence of anomalies of tryptophan's metabolism is
 certainly shown in many diseases, however the true
 physiopathogenetic meaning of these metabolic
 alterations is not yet specified. Particularly it is not
 definite if these alterations are the cause of diseases,
 which they appear in, or if they are secondary
 alterations.”(109)

 “The serotonin system has been implicated as a factor in
 some cases of autism since the finding in 1961(Himwich et
 al) of elevated serotonin in the blood of patients with
 autism.”(110)

 To date the lack of understanding of the immune systems
 role in regulation of tryptophan has been a major problem.
 The duel role of tryptophan as a pigment containing amino
 acid as well as its role in binding to pigments makes this
 substance a target for immune system regulation in a
 metabolism which has identified a pigment as a pathogen.
 The specific ways in which the immune system
 manipulates the tryptophan leads to variations most
 commonly referred to as autism spectrum disorders.
 Further complications in understanding this interaction
 occurs as a result of the hapten nature of the
 pigment/pterin lutein.

 “Cathepsin G purified from neutrophil granules triggered
 platelet aggregation and serotonin release independent of
 arachidonic acid metabolites and platelet-activating
 factor formation.”(111) Cathepsin G, similar to
 chymotrypsin is one of the cathepsin proteases which
 have been proven to function in HLA class II mediated
 antigen presentation.

 “Because the major neurologic complication is a peripheral
 neuropathy and the causes of this condition are myriad,
 pyridoxine may cause neuropathy only in patients with a
 pre-existing susceptibility to this condition.” (116) We
 have not been given the assessment to identify
 individuals with the pre-existing susceptibility. “When
 evaluating vitamin B-6 requirements or status in humans,
 protein intake must be considered.”(117)

 Favorable reports on B6 supplementation influence
 caregivers to utilize this information. Identifying the
 nutritional status of the individual could result in a more
 positive outcome should supplementation be chosen as a
 form of intervention. It has been my experience that
 supplementation with B6 could be greatly reduced or
 eliminated entirely in individuals diagnosed with autism
 who choose to implement the pigment restricted/balanced
 nutrient intake dietary intervention. Thus far autism
 therapies have primarily consisted of treating symptoms.
 The elucidation of a specific cause as well as the
 interventions that treat that cause, are likely to produce
 superior outcome, whereas attempting to manipulate the
 metabolism without considering the nutritional status of
 the individual and cause of symptoms can lead to
 “diarrhoea, drowsiness, nausea, vomiting and
 agitation”(118) as well as itching, blister type eruptions,
 panic, headache, profuse sweating, stress, refusal to eat
 etc.

 In order to achieve optimal metabolism in the autist the
 regulation of amino acids must involve providing the
 essential fatty acid interaction. (120) (121) “The data
 obtained suggest that kynurenine and serotonin pathways
 of tryptophan metabolism were intensified in vitiligo.”(124)

 “Urinary excretion of indolyl-3-acryloylglycine (chromogen
 of the so-called Kimmig's light band) in 15 normal subjects
 was highly significantly increased in June-September
 ("summer") against the November-April ("winter")
 collection in the same subjects.”(125)

 “Many specific gene products are sequentially made and
 utilized by the melanocyte as it emigrates from its
 embryonic origin, migrates into specific target sites,
 synthesizes melanin(s) within a specialized organelle,
 transfers pigment granules to neighboring cells, and
 responds to various exogenous cues. A mutation in many
 of the respective encoding genes can disrupt this process
 of melanogenesis and can result in hypopigmentary
 disorders. Vitiligo, in contrast, results from the destruction
 and removal of the melanocyte in the epidermis and
 mucous membranes.”(126)

 My case history files contain many instances of
 co-occurring vitiligo with autism and additionally reports
 of familial instances of vitiligo.

 “Epoxide carboxylase from the bacterium Xanthobacter
 strain Py2 is a multicomponent enzyme system which
 catalyzes the pyridine nucleotide-dependent carboxylation
 of aliphatic epoxides to beta-ketoacids as illustrated by
 the reaction epoxypropane + CO2 + NADPH + NAD+ -->
 acetoacetate + H+ + NADP+ + NADH. The stereoselective
 dehydrogenases of the Xanthobacter epoxide carboxylase
 system were able to substitute for the corresponding
 components of the N. corallina system when using (R) and
 (S)-epoxypropane as substrates, and vice versa. These
 results provide the first demonstration of the involvement
 of stereospecific dehydrogenases in aliphatic epoxide
 metabolism and provide new insights into microbial
 strategies for the utilization of chiral organic
 molecules.”(123) This shows the pyridine utilization of the
 bacterium in the manufacture of chiral organic molecules
 using epoxide carboxylase. In the autist the substances
 released back into the body when the macrophage engulfs
 and removes the pigment can be epoxides, carboxylase
 and potentially mu opioids. Thus the basic understanding
 of how the autist can manufacture opioids such as
 dermorphin and deltorphin. Reducing the naturally
 manufactured pain killers in the autist requires reducing
 the number of immune cells produced in response to the
 incoming pathogen as well as dietary opioids. This requires
 a lutein free diet.

 The peptides generated by the immune macrophage cells
 can be opioid peptides. Changes made to the diets of
 autistic individuals which may reduce specific food derived
 opioids will not eliminate the natural potential of the autist
 to manufacture opioid peptides: “In vitro human
 hemoglobin hydrolysis by cathepsin D was investigated. It
 confirmed that hemoglobin could appear as a precursor of
 some bioactive peptides following proteolytic
 degradation.” “Using this method, a kinetic study of
 hemorphins appearance has been undertaken. In this
 paper, we also evidenced the generation of
 VV-hemorphin-7 from globin by peritoneal
 macrophages.”(1-2)

 Increasing the autists potential to produce natural
 carboxyl proteinase can result in a decrease in the
 production of the immune macrophage generation of
 natural pain killers. This can result in a more normal
 sensitivity to pain stimuli. To accomplish this the autist
 must have adequate digestive enzymes and regulated
 intake of dietary protein as well as the removal of the
 immune pathogen – lutein. (3)

 Immune activation of neuroactive kynurenines directly
 effect the availability of essential nutrients revealed as
 low or deficiency levels of some B-vitamins, particularly
 riboflavin. Dietary regulation of food substances which
 increase the conversion of tryptophan to kynurenine must
 be regulated. And, adequate intake of B-vitamins will
 produce results which are not obtainable with
 supplementing the B-vitamins and no dietary regulation.
 (4) Elevated levels of free radicals from immune activation
 produced by dietary intake of food substances identified
 as pathogens in the autist contribute significantly to the
 production of toxic and neurotoxic substances. (5)

 To accomplish the strategies to augment mitochodrial
 function requires that the dietary pathogens be identified
 and eliminated, the nitrogen containing amino acids be
 regulated and the metabolism functioning at optimal level
 with healed mucosal linings and the recognized essential
 nutrients present and available. When the pigment
 pathogen is eliminated and testing confirms improved
 gastrointestinal functioning resulting from dietary
 intervention and dietary sources of natural enzymes are
 supplied the results are increase in cognitive abilities and
 a reduction or elimination of the behaviors which
 characterize autism:

 “Mitochondria are vulnerable to a wide array of
 endogenous and exogenous factors which appear to be
 linked by excessive nitric oxide production. Strategies to
 augment mitochondrial function, either by decreasing
 production of endogenous toxic metabolites, reducing
 nitric oxide production, or stimulating mitochondrial
 enzyme activity may be beneficial in the treatment of
 autism.”6

 Improvements in cognitive abilities and a decrease in
 behaviors which are measured to identify autism are the
 results of dietary intervention which removes the immune
 triggering pathogen. Superior results can be obtained
 when additional therapies are used in conjunction with
 dietary intervention. Presently under study is the use of
 secretin. Further research which confirms the potential for
 sources of galanin regulation will increase the opportunity
 for including these substances or products in the
 therapeutic regimen. One such product which has this
 potential is Growth Hormone Releaser.

 “Nitric oxide synthase (NOS)-containing neurons are found
 in many loci throughout the central nervous system,
 which include the cerebral cortex, the cerebellum, the
 hippocampus, and the hypothalamus. NO plays a very
 important role in control of neuronal activity in all of these
 areas by diffusing into neurons where it activates soluble
 guanylate cyclase (sGC) leading to generation of cyclic
 guanosine monophosphate (cGMP) and cyclooxygenase 1
 leading to generation of prostaglandins. Both of these
 active agents are involved in mediating the actions of NO,
 the first gaseous transmitter. In the cerebellum, NO is
 extremely important and it is also thought to mediate
 long-term potentiation in the hippocampus.

 Various stresses and corticoids have been shown in
 monkeys and also in rodents to cause neuronal cell death.
 This may be via the stimulation of glutamic acid release,
 which by N-methyl-D-aspartate (NMDA) receptors causes
 release of NO, which can lead to neuronal cell death. In
 the hypothalamus,. NO stimulates corticotropin-releasing
 hormone (CRH), prolactin releasing factor, growth
 hormone-releasing hormone (GHRH), and somatostatin,
 lutenizing hormone-releasing hormone (LHRH), but not
 follicle stimulating hormone-releasing factor (FSHRF)
 release. In situations of increased release of NO in the
 hypothalamus, it could cause neuronal cell death.
 Following bacterial or viral infections, toxic products of
 the ineffective agents, such as bacterial
 lipopolysaccharide (LPS), circulate to the brain, where
 they induce interleukin-1 and iNOS mRNA and synthesis.
 After several hours delay, massive quantities of NO are
 released. Induction of iNOS occurs in the choroid plexus,
 meninges, in circumventricular organs, and in large
 numbers of iNOS neurons in the arcuate and
 paraventricular nuclei. The large amounts of NO released
 by iNOS may well produce death not only of neurons but
 also glial. Repeated bouts of systemic infection even
 without direct neural involvement could result in induction
 of iNOS in the central nervous system and lead to large
 fall out of neurons in hippocampus to impair memory,
 hypothalamus to decrease fever, and neuroendocrine
 response to infection, and could play a role in the
 pathogenesis of degenerative neuronal diseases of aging,
 such as Alzheimers. The largest induction of iNOS occurs
 in the anterior pituitary and pineal glands. The damage to
 the pituitary could also impair responses to stress and
 infection, and the release of NO during infection could be
 responsible for the degenerative changes in the pineal and
 diminished release of melatonin, an antioxident, and
 consequently, an antiaging hormone, that occur with
 age.”7

 Improving the characteristic eating disorders recognized
 to accompany an autism diagnosis can be accomplished
 with dietary intervention and supportive therapies.
 Improving the signals which regulate eating behaviors can
 result in superior outcome. Therapies used in conjunction
 with dietary intervention such as squeeze therapy,
 massage therapy, secretin infusion and GHR 15 may result
 in the improved signaling needed to reduce abnormal
 eating behavior and increase normal eating behavior.
 Sensory integration and behavioral intervention therapies
 can play a contributing role in improving the feeding
 practices of the autist and therefore increasing the
 opportunity for providing a nutrient rich diet.

  “Patients with GH deficiency appear to have impaired
 psychological well being and potentially significant
 neuropsychiatric manifestations, such as lack of
 concentration and memory impairment. However, it
 is unknown whether this impairment in psychological well
 being is associated specifically with GH deficiency or is
 due to another factor associated with hypopituitarism.” 18-19

 “Indoloyl-Acriloyl Glycine (IAG) has many but not all of the
 properties of a peptide. The two major elements of the
 molecule are joined by way of a peptide bond. One of the
 elements (glycine) is an amino-acid whereas the other
 element, the indole part of the molecule, although almost
 certainly derived from the amino-acid tryptophan is not,
 strictly speaking, an amino-acid. The compound is,
 therefore peptide like or “peptoid”in nature. For the
 purposes of our interpretation, we assume that the other
 peaks which appear in our profiles, between 17 and 30
 minutes are similarly peptide (or peptoid) in nature and
 that many of these are derived from the incomplete
 breakdown of food.”21

 Elevated levels of IAG are also found in Hartnup’s and
 SAD. The inconsistency in the diets of the autists and
 sometimes very self-limited or intentionally restricted diets
 might indicate that a source other than dietary is
 responsible for the unusual peptides or peptoids. The
 tryptophan component indole is also a pigment and
 tryptophan metabolism irregularity is a consistent
 biochemical marker for autism.

 Neurotransmitter irregularities in the autist is a strong
 indication that the ACTH/cortisol axis is abnormal and that
 stress and immune function contributes to the altered
 metabolism in the autist. (22)

 Removing the immune triggering pathogen may be
 insufficient to improve GH release or regulation in the
 autist. Additional therapies are being used and reported to
 influence hypothalamic and hypophyseal regulation. Food
 deprivation or the potentially nutrient deficient diets of
 the autist following a restricted or self limited diet has not
 been adequately researched. (35) The manufacture of
 drug-like opioids by the immune system macrophages or
 derived from food contribute to the behavioral
 characteristics which define the disorder of autism.

 “The chimeric peptides C7, M15, M32, and M40, which
 have been reported to antagonize some actions of
 galanin, all produced varying degrees of depression of
 evoked EPSCs.”(40) Stimulating galanin production with
 squeeze therapy or using growth hormone releasing food
 supplements in conjunction with decreasing the levels of
 naturally produced opioids in the autist should be given
 further attention. Dietary intervention is the most
 comprehensive tool available for use in treating autism.

References
 

Introduction

 (AA) (Modern Nutrition in Health and Disease, 8th edition
 Pg. 298)

 (BB) April 16th issue of Science

 (CC) Imperial College of Science Technology and Medicine
 in London, UK,

 1. Pigment and kinesia; Carman JS; Lancet, 1973 Feb 17,
 1:799, 374.

 2. Evidence for several roles of dynein in pigment
 transport in melanophores; Nilsson H, Wallin M;
 Department of Zoophysiology, University of Göteborg,
 Sweden.

 3. Motility of human spermatozoa; David G, Serres C,
 Escalier D; Ann. Endocrinol. (Paris) 1981 Oct-Nov, 42:4-5,
 391-7.

 4. Distribution of cytoplasmic and axonemal dyneins in rat
 tissues; Yoshida T, Takanari H, Izutsu K; Department of
 Pathology, Mie University School of Medicine, Japan; J.
 Cell. Sci. 1992 Mar, 101 ( Pt 3), 579-87.

 5. Brief report on Immunoglobulin A deficiency; Warren;
 J.A.D.D. April 1997.

 6. Brief report: Immunoglobulin A deficiency in a subset of
 autistic subjects; Warren, Odell, et al; Journal  of autism
 and developmental disorders 1997 Vol 27 no2; 187-192

 7. Possible Association of the Extended MHC Haplotype
 B44-SC30-DR4 in autism; Warren, R. P., Singh, V. K.,
 Cole, P., Odell, J. D., Pingree, C. B., Warren, W. L., DeWit,
 C. W, McCullough, M.; Immunogenetics 36, 203-207,
 1992.

 8. Increased frequency of the extended or ancestral
 haplotype B44-SC30-DR4 in autism; Daniels, W.W.,
 Warren, R.P., Odell, J.D., Maciulis, A., Burger, R.A.,
 Warren, W.L., Torres, A.R.; Center for Persons with
 Disabilities, Utah State University, Logan 84322, USA;
 Neuropsychobiology 1995, 32:3, 120-3

 9. DR-positive T cells in autism: association with
 decreased plasma levels of the complement C4B protein;
 Warren RP; Yonk J; Burger RW; Odell D; Warren WL;
 Center for Persons with Disabilities, Utah State University,
 Logan 84322, USA; Neuropsychobiology, 1995, 31:2, 53-7

 10. Elevated serotonin levels in autism: association with
 the major histocompatibility complex; Warren, R.P., Singh,
 V.K.; Center for Persons with Disabilities, Utah State
 University, Logan 84322, USA; Neuropsychobiology, 1996,
 34:2, 72-5.

 11. Unconjugated Pterins in Neurobiology; Lovinberg,
 Levine; 1984.

 12. Ernström, U., Pettersson, T., Jörnvall, H.; Department
 of Neuroscience, Karolinska Institutet, Stokholm Sweden;
 FEBS Lett, 360: 2, 1995 Feb 27, 177-82.

 13. Sara’s Story, the Adoption of  an Autistic Child, fully
 revised edition; Johnson, S.O., Desorgher, M.E., 1997.

 14. Re: Melatonin, A look at Humoral Factors in the
 Cerebellum; Jansen, R.A.; Autism and Developmental
 Disabilities List (internet: bit.listserv.autism); Feb 1997.

 15. Kinesin and dynein superfamily proteins and the
 mechanism of organelle transport; Hirokawa, N;
 Department of Cell Biology and Anatomy, Graduate School
 of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo,
 Japan; Science, 1998 Jan, 279:5350, 519-26.

 16. Molecular requirements for bi-directional movement of
 phagosomes along microtubules; Blocker, A, Severin, F.F.,
 Burkhardt, J.K., Bingham, J.B., Yu, H., Olivo, J.C., Schroer,
 T.A., Hyman, A.A., Griffiths, G.; Cell Biology Programme,
 European Molecular Biology Laboratory, Heidelberg,
 Germany; J. Cell. Biol., 1997 Apr, 137:1, 113-29.

 17. Glial fibrillary acidic protein in the cerebrospinal fluid of
 children with autism and other  neuropsychiatric
 disorders; Ahlsen, G., Rosengren, L., Belfrage, M., Palm,
 A., Haglid, K., Hamberger, A.,  Gillberg, C.; Department of
 Child Neuropsychiatry, University of Gøteborg, Sweden;
 Biol. Psychiatry, 33(10):734-43 1993 May 15.

 18. Autism and Developmental Disabilities List (internet:
 bit.listserv.autism).

 19. The putative role of arylsulfatase in
 interleukin-2-mediated cytotoxicity and
 interleukin-7-mediated bactericidal activity of natural killer
 cells; Toren, A., Gadish, M., Fabian, I., Nagler, A.;
 Department of Bone Marrow Transplantation, Hadassah
 University Hospital, Jerusalem, Israel; Annals of
 Hematology 74(2):83-7, 1997 Feb.

 20. Sulphate Metabolism in Allergy-Induced Autism:
 relevance to the Disease Aetiology; Waring, R.H., Ngong,
 J.M.; 1993

 21. Dorland’s 28th edition

 22. Amniocentesis in Rh Incompatibilities; Bevis; 1952.
 (from: Gradwohl’s 7th edition, Clinical laboratory methods
 and diagnosis, Vol. 1 1970, The C.V.Mosby Company)

 23. Hyperbilirubinemia in preterm infants and
 neurodevelopmental outcome at 2 years of age: results of
 a national collaborative survey; van de Bor, M., et al.;
 Pediatrics 83(6):915-20, 1989 Jun.

 24. Pigment-restricted diets alleviate the symptoms of
 autism – some case histories; Johnson, S.A., Desorgher,
 M.E.; 1999.

 25. Giant cells in cortical tubers in tuberous sclerosis
 showing synaptophysin-immunoreactive halos;
 Yamanouchi, H., Ho, M., Jay, V., Becker, L.E.; Department
 of Pathology, Hospital for Sick Children, Toronto, Ontario,
 Canada; Brain Dev 1997 Jan, 19:1, 21-4.

 26. Circulating autoantibodies to neuronal and glial
 filament proteins in autism; Singh, V.K., Warren, R.,
 Averett, R., Ghaziuddin, M.; Department of Psychiatry,
 University of Michigan, Ann Arbor 48109-1065, USA;
 Pediatr Neurol 1997 Jul, 17:1, 88-90.

 27. Gangliosides in cerebrospinal fluid in children with
 autism spectrum disorders; Nordin, V., Lekman, A.,
 Johansson, M., Fredman, P., Gillberg, C.; Department of
 Child and Adolescent Psychiatry, Annedals Clinics,
 Göteborg, Sweden; Dev. Med. Child. Neurol. 1998 Sep,
 40:9, 587-94.

 28. I kappaB alpha physically interacts with a
 cytoskeleton-associated protein through its signal
 response domain; Crépieux, P., Kwon, H., Leclerc, N.,
 Spencer, W., Richard, S., Lin, R., Hiscott, J.; Terry Fox
 Molecular Oncology Group, Lady Davis Institute for
 Medical Research, Department of Medicine, McGill
 University, Montreal, Que., Canada; Mol. Cell. Biol. 1997
 Dec, 17:12, 7375-85.

 29. Handedness and cognitive functions in pervasive
 developmental disorders; Fein, D., Waterhouse, L., Lucci,
 D., Pennington, B., Humes M; J. Autism Dev. Disord. 1985
 Sep, 15:3, 323-33.

 30. Case study: anorexia nervosa and autistic disorder in
 an adolescent girl; Fisman, S., Steele, M., Short, J.,
 Byrne, T., Lavallee, C.; Division of Child and Adolescent
 Psychiatry, Children's Hospital of Western Ontario,
 London, Canada; J. Am. Acad. Child Adolesc. Psychiatry
 1996 Jul, 35:7, 937-40.

 31. Treatment of atypical anorexia nervosa in the public
 school: an autistic girl; Stiver, RL., Dobbins, J.P.; J.
 Autism Dev. Disord. 1980 Mar, 10:1, 67-73.

 32. Self-administered gastric tube nutrition in a child with
 infantile autism; Dyrborg, J.; Københavns Amts. Sygehus i
 Glostrup, børnepsykiatrisk afdeling; Ugeskr. Laeger 1991
 Oct 14, 153:42, 2954.

 33. Hearing-impaired autistic children; Jure, R., Rapin, I.,
 Tuchman, R.F., Saul, R.; Korey Department of Neurology,
 Rose F. Kennedy Center for Research in Mental
 Retardation and Human Development, Albert Einstein
 College of Medicine, Bronx, NY.; Dev. Med. Child. Neurol.
 1991 Dec, 33:12, 1062-72.

 34. Hypomelanosis of Ito: autism, segmental dilatation of
 colon and unusual neuroimaging findings; Hermida, A.,
 Eirís, J., Alvarez Moreno, A., Alonso Martín, A., Barreiro,
 J., Castro Gago, M.; Departamento de Pediatria, Complejo
 Hospitalario Universitario de Santiago, La Coruña,
 España; Rev. Neurol. 1997 Jan, 25:137, 71-4.

 35. Autism and hypomelanosis of Ito in twins; Zappella,
 M., Department of Child Neuropsychiatry, USL 30, Siena,
 Italy; Dev. Med. Child Neurol. 1993 Sep, 35:9, 826-32.

 36.Hypomelanosis of Ito in three cases with autism and
 autistic-like conditions; Akefeldt, A., Gillberg, C.;
 Department of Pediatrics and Child Psychiatry, Child
 Neuropsychiatry Centre, Göteborg, Sweden; Dev. Med.
 Child Neurol. 1991 Aug, 33:8, 737-43.

 37. Hypopigmentation in Angelman syndrome, King, R.A.,
 Wiesner, G.L., Townsend, D., White, J.G., Department of
 Medicine, University of Minnesota, Minneapolis 55455; Am.
 J. Med. Genet. 1993 Apr 1, 46:1, 40-4.

 38. Autism in Angelman syndrome: a population-based
 study; Steffenburg, S., Gillberg, C.L., Steffenburg, U.,
 Kyllerman, M., Child. Neuropsychiatry Clinic, Annedals
 Clinics, Göteborg, Sweden; Pediatr. Neurol. 1996 Feb,
 14:2, 131-6.

 39. Sara’s Diet study group – a database of 1500 case
 histories (unpublished); Johnson-Desorgher.

 40. Angelman and Prader-Willi syndromes share a common
 chromosome 15 deletion but differ in parental origin of the
 deletion; Knoll, J.H., Nicholls, R.D., Magenis, R.E., Graham,
 J.M. Jr., Lalande, M., Latt, S.A.; Division of Genetics,
 Children's Hospital, Boston, MA 02115; Am. J. Med. Genet.
 1989 Feb, 32:2, 285-90.

 41. Autism and tuberous sclerosis;  Smalley; Department
 of Psychiatry, University of California-Los Angeles-School
 of Medicine 90024, USA; J Autism Dev Disord, 1998 Oct,
 28:5, 407-14.

 42. Xeroderma pigmentosum group C splice mutation
 associated with autism and hypoglycinemia, S.G. Khan,
 H.L. Levy, R. Legerski, et al.; Journal of Investigative
 Dermatology 111:5 Page No: 791 November 1998.

 43. Ocular findings in Angelman's (happy puppet)
 syndrome; Dickinson AJ; Fielder AR; Young ID; Duckett
 DP; Department of Ophthalmology, Leicester Royal
 Infirmary, UK. Ophthalmic Paediatr Genet, 1990 Mar, 11:1,
 1-6.

 44. Expanded (CAG)n, (CGG)n and (GAA)n trinucleotide
 repeat microsatellites, and mutant purine synthesis and
 pigmentation genes cause schizophrenia and autism;
 Fischer, K.M. Med Hypotheses, 1998 Sep, 51:3, 223-33.

 45. A new case of trichothiodystrophy associated with
 autism, seizures, and mental retardation; C. Schepis, M.
 Elia, M. Siragusa, M. Barbareschi; Pediatric Dermatology
 14:2 March/April 1997 Page No: 125.

 46. Congenital dyschromia with erythrocyte, platelet, and
 tryptophan metabolism abnormalities; Foldès, C., Wallach,
 D., Launay, J.M., Chirio, R; Department of Dermatology,
 Hôpital Saint-Louis, Paris, France; J. Am. Acad. Dermatol.
 1988 Oct, 19:4, 642-55.

 47. Brief report: an autistic male presenting seasonal
 affective disorder (SAD) and trichotillomania; Kurita, H.,
 Nakayasu, N.; Department of Mental Health, Tokyo
 University, Japan; J. Autism Dev. Disord. 1994 Oct, 24:5,
 687-92.

 48. Glued participates in distinct microtubule-based
 activities in Drosophila eye development; Fan, S.S.,
 Ready, D.F., Department of Biological Sciences, Purdue
 University, West Lafayette, IN 47907, USA;
 Development, 1997 Apr, 124:8, 1497-507.

 49. Presumed glial retinal hamartomas in Usher's
 syndrome; Awan, K.J.; Can. J. Ophthalmol. 1976 Jul, 11:3,
 258-60.

 50. Additional research has identified markers so
 consistent that they have been identified in up to 100%
 of the study groups, including research by Paul Shattock:
 “Some of you are aware that in the last year our listmate,
 Paul Shattock, has been able to identify the "peak" that
 shows up in urinary profiles performed by his lab and by
 Dr. Reichelt's lab in Norway.  In a paper presented in
 Durham this spring, Paul explained that this substance is
 IAG, indolyl-acriloyl glycine. Dr. Reichelt reported finding
 this substance in 96% of 200 children with autism he has
 tested in the last four years.  This peak has been used by
 them as a marker for the opiate excess problem, but
 curiously, Paul told me that this substance has been seen
 before associated with something called Hartnup Disease.”
 (From the Internet)

 51. Phenotypic variation in xenobiotic metabolism and
 adverse environmental response: focus on
 sulfur-dependent detoxification pathways; McFadden,
 S.A.; Independent Research Advocates, Dallas, TX 75206,
 USA. Toxicology, 1996 Jul, 111:1-3, 43-65.

 52. Out of pure curiousity, what does it mean when they
 have a constant brownish black discharge.....my son has
 had that every since he had tubes put in at 10 months
 old.  He is almost eight.  Even after the tubes were
 removed at four or five years old, he still has this
 discharge...it's thick and waxy...he has only had two ear
 infections in the last 12 months or so,...the ped. never
 seems concerned.  I always have wondered

 about it though.  Any idea's? Sincerely, Terry J. (from the
 internet)

 53. Molecular basis of congenital hypopigmentary
 disorders in humans: a review; Boissy, R.E., Nordlund,
 J.J.; Department of Dermatology, University of Cincinnati
 College of Medicine, Ohio 45267-0592, USA.; Pigment Cell
 Res. 1997 Feb, 10:1-2, 12-24.

 54. Modern Nutrition in Health and Disease, 8th edition Pg.
 298

 55. Melatonin - “The Sleep Master” Lost and Found;
 Panskepp, Jaak; 1996.

 57. Melanin in the ascending reticular activating system
 and its possible relationship to autism; Happy, R., Collins,
 J.K.; Med. J. Aust. 1972 Dec 30, 2:27, 1484-6.

 58. Midlatency auditory evoked responses: P1
 abnormalities in adult autistic subjects; Buchwald, J.S.,
 Erwin, R., Van Lancker, D., Guthrie, D., Schwafel, J.,
 Tanguay, P.; Department of Physiology, UCLA School of
 Medicine 90024; Electroencephalogr. Clin. Neurophysiol.
 1992 Mar-Apr, 84:2, 164-71.

  59. Phenylketonuria: an underlying etiology of autistic
 syndrome. A case report; Miladi, N., Larnaout, A.,
 Kaabachi, N., Helayem M., Ben Hamida, M.; National
 Institute of Neurology, Tunis, Tunisia; J. Child Neurol.1992
 Jan, 7:1, 22-3.

 60. Ophthalmologic signs in children with autism; Denis,
 D., Burillon, C., Livet, M.O., Burguière, O.; Departement
 de Strabologie et d'Ophtalmopediatrie, Hopital La Timone,
 Marseille; J. Fr. Ophtalmol. 1997, 20:2, 103-10.

 61. Reuters Health; New York, Apr 14

 62. A yellow component associated with human
 transthyretin has properties like a pterin derivative,
 7,8-dihydropterin-6-carboxaldehyde; Ernström, U.,
 Pettersson, T., Jörnvall, H.; Department of Neuroscience,
 Karolinska Institutet, Stockholm, Sweden; FEBS Lett.
 1995 Feb, 360:2, 177-82.

 63. The evolution of gene expression, structure and
 function of transthyretin; Schreiber, G., Richardson, S.J.;
 Department of Biochemistry and Molecular Biology,
 University of Melbourne, Parkville, Victoria, Australia;
 Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 1997 Feb,
 116:2, 137-60

 64. Historic perspectives. Macular yellow pigment. The
 first 200 years; Nussbaum, J.J., Pruett, R.C., Delori, F.C.;
 Retina, 1981, 1:4, 296-310.

 65. Dissection of multi-protein complexes using mass
 spectrometry: subunit interactions in transthyretin and
 retinol-binding protein complexes; Rostom, A.A., Sunde,
 M., Richardson, S.J., Schreiber, G., Jarvis, S., Bateman,
 R., Dobson, C.M., Robinson, C.V.; Oxford Centre for
 Molecular Sciences, New Chemistry Laboratory, United
 Kingdom; Proteins 1998, Suppl 2:, 3-11.

 66. Evolution of thyroid hormone binding by transthyretins
 in birds and mammals; Chang, L., Munro, S.L., Richardson,
 S.J., Schreiber, G.; Russell Grinwade School of
 Biochemistry and Molecular Biology, University of
 Melbourne, Australia; Eur. J. Biochem. 1999 Jan, 259:1-2,
 534-42.

 67. Investigation into thiol conjugation of transthyretin in
 hereditary transthyretin amyloidosis; Suhr, O.B., Ando, Y.,
 Ohlsson, P.I., Olofsson, A., Andersson, K., Lundgren, E.,
 Ando, M., Holmgren, G.; Department of Medicine, UmeÁa
 University Hospital, Sweden; Eur. J. Clin. Invest. 1998
 Aug, 28:8, 687-92.

 68. Laryngoscope, 1997 Feb, 107:2, 216-21

 69. Structural characteristics of bullfrog (Rana
 catesbeiana) transthyretin and its cDNA--comparison of
 its pattern of expression during metamorphosis with that
 of lipocalin; Yamauchi, K., Takeuchi, H., Overall, M.,
 Dziadek, M., Munro, S.L., Schreiber, G.; Department of
 Biology, Faculty of Science, Shizuoka University, Japan;
 Eur. J. Biochem. 1998 Sep, 256:2, 287-96.

 70. Reptilian behavioural patterns in childhood autism;
 Thong, Y.H.; Med. Hypotheses 1984 Apr, 13:4, 399-405.

 71. Expression of retinol binding protein and transthyretin
 during early embryogenesis; Barron, M., McAllister, D.,
 Smith, S.M., Lough, J.; Department of Cell Biology,
 Neurobiology, and Anatomy and Cardiovascular Research
 Center, Medical College of Wisconsin, Milwaukee 53226,
 USA; Dev. Dyn. 1998 Jul, 212:3, 413-22.

 72. Quantification of cerebrospinal fluid proteins in
 children by high-resolution agarose gel electrophoresis;
 Barnard, K., Herold, R., Siemes, H., Siegert, M.; Center for
 Blood and Neoplastic Diseases, Berlin, Germany; J. Child
 Neurol. 1998 Feb, 13:2, 51-8.

 73. Screening and biochemical characterization of
 transthyretin variants in the Portuguese population;
 Alves, I.L., Altland, K., Almeida, M.R., Winter, P., Saraiva,
 M.J.; Centro de Escudos de Paramiloidose, Hospital de
 Santo AntÆonio, Porto, Portugal; Hum. Mutat. 1997, 9:3,
 226-33.

 74. A low molar ratio of retinol binding protein to
 transthyretin indicates vitamin A deficiency during
 inflammation: studies in rats and a posterior analysis of
 vitamin A-supplemented children with measles;  J. Nutr.
 1998 Oct, 128:10, 1681-7.

 75. Xanthophyll esters in human skin; Wingerath, T., Sies,
 H., Stahl, W.; Institut für Physiologische Chemie I,
 Heinrich-Heine-Universitat, Düsseldorf, Düsseldorf,
 D-40001, Germany; Arch. Biochem. Biophys. 1998 Jul,
 355:2, 271-4.

Part I - Affective Disorders  - References

 1. Antidepressants can break through the wall of many
 children's autism, Duke researchers say; SJU Autism and
 Developmental Disabilities List; Tue, 13 Apr 1999.

 2. Role of serotonin in obsessive-compulsive disorder;
 Baumgarten, H.G., Grozdanovic, Z.; Institute of Anatomy,
 University Clinic Benjamin Franklin, Free University of
 Berlin, Germany; Br. J. Psychiatry Suppl. 1998, :35,
 13-20.

 3. Brain 5-HT function in obsessive-compulsive disorder.
 Prolactin responses to d-fenfluramine; Fineberg, N.A.,
 Roberts, A., Montgomery, S.A., Cowen, P.J.; St. Mary's
 Hospital, London; Br. J. Psychiatry 1997 Sep, 171:, 280-2.

 4. Galanin-5-hydroxytryptamine interactions:
 electrophysiological, immunohistochemical and in situ
 hybridization studies on rat dorsal raphe neurons with a
 note on galanin R1 and R2 receptors; Xu, Z.Q., Zhang, X.,
 Pieribone, V.A., Grillner, S., Hökfelt, T.; Department of
 Neuroscience, Karolinska Institute, Stockholm, Sweden;
 Neuroscience 1998 Nov, 87:1, 79-94.

 5. Modulation of acetylcholine and serotonin transmission
 by galanin. Relationship to spatial and aversive learning;
 Ogren, S.O., Schött, P.A., Kehr, J., Yoshitake, T., Misane,
 I., Mannström, P., Sandin, J., Department of
 Neuroscience, Karolinska Institute, Stockholm, Sweden;
 Ann. N.Y. Acad. Sci 1998 Dec 21, 863:, 342-63.

 6. Galanin modulates 5-hydroxytryptamine functions.
 Focus on galanin and galanin
 fragment/5-hydroxytryptamine1A receptor interactions in
 the brain; Fuxe, K., Jansson, A., Diaz-Cabiale, Z.,
 Andersson, A., Tinner, B., Finnman, U.B., Misane, I.,
 Razani, H., Wang, F.H., Agnati, L.F., Ogren, S.O.;
 Department of Neuroscience, Karolinska Institute,
 Stockholm, Sweden; Ann. N.Y. Acad. Sci. 1998 Dec 21,
 863:, 274-90.

 7. Distribution and kinetics of galanin infused into the
 ventral hippocampus of the rat: relationship to spatial
 learning; Schött, P.A., Bjelke, B., Ogren, S.O.;
 Department of Neuroscience, Karolinska Institute,
 Stockholm, Sweden; Neuroscience 1998 Mar, 83:1,
 123-36.

 8. Regulation of galanin in memory pathways; Miller, M.A.;
 Department of Psychiatry and Behavioral Sciences,
 University of Washington, Seattle 98195, USA; Ann. N.Y.
 Acad. Sci. 1998 Dec 21, 863:, 323-41.

 9. Galanin in somatosensory function; Wiesenfeld-Hallin,
 Z., Xu, X.J.; Department of Medical Laboratory Sciences
 and Technology, Huddinge University Hospital, Sweden;
 Ann. N.Y. Acad. Sci. 1998 Dec 21, 863:, 383-9.

 10. Electrophysiologic effects of galanin on neurons of the
 central nervous system; Pieribone, V.A., Xu, Z.Q., Zhang,
 X., Hökfelt, T.; John B. Pierce Laboratory, Department of
 Cellular and Molecular Physiology, Yale University School
 of Medicine, New Haven, Connecticut 06519, USA; Ann.
 N.Y. Acad. Sci. 1998 Dec 21, 863:, 264-73.

 11. The effects of fenfluramine (hydrochloride) on the
 behaviors of fifteen autistic children; Sherman, J., Factor,
 D.C., Swinson, R., Darjes, R.W., TRE-ADD, Thistletown
 Regional Centre, Rexdale, Ontario, Canada; J. Autism Dev.
 Disord. 1989 Dec, 19:4, 533-43.

 12. Regulation of anterior pituitary galanin gene
 expression by thyroid hormone; Hooi, S.C., Koenig, J.I.,
 Abraczinskas, D.R., Kaplan, L.M.; Department of
 Physiology, Faculty of Medicine, National University of

 Singapore, Singapore; Brain Res. Mol. Brain Res. 1997
 Nov, 51:1-2, 15-22.

 13. The neuropeptide galanin and the seizure reactions of
 the developing brain; Chepurnov, S.A., Chepurnova, N.E.,
 Abbasova, K.R., Smirnova, M.P.; Usp. Fiziol. Nauk. 1997
 Apr, 28:2, 3-20.

 14. Imipramine induces alterations in proenkephalin and
 prodynorphin mRNAs level in the nucleus accumbens and
 striatum in the rat; Przewocki, R., Lason, W., Turchan, J.,
 Przewocka, B.; Department of Molecular
 Neuropharmacology, Polish Academy of Sciences, Krakow,
 Poland; Pol. J. Pharmacol. 1997 Sep, 49:5, 351-5.

 15. L-kynurenine: its synthesis and possible regulatory
 function in brain; Gál, E.M., Sherman, A.D.; Neurochem.
 Res. 1980 Mar, 5:3, 223-39.

 16. Preliminary brain autopsy findings in progredient Rett
 syndrome; Riederer, P., Weiser, M., Wichart, I., Schmidt,
 B., Killian, W., Rett, A.; Am. J. Med. Genet. Suppl. 1986,
 1:, 305-15.

 17. CSF beta-endorphins in childhood neuropsychiatric
 disorders; Gillberg, C., Terenius, L., Hagberg, B.,
 Witt-Engerström, I., Eriksson, I.; Child Neuropsychiatry
 Centre, University of Gothenburg, Sweden; Brain Dev.
 1990, 12:1, 88-92.

 18. Kynurenine metabolites of tryptophan: implications for
 neurologic diseases; Freese, A., Swartz, K.J., During,
 M.J., Martin, J.B.; Department of Neurology,
 Massachusetts General Hospital, Boston;

 Neurology 1990 Apr, 40:4, 691-5.

 19. Hypothesis: is infantile autism a hypoglutamatergic
 disorder? Relevance of glutamate - serotonin interactions
 for pharmacotherapy; Carlsson, M.L.; Department of
 Pharmacology, University of Göteborg, Sweden; J. Neural.
 Transm. 1998, 105:4-5, 525-35.

 20. Hyperprolactinemia, a tool in treatment control of
 tetrahydrobiopterin deficiency: endocrine studies in an
 affected girl; Birnbacher, R., Scheibenreiter, S., Blau, N.,
 Bieglmayer, C., Frisch, H., Waldhauser, F.; Department of
 Pediatrics, University of Vienna, Austria; Pediatr. Res.
 1998 Apr, 43:4 Pt 1, 472-7.

 21. Abnormalities of biogenic amines affecting the
 metabolism of serotonin and catecholamines; Lamers, K.J.,
 Wevers, R.A.; University Hospital Nijmegen, Institute of
 Neurology, The Netherlands; Mult. Scler. 1998 Feb, 4:1,
 37-8.

 22. Sara’s Diet study group – a database of 1500 case
 histories (unpublished); Johnson-Desorgher.

 23. Plasma excitatory amino acids in autism; Moreno
 Fuenmayor, H., Borjas, L., Arrieta, A., Valera, V., Socorro
 Candanoza, L.; Servicio de Medicina Genetica Perinatal,
 Hospital Chiquinquira, Maracaibo, Venezuela; Invest. Clin.
 1996 Jun, 37:2, 113-28.

 24. How antidepressants work: cautionary conclusions
 based on clinical and laboratory studies of the longer-term
 consequences of antidepressant drug treatment; Murphy,
 D.L., Aulakh, C.S., Garrick, N.A.;

 Ciba Found. Symp. 1986, 123:, 106-25.

 25. Tonic clonic seizures and tachycardia induced by
 fluoxetine (Prozac) overdose; Neely, J.L.; Department of
 Medicine, Robert C. Byrd Health Sciences Center of West
 Virginia University, Morgantown, USA; W. V. Med. J. 1998
 Sep, 94:5, 283-5.

 26. Galanin modulation of seizures and seizure modulation
 of hippocampal galanin in animal models of status
 epilepticus; Mazarati, A.M., Liu, H., Soomets, U., Sankar,
 R., Shin, D., Katsumori, H., Langel, L., Wasterlain, C.G.;
 Department of Neurology, University of California, Los
 Angeles, School of Medicine, Los Angeles, California, USA;
 J. Neurosci. 1998 Dec, 18:23, 10070-7.

 27. Anorexia nervosa 6 years after onset: Part I.
 Personality disorders; Gillberg, I.C., Rástam, M., Gillberg,
 C.; University of Göteborg, Child Neuropsychiatry Clinic,
 Sweden; Compr. Psychiatry 1995 Jan, 36:1, 61-9.

 28. Brain 5-HT function in obsessive-compulsive disorder.
 Prolactin responses to d-fenfluramine; Fineberg, N.A.,
 Roberts, A., Montgomery, S.A., Cowen, P.J.; St Mary's
 Hospital, London; Br. J. Psychiatry 1997 Sep, 171:, 280-2.

 29. Decreased blood levels of tumor necrosis factor-alpha
 in patients with obsessive-compulsive disorder;

 Monteleone, P., Catapano, F., Fabrazzo, M., Tortorella,
 A., Maj, M.; Institute of Psychiatry, School of Medicine,
 University of Naples SUN, Italy; Neuropsychobiology 1998,
 37:4, 182-5.

 30. Brief report: circadian melatonin, thyroid-stimulating
 hormone, prolactin, and cortisol levels in serum of young
 adults with autism; Nir, I., Meir, D., Zilber, N., Knobler, H.,
 Hadjez, J., Lerner, Y.; Eitanim Psychiatric Hospital,
 Jerusalem, Israel; J. Autism Dev. Disord. 1995 Dec, 25:6,
 641-54.

 31. Effects of hormones on sleep; Steiger, A., Antonijevic,
 I.A., Bohlhalter, S., Frieboes, R.M., Friess, E., Murck, H.;
 Max Planck Institute of Psychiatry, Department of
 Psychiatry, Munich, Germany; Horm. Res. 1998, 49:3-4,
 125-30.

 32. Neuropeptides and human sleep; Steiger. A., Holsboer,
 F., Max Planck Institute of Psychiatry, Department of
 Psychiatry, Munich, Germany; Sleep 1997 Nov, 20:11,
 1038-52.

 33. Innervation of histaminergic tuberomammillary neurons
 by GABAergic and galaninergic neurons in the ventrolateral
 preoptic nucleus of the rat; Sherin, J.E., Elmquist, J.K.,
 Torrealba, F., Saper, C.B.; Department of Neurology and
 Program in Neuroscience, Beth Israel Deaconess Medical
 Center, Harvard Medical School, Boston, Massachusetts;
 J. Neurosci. 1998 Jun, 18:12, 4705-21.

 34. Psychoneuroendocrinology of depression. Growth
 hormone; Dinan, T.G., Department of Psychiatry, Royal
 College of Surgeons, Dublin, Ireland; Psychiatr. Clin. North
 Am. 1998 Jun, 21:2, 325-39.

 35. Galanin: analysis of its coexpression in
 gonadotropin-releasing hormone and growth
 hormone-releasing hormone neurons; Hohmann, J.G.,
 Clifton, D.K., Steiner, R.A.; Program for Neurobiology and
 Behavior, University of Washington, Seattle, USA; Ann.
 N.Y. Acad. Sci. 1998 Dec 21, 863:, 221-35.

 36. Hypothalamic and hypophyseal regulation of growth
 hormone secretion; Bluet Pajot, M.T., Epelbaum, J.,
 Gourdji, D., Hammond, C., Kordon, C.; Unite de Recherche
 sur la Dynamique des Systemes Neuroendocriniens (U159),
 INSERM, Paris, France; Cell. Mol. Neurobiol. 1998 Feb,
 18:1, 101-23.

 37. Case study: anorexia nervosa and autistic disorder in
 an adolescent girl; Fisman, S., Steele, M., Short, J.,
 Byrne, T., Lavallee, C.; Division of Child and Adolescent
 Psychiatry, Children's Hospital of Western Ontario,
 London, Canada; J. Am. Acad. Child Adolesc. Psychiatry
 1996 Jul, 35:7, 937-40.

 38. Treatment of atypical anorexia nervosa in the public
 school: an autistic girl; Stiver, R.L., Dobbins, J.P.; J.
 Autism Dev. Disord. 1980 Mar, 10:1, 67-73.

 39. Self-administered gastric tube nutrition in a child with
 infantile autism; Dyrborg, J.; Københavns Amts. Sygehus i
 Glostrup, børnepsykiatrisk afdeling; Ugeskr. Laeger 1991
 Oct 14, 153:42, 2954.

 40. Obsessive-compulsive disorder, trichotillomania, and
 anorexia nervosa: a case report; Pryor, T.L., Martin, R.L.,
 Roach, N.; Department of Psychiatry and Behavioral
 Sciences, University of Kansas

 School of Medicine-Wichita 67214-3199, USA; Int. J. Eat.
 Disord. 1995 Dec, 18:4, 375-9.

 41. Sleep-wake rhythm of autistic children; Takase, M.,
 Taira, M., Sasaki, H.; Institute of Special Education,
 University of Tsukuba, Japan; Psychiatry Clin. Neurosci.
 1998 Apr, 52:2, 181-2.

 42. Brief report: an autistic male presenting seasonal
 affective disorder (SAD) and trichotillomania; Kurita, H.,
 Nakayasu, N.; Department of Mental Health, Tokyo
 University, Japan; J. Autism Dev. Disord. 1994 Oct, 24:5,
 687-92.

 43. The retino-hypothalamic tract is involved in prolactin
 regulation in fetal sheep; Vergara, M., Parraguez, V.H.,
 Recabarren, S., Riquelme, R., Garay, F., Valenzuela, G.,
 Serón-Ferré, M.; Unidad de Reproducción y Desarrollo,
 Facultad de Ciencias Biológicas, P. Universidad Católica de
 Chile; J. Dev. Physiol. 1992 Jul, 18:1, 19-23.

 44. Intraocular pressure and prolactin measures in
 seasonal affective disorder; Stojek, A., Kasprzak, B.,
 Sabikowski, A.; Poradni Zdrowia Psychicznego, Jastrz;
 Psychiatr. Pol. 1991 May-Aug, 25:3-4, 8-12.

 45. Comprehensive management of trichotillomania in a
 young autistic girl; Holttum, J.R., Lubetsky, M.J.,
 Eastman, L.E.; Western Psychiatric Institute and Clinic,
 Pittsburgh, PA 15213; J. Am. Acad. Child. Adolesc.
 Psychiatry 1994 May, 33:4, 577-81.

 46. Brief report: haloperidol treatment of trichotillomania
 in a boy with autism and mental retardation; Ghaziuddin,
 M., Tsai, L.Y., Ghaziuddin, N.; University of Michigan, Ann
 Arbor; J. Autism Dev. Disord. 1991 Sep, 21:3, 365-71.

 47. Brief report: trichotillomania in an autistic male;
 Hamdan-Allen, G.; College of Medicine, University of Iowa;
 J. Autism Dev. Disord. 1991 Mar, 21:1, 79-82.

 48. Expanded (CAG)n, (CGG)n and (GAA)n trinucleotide
 repeat microsatellites, and mutant purine synthesis and
 pigmentation genes cause schizophrenia and autism;
 Fischer, K.M.; Med Hypotheses, 1998 Sep, 51:3, 223-33.

 49. When to investigate for purine and pyrimidine
 disorders. Introduction and review of clinical and
 laboratory indications; Simmonds, H.A., Duley, J.A.,
 Fairbanks, L.D., McBride, M.B.; Purine Research
 Laboratories, UMDS, Guy's Hospital, London Bridge, UK; J.
 Inherit. Metab. Dis. 1997 Jun, 20:2, 214-26

 50. When and how does one search for inborn errors of
 purine and pyrimidine metabolism?; Simmonds, H.A.; Purine
 Research Laboratory, UMDS, Guy's Hospital, London
 Bridge, United Kingdom; Pharm. World Sci. 1994 Apr, 16:2,
 139-48.

 51. Developmental expression of galanin-like
 immunoreactivity by members of the avian
 sympathoadrenal cell lineage; García-Arrarás, J.E.,
 Torres-Avillán, I.; Department of Biology, University of
 Puerto Rico, Río Piedras, Puerto Rico, 00931-3360, USA;
 Cell Tissue Res, 1999 Jan, 295:1, 33-41.

 52. Paracrine control of steroid hormone secretion by
 chromaffin cells in the adrenal gland of lower vertebrates;
 Mazzocchi, G., Gottardo, G., Nussdorfer, G.G.;
 Department of Anatomy, University of Padua, Italy; Histol.
 Histopathol. 1998 Jan, 13:1, 209-20.

 53. Expression and regulation of galanin-R2 receptors in
 rat primary sensory neurons: effect of axotomy and
 inflammation; Sten Shi, T.J., Zhang, X., Holmberg, K., Xu,
 Z.Q., Hökfelt, T.; Department of Neuroscience, Karolinska
 Institutet, Stockholm, Sweden; Neurosci. Lett. 1997 Nov,
 237:2-3, 57-60

 54. Hypothalamic galanin gene expression and peptide
 levels in relation to circulating insulin: possible role in
 energy balance; Tang, C., Akabayashi, A., Manitiu, A.,
 Leibowitz, S.F.; Rockefeller University, New York, NY
 10021, USA; Neuroendocrinology 1997 Apr, 65:4, 265-75.

 55. Effects of ovine corticotropin-releasing hormone
 injection and desmopressin coadministration on galanin
 and adrenocorticotropin plasma levels in normal women;
 Ceresini, G., Freddi, M., Paccotti, P., Valenti, G.,
 Merchenthaler, I.; Chair of Geriatrics, University of Parma,
 Italy; J. Clin. Endocrinol. Metab. 1997 Feb, 82:2, 607-10.

 56. Galanin messenger RNA during postnatal development
 of the rat brain: expression patterns in Purkinje cells
 differentiate anterior and posterior lobes of cerebellum;
 Ryan, M.C., Loiacono, R.E., Gundlach, A.L.; The University
 of Melbourne, Department of Medicine, Austin and
 Repatriation Medical Centre, Heidelberg, Australia;
 Neuroscience 1997 Jun, 78:4, 1113-27.

 57. Brainstem, cerebellar and limbic neuroanatomical
 abnormalities in autism; Courchesne, E.; Department of
 Neurosciences, School of Medicine, University of
 California, San Diego, CA 92093, USA; Curr. Opin.
 Neurobiol. 1997 Apr, 7:2, 269-78.

 58. The brain in infantile autism: posterior fossa
 structures are abnormal; Courchesne, E., Townsend, J.,
 Saitoh, O.; Neurosciences Department, School of
 Medicine, University of California at San Diego, La Jolla;
 Neurology 1994 Feb.

 59. Changes in the processing of pro-dynorphin end
 products in the substantia nigra during neonatal
 development Sei, C.A., Dores, R.M.; University of Denver,
 Department of Biological Sciences, CO 80208;

 Peptides 1990 Jan-Feb, 11:1, 89-94.

 60. Reduced brainstem size in children with autism;
 Hashimoto, T., Tayama, M., Miyazaki, M., Sakurama, N.,
 Yoshimoto, T., Murakawa, K., Kuroda, Y.; Department of
 Pediatrics, University of Tokushima School of Medicine,
 Japan; Brain Dev. 1992 Mar, 14:2, 94-7.

 61. Galanin-immunoreactive synaptic terminals on basal
 forebrain cholinergic neurons in the rat; Henderson, Z.,
 Morris, N.; Department of Physiology, University of Leeds,
 United Kingdom; J. Comp. Neurol. 1997 Jun, 383:1, 82-93.

 62. Nerve growth factor inhibits sympathetic neurons'
 response to an injury cytokine; Shadiack, A.M.,
 Vaccariello, S.A., Sun, Y., Zigmond, R.E.; Department of
 Neurosciences, Case Western Reserve University, 10900
 Euclid Avenue, Cleveland, OH 44106-4975, USA; Proc.
 Natl. Acad. Sci. U S A, 1998. Jun, 95:13, 7727-30.

 63. Magnetic resonance imaging in autism: preliminary
 report; Hashimoto, T., Tayama, M., Mori, K., Fujino, K.,
 Miyazaki, M., Kuroda, Y.; Department of Pediatrics,
 University of Tokushima School of Medicine, Japan;
 Neuropediatrics 1989 Aug, 20:3, 142-6.

 64. Brainstem involvement in high functioning autistic
 children; Hashimoto, T., Tayama, M., Miyazaki, M.,
 Murakawa, K., Shimakawa, S., Yoneda, Y., Kuroda, Y.;
 Department of Pediatrics, University of Tokushima School
 of Medicine, Japan; Acta. Neurol. Scand. 1993 Aug, 88:2,
 123-8.

 65. Development of the brainstem and cerebellum in
 autistic children; Hashimoto, T., Tayama, M., Murakawa,
 K., Miyazaki, M., Yoshimoto, T.; Harada, M., Kuroda, Y.;
 Department of Pediatrics, University of Tokushima School
 of Medicine; No To Hattatsu 1994 Nov, 26:6, 480-5.

 66. Development of the brainstem and cerebellum in
 autistic patients; Hashimoto, T., Tayama, M., Murakawa,
 K., Yoshimoto, T., Miyazaki, M., Harada, M., Kuroda, Y.;
 University of Tokushima School of Medicine; J. Autism
 Dev. Disord. 1995 Feb, 25:1, 1-18.

 67. Neurobiology of autism; Rapin, I., Katzman, R.; Saul R.
 Korey Department of Neurology, and Rose F. Kennedy
 Center for Research in Mental Retardation and Human
 Development, Albert Einstein College of Medicine, Bronx,
 NY 10461, USA; Ann. Neurol. 1998 Jan, 43:1, 7-14.

 68. Modern Nutrition in Health and Disease, 8th edition,
 Shils, Olsen and Shike

 69. Influence of the hypothalamic-pituitary axis on the
 androgen regulation of the ocular secretory immune
 system; Sullivan, D.A.; Department of Ophthalmology,
 Harvard Medical School, Boston, MA 02114; J. Steroid.
 Biochem. 1988, 30:1-6, 429-33.

 70. Influence of iron and ascorbic acid on tryptophan
 metabolism in man; Hankes, L.V.; Acta Vitaminol. Enzymol.
 1975, 29:1-6, 174-6.

 71. Serotonin metabolism is pellagra; Raghuram, T.C.,
 Krishnaswamy, K.; Arch. Neurol. 1975 Oct, 32:10, 708-10.

 72. Particular features of clinical pellagra; Dumitrescu, C.,
 Lichiardopol, R.; Clinic of Diabetes, Nutrition and Metabolic
 Diseases, Hospital N. Malaxa, Bucharest, Romania; Rom. J.
 Intern. Med. 1994 Apr, 32:2, 165-70.

 73. Skin diseases with photosensitivity; Amblard, P.,
 Leccia, M.T.; Clinique de dermatophlebologie, hôpital
 A.-Michallon, Grenoble; Rev. Prat. 1992 Jun, 42:11,
 1365-8.

 74. The major psychoses and neuroses as omega-3
 essential fatty acid deficiency syndrome: substrate
 pellagra; Rudin, D.O.; Biol. Psychiatry 1981 Sep, 16:9,
 837-50.

 75. The dominant diseases of modernized societies as
 omega-3 essential fatty acid deficiency syndrome:
 substrate beriberi; Rudin, D.O.; Med. Hypotheses 1982
 Jan, 8:1, 17-47.

 76. The use of diet and dietary components in the study
 of factors controlling affect in humans: a review;

 Young, S.N.; Department of Psychiatry, McGill University,
 Montreal, Quebec, Canada; J. Psychiatry Neurosci. 1993
 Nov, 18:5, 235-44.

 77. Pellagra with colitis due to a defect in tryptophan
 metabolism; Clayton P.T., Bridges. N.A., Atherton, D.J.,
 Milla, P.J., Malone, M., Bender, D.A.; Hospital for Sick
 Children, London, United Kingdom; Eur. J. Pediatr. 1991
 May, 150:7, 498-502.

 78. In vitro platelet function in infantile autism; Safai
 Kutti, S., Denfors, I., Kutti, J., Wadenvik, H.;
 Paediatric Clinic, Biskopsgarden, Göteborg, Sweden; Folia.
 Haematol. Int. Mag. Klin. Morphol. Blutforsch. 1988,
 115:6, 897-901.

 79. Cytochrome P450 inactivation in microsomal
 membranes damaged by Fe2+-ascorbate-dependent lipid
 peroxidation; Borodin, E.A.; Nauchnye Doki Vyss Shkoly
 Biol. Nauki. 1986, :5, 30-4.

 80. The role of retinal pigment epithelium melanin in
 photoinduced oxidation of ascorbate; Róanowska, M.,
 Bober, A., Burke, J.M., Sarna, T.; Department of
 Biophysics, Jagiellonian University, Krakow, Poland;
 Photochem. Photobiol. 1997 Mar, 65:3, 472-9.

 81. Microsomal lipid peroxidation: the role of
 NADPH--cytochrome P450 reductase and cytochrome
 P450; Sevanian, A., Nordenbrand, K., Kim, E., Ernster, L.,
 Hochstein, P.; Institute for Toxicology, University of
 Southern California, Los Angeles; Free Radic. Biol. Med.
 1990, 8:2, 145-52.

 82. Detection of free radicals produced from the reaction
 of cytochrome P-450 with linoleic acid hydroperoxide;
 Rota, C., Barr, D.P., Martin, M.V., Guengerich, F.P.,
 Tomasi. A., Mason, R.P.; Department of Biomedical
 Sciences, University of Modena, Modena, Italy; Biochem.
 J. 1997 Dec, 328 ( Pt 2):, 565-71.

 83. Mechanism-based inactivation of cytochrome P450
 2B4 by aldehydes: relationship to aldehyde deformylation
 via a peroxyhemiacetal intermediate; Raner, G.M., Chiang,
 E.W., Vaz, A.D., Coon, M.J.; Department of Biological
 Chemistry, Medical School, The University of Michigan,
 Ann Arbor, USA;

 Biochemistry 1997 Apr, 36:16, 4895-902.

 84. NADPH-initiated cytochrome P450-dependent free
 iron-independent microsomal lipid peroxidation: specific
 prevention by ascorbic acid; Ghosh, M.K., Mukhopadhyay,
 M., Chatterjee, I.B.; Dr. B.C. Guha Centre for Genetic
 Engineering and Biotechnology and Department of
 Biochemistry, University College of Science, Calcutta,
 India; Mol. Cell. Biochem. 1997 Jan, 166:1-2, 35-44.

 85. Evolutionary significance of vitamin C biosynthesis in
 terrestrial vertebrates; Nandi, A., Mukhopadhyay, C.K.,
 Ghosh, M.K., Chattopadhyay, D.J., Chatterjee. I.B.;
 Department of Biochemistry, University College of
 Science, Calcutta, India; Free Radic. Biol. Med. 1997,
 22:6, 1047-54.

 86. Human cytochrome P450's are pro-oxidants in
 iron/ascorbate-initiated microsomal lipid peroxidation;

 Lambert, N., Chambers, S.J., Plumb, G.W., Williamson, G.;
 Department of Food Molecular Biochemistry, Norwich
 Research Park, Colney, UK; Free Radic. Res. 1996 Mar,
 24:3, 177-85.

 87. Effects of dietary excess amino acids on the
 concentrations of cholesterol, alpha-tocopherol, ascorbic
 acid, and copper in serum and tissues of rats; Katayama,
 T., Hayashi, J., Kishida, M., Kato, N.; Department of
 Applied Biochemistry, Faculty of Applied Biological
 Science, Hiroshima University, Higashi-Hiroshima, Japan; J.
 Nutr. Sci. Vitaminol. (Tokyo), 1990 Oct, 36:5, 485-95.

 88. Ascorbic acid in cholesterol metabolism and in
 detoxification of xenobiotic substances: problem of
 optimum vitamin C intake; Ginter, E.; Research Institute
 of Human Nutrition, Bratislava, Czechoslovakia; Nutrition
 1989 Nov, 5:6, 369-74.

 89. Estimation of the functional reserve of the human liver
 by urinary D-glucaric acid excretion after vitamin C
 administration; Hanaue, H., Kanno, K., Mukai, M., Kubo,
 H., Tobita, K., Nakasaki, H., Tajima, T., Mitomi, T., Endo,
 R.; Department of Surgery, Tokai University Oiso Hospital,
 Kanagawa, Japan; Tokai J. Exp. Clin. Med. 1993 Jun,
 18:1-2, 1-4.

 90. Interrelationship of dietary lipids and ascorbic acid
 with hepatic enzymes of cholesterol metabolic pathway;
 Sen, S., Mukherjee, S.; Department of Chemical
 Technology, Calcutta University, India;

 Indian J. Exp. Biol. 1997 Jan, 35:1, 42-5.

 91. Conversion of pentahalogenated phenols by
 microperoxidase-8/H2O2 to benzoquinone-type products;

 Osman, A.M., Posthumus, M.A., Veeger, C., van Bladeren,
 P.J., Laane, C., Rietjens, I.M.; Department of Biomolecular
 Sciences, Laboratory of Biochemistry, Agricultural
 University, Wageningen, The Netherlands; Chem. Res.
 Toxicol. 1998 Nov, 11:11, 1319-25.

 92. Relative hyperoxaluria, crystalluria and haematuria
 after megadose ingestion of vitamin C; Auer, B.L., Auer,
 D., Rodgers, A.L.; Department of Chemistry, University of
 Cape Town, South Africa;  Eur. J. Clin. Invest. 1998 Sep,
 28:9, 695-700.

 93. Ascorbic acid inhibits lipid peroxidation but enhances
 DNA damage in rat liver nuclei incubated with iron ions;
 Hu, M.L., Shih, M.K.; Department of Food Science,
 National Chung-Hsing University, Taichung, Taiwan; Free
 Radic. Res. 1997 Jun, 26:6, 585-92.

 94. Effect of cytokines and nitric oxide on tight junctions
 in cultured rat retinal pigment epithelium;

 Zech, J.C., Pouvreau, I., Cotinet, A., Goureau, O., Le
 Varlet, B., de Kozak, Y.; Laboratoire d'Immunopathologie
 de l'Oeil, Paris, France; Invest. Ophthalmol. Vis. Sci. 1998
 Aug, 39:9, 1600-8.

 95. Two different families of NMDA receptors in mammalian
 brain: physiological function and role in neuronal
 development and degeneration; Michaelis, E.K.;
 Department of Pharmacology and Toxicology, University of
 Kansas, Lawrence 66045; Adv. Exp. Med. Biol. 1993, 341:,
 119-28.

 96. Increased hippocampal AMPA and NMDA receptor
 subunit immunoreactivity in temporal lobe epilepsy
 patients; Mathern, G.W., Pretorius, J.K., Mendoza, D.,
 Lozada, A., Leite, J.P., Chimelli, L., Fried, I., Sakamoto,
 A.C., Assirati, J.A., Adelson, P.D.; Division of
 Neurosurgery, and The Brain Research Institute,
 University of California, Los Angeles, USA; J. Neuropathol.
 Exp. Neurol. 1998 Jun, 57:6, 615-34.

 97. Expression of NMDA 2B receptor subunit mRNA in
 Bergmann glia; Luque, J.M., Richards, J.G.; Pharma
 Division, F. Hoffmann-La Roche Ltd., Basle, Switzerland;
 Glia 1995 Mar, 13:3, 228-32.

 98. Persisting expression of galanin in axotomized
 mamillary and septal neurons of adult rats labeled for
 c-Jun and NADPH-diaphorase; Brecht, S., Buschmann, T.,
 Grimm, S., Zimmermann, M., Herdegen, T.; II. Institute of
 Physiology, University of Heidelberg, Germany; Brain Res.
 Mol. Brain. Res. 1997 Aug, 48:1, 7-16.

 99. Evidence for the existence of galanin receptors on
 cultured astrocytes of rat CNS: colocalization with
 cholinergic receptors; Hösli, E., Ledergerber, M., Kofler,
 A., Hösli, L.; Department of Physiology, University of
 Basel, Switzerland; J. Chem. Neuroanat. 1997 Jul, 13:2,
 95-103.

 100. NMDA induces NO release from primary cell cultures
 of human fetal cerebral cortex; Liu, D.M., Wu, J.N., Chiou,
 A.L., Liu, J.Y., Wang, Y.; Department of Pharmacology,
 National Defense Medical Center, Taipei, Taiwan, ROC;
 Neurosci. Lett. 1997 Feb, 223:3, 145-8.

 101. Testing the NMDA, long-term potentiation, and
 cholinergic hypotheses of spatial learning; Cain, D.P.;

 Department of Psychology and Graduate Program in
 Neuroscience, University of Western Ontario, London,
 Canada; Neurosci. Biobehav. Rev. 1998 Mar, 22:2,
 181-93.

 102. Reactivity of beta-carotene towards peroxyl radicals
 studied by laser flash and steady-state photolysis;

 Mortensen, A., Skibsted, L.H.; Food Chemistry,
 Department of Dairy and Food Science, Royal Veterinary
 and Agricultural University, Frederiksberg C, Denmark;
 FEBS Lett. 1998 Apr, 426:3, 392-6.

 103. Nitric oxide protects cardiomyocytes against
 tert-butyl hydroperoxide-induced formation of alkoxyl and
 peroxyl radicals and peroxidation of phosphatidylserine;
 Gorbunov, N.V., Tyurina, Y.Y., Salama, G., Day, B.W.,
 Claycamp, H.G., Argyros, G., Elsayed, N.M., Kagan, V.E.;
 Department of Environmental and Occupational Health,
 University of Pittsburgh, Pennsylvania 15238, USA;
 Biochem. Biophys. Res. Commun. 1998 Mar, 244:3,
 647-51.

 104. ‘AT WAR WITHIN - A Double-Edged Sword of
 Immunity’; William Clark, 1995.

 105. Immunology 3rd edition; Roitt, Brostoff, Male.

 106. Unconjugated Pterins in Neurobiology; Lovinberg,
 Levine; 1984.

 107. Unconjugated pterins in neurobiology - Basic and
 Clinical aspects; Lovenberg, Levine, 1987.

 108. Online Medical Dictionary.

 109. Clinical significance of changes in tryptophan
 metabolism; Ambanelli, U., Manganelli, P.; Ateneo
 Parmense; Acta Biomed. 1975 Jan-Apr, 46:1-2, 5-19.

 110. The Serotonin System in Autism; Cook, Jr., Edwin,
 H., Leventhal, Bennett, L.; Laboratory of Developmental
 Neuroscience, Department of Psychiatry, University of
 Chicago, Chicago, IL; Current Opinion in Pediatrics 1996,
 8:348-354.

 111. Activation of human platelets by C5a-stimulated
 neutrophils: a role for cathepsin G; Ferrer-Lopez, P.,,
 Renesto, P., Schattner, M., Bassot, S., Laurent, P.,
 Chignard, M.; Unité Associée IP-Institut National de la

 Santé et de la Recherche, Médicale 285, Institut Pasteur,
 France; Am. J. Physiol. 1990 Jun, 258:6 Pt 1, C1100-7.

 112. Cathepsin G is a strong platelet agonist released by
 neutrophils; Selak, M.A., Chignard, M., Smith, J.B.;
 Department of Pharmacology, Temple University Medical
 School, Philadelphia, PA 19140; Biochem. J. 1988 Apr,
 251:1, 293-9.

 113. Interaction of Doc2 with tctex-1, a light chain of
 cytoplasmic dynein. Implication in dynein-dependent
 vesicle transport; Nagano, F., Orita, S., Sasaki, T., Naito,
 A., Sakaguchi, G., Maeda, M., Watanabe, T., Kominami, E,
 Uchiyama, Y., Takai, Y.; Department of Molecular Biology
 and Biochemistry, University Medical School, Suita, Japan;
 J. Biol. Chem. 1998 Nov, 273:46, 30065-8.

 114. Specific roles for the asparagine-linked carbohydrate
 residues of recombinant human follicle stimulating hormone
 in receptor binding and signal transduction; Bishop, L.A.,
 Robertson, D.M., Cahir, N., Schofield, P.R.; Garvan
 Institute of Medical Research, St. Vincent's Hospital,
 Darlinghurst, Sydney, Australia; Mol. Endocrinol. 1994 Jun,
 8:6, 722-31.

 115. Serotonin metabolism and other biochemical
 parameters in infantile autism. A controlled study of 22
 autistic children; Launay, J.M., Ferrari, P., Haimart, M.,
 Bursztejn, C., Tabuteau, F., Braconnier, A.,
 Pasques-Bondoux, D., Luong, C., Dreux, C.; Service de
 Biochimie et Neuroendocrinologie, Hôpital Saint-Louis,
 Paris, France; Neuropsychobiology, 1988, 20:1, 1-11.

 116. Vitamin B6 in clinical neurology; Bernstein, A.L.;
 Department of Neurology, Kaiser Permanente Medical
 Center, Hayward, California 94545; Ann. N.Y. Acad. Sci.
 1990, 585:, 250-60.

 117. The effect of dietary protein on the metabolism of
 vitamin B-6 in humans; Miller, L.T., Leklem, J.E., Shultz,
 T.D.; J. Nutr. 1985 Dec, 115:12, 1663-72.

 118. Neurotransmitter precursor amino acids in the
 treatment of multi-infarct dementia and Alzheimer's
 disease; Meyer, J.S., Welch, K.M., Deshmukh, V.D., Perez,
 F.I., Jacob, R.H., Haufrect, D.B., Mathew, N.T., Morrell,
 R.M.; J. Am. Geriatr. Soc. 1977 Jul, 25:7, 289-98.

 119. The distribution and metabolism of L-tryptophan in
 healthy probands under dietary conditions; Riederer, P.;
 Int. J. Clin. Pharmacol. Ther. Toxicol. 1980 Jan, 18:1,
 31-6.

 120. Aggression and personality: association with amino
 acids and monoamine metabolites; Müller, S.E.,
 Mortensen, E.L., Breum, L., Alling, C., Larsen, O.G., Büge
 Rasmussen, T., Jensen, C., Bennicke, K.; Research
 Institute of Biological Psychiatry, St Hans Hospital,
 Roskilde, Denmark; Psychol. Med. 1996 Mar, 26:2, 323-31.

 121. Essential fatty acids predict metabolites of serotonin
 and dopamine in cerebrospinal fluid among healthy control
 subjects, and early- and late-onset alcoholics; Hibbeln,
 J.R., Linnoila, M., Umhau, J.C., Rawlings, R., George, D.T.,
 Salem, N. Jr.; Laboratory of Membrane Biochemistry and
 Biophysics, National Institute on Alcohol Abuse and
 Alcoholism, Bethesda, Maryland, USA; Biol. Psychiatry,
 1998 Aug, 44:4, 235-42.

 122. Effects of the ratio of exogenous eicosapentaenoic
 acid to arachidonic acid on platelet aggregation and
 serotonin release; Hashimoto, Y., Naito, C., Kawamura,
 M., Oka, H.; Thromb. Res. 1984 Jun, 34:5, 439-46.

 123. Two short-chain dehydrogenases confer
 stereoselectivity for enantiomers of epoxypropane in the
 multiprotein epoxide carboxylating systems of
 Xanthobacter strain Py2 and Nocardia corallina B276;

 Allen, J.R., Ensign, S.A.; Department of Chemistry and
 Biochemistry, Utah State University, Logan, Utah
 84322-0300, USA; Biochemistry, 1999 Jan 5, 38:1,
 247-56.

 124. Tryptophan metabolism in vitiligo; Kurbanov, Kh.;
 Berezov, T.T.; Vopr. Med. Khim. 1976 Sep, 22:5, 683-7.

 125. Urinary excretion of indolyl-3-acryloylglycine in some
 skin affections; Marklová, E., Malina, L., Hais, I.M.; Clin.
 Chim. Acta. 1975 Nov 3, 64:3, 273-80.

 126. Molecular basis of congenital hypopigmentary
 disorders in humans: a review; Boissy, R.E., Nordlund,
 J.J.; Department of Dermatology, University of Cincinnati
 College of Medicine, Ohio 45267-0592, USA;

 Pigment Cell Res. 1997 Feb, 10:1-2, 12-24.

References:  Natural pain killers from our immune
 system

 1) Neokyotorphin formation and quantitative evolution
 following human hemoglobin hydrolysis with cathepsin D;
 Zhao Q; Piot JM; Laboratoire de Génie Protéique et
 Cellulaire, Pôle Sciences et Technologies, Université de La
 Rochelle, France; Peptides, 1998, 19:4, 759-66

  2)  Opioid peptides derived from hemoglobin: hemorphins;
 Zhao Q; Garreau I; Sannier F; Piot JM; Laboratoire de
 GÆenie ProtÆeique, UniversitÆe de La Rochelle, France;
 Biopolymers, 1997, 43:2, 75-98

 3)  Generation of VV-hemorphin-7 from globin by
 peritoneal macrophages; Dagouassat N; Garreau I;
 Sannier F; Zhao Q; Piot JM; Laboratoire de GÆenie
 ProtÆeique et Cellulaire, PÈole Sciences et

 Technologies, La Rochelle, France; FEBS Lett, 1996 Mar,
 382:1-2, 37-42

 4) Inter-relationships between quinolinic acid, neuroactive
 kynurenines, neopterin and beta 2-microglobulin in
 cerebrospinal fluid and serum of HIV-1-infected patients;
 Heyes MP; Brew BJ; Saito K; Quearry BJ; Price RW; Lee K;
 Bhalla RB; Der M; Markey SP; Section on Analytical
 Biochemistry, NIMH, NIH, Bethesda, MD 20892; J
 Neuroimmunol, 1992 Sep, 40:1, 71-80

 5) Oxidation of serotonin by superoxide radical:
 implications to neurodegenerative brain disorders; Wrona
 MZ; Dryhurst G; Department of Chemistry and
 Biochemistry, University of Oklahoma, Norman, Oklahoma
 73019, USA; Chem Res Toxicol, 1998 Jun, 11:6, 639-50

 6) Autism: a mitochondrial disorder?; Lombard J;
 Westchester Square Medical Center, New York, NY 10461,
 USA; Med Hypotheses, 1998 Jun, 50:6, 497-500

 7) The nitric oxide hypothesis of brain aging; McCann SM;
 Pennington Biomedical Research Center, Louisiana State
 University, Baton Rouge 70808-4124, USA; Exp Gerontol,
 1997 Jul, 32:4-5, 431-40

 8) Modulation by galanin of growth hormone and
 gonadotropin secretion from perifused pituitary and
 median eminence of prepubertal male calves; Baratta M;
 Saleri R; Mascadri C; Coy DH; Negro Vilar A; Tamanini C;
 Giustina A; Istituto di Fisiologia Veterinaria, UniversitÄa di
 Parma, Italy; Neuroendocrinology, 1997 Oct, 66:4, 271-7

 9) MERCK Pg 1759

 10) Expression of functional estrogen receptors and
 galanin messenger ribonucleic acid in immortalized
 luteinizing hormone-releasing hormone neurons: estrogenic
 control of galanin gene expression; Shen ES; Meade EH;
 Pérez MC; Deecher DC; Negro Vilar A; López FJ; Peptide
 Pharmacology Section, Women's Health Research
 Institute, Wyeth-Ayerst Research, Radnor, Pennsylvania
 19087; Endocrinology, 1998 Mar, 139:3, 939-48

 11) Growth hormone inhibits the hypophysectomy-induced
 expression of galanin in hypothalamic neurons of the toad
 (Bufo arenarum hensel); González Nicolini MV; Orezzoli AA;
 Achi MV; Villar MJ; Tramezzani JH; Instituto de
 NeurobiologÆia, Buenos Aires, Argentina; Gen Comp
 Endocrinol, 1997 Mar, 105:3, 323-32

 12) An alternate pathway for visual signal integration into
 the hypothalamo-pituitary axis: retinorecipient
 intergeniculate neurons project to various regions of the
 hypothalamus and innervate neuroendocrine

 cells including those producing dopamine; Horvath TL ;
 Department of Obstetrics and Gynecology, Yale University
 School of Medicine, New Haven, Connecticut 06520, USA.

 13) Regulation of anterior pituitary galanin and vasoactive
 intestinal peptide by oestrogen and prolactin status;
 Hammond PJ; Khandan Nia N; Withers DJ; Jones PM;
 Ghatei MA; Bloom SR; Department of Medicine, Royal
 Postgraduate Medical School, London, UK; J Endocrinol,
 1997 Feb, 152:2, 211-9

 14) Hypothalamic galanin: control by signals of fat
 metabolism; Wang J; Akabayashi A; Yu HJ; Dourmashkin J;
 Alexander JT; Silva I; Lighter J; Leibowitz SF The
 Rockefeller University, 1230 York Avenue, New York,
 NY10021, USA; Brain Res, 1998 Aug, 804:1, 7-20

 15) Elevated serum prolactin concentrations in
 phenylketonuric patients on a 'loose diet'; Schulpis KH;
 Papakonstantinou E; Michelakakis H; Theodoridis T;
 Papandreou U; Constantopoulos A;  Institute of Child
 Health, Aghia Sophia Children's Hospital, Athens, Greece;
 Clin Endocrinol (Oxf), 1998 Jan, 48:1, 99-101

 16) Prolactin activates tyrosyl phosphorylation of insulin
 receptor substrate 1and phosphatidylinositol-3-OH kinase;
 Berlanga JJ; Gualillo O; Buteau H; Applanat M; Kelly PA;
 Edery M; Departamento de Biologia Molecular, Universidad
 Autonoma de Madrid, Facultad de Ciencias, 28049 Madrid,
 Spain; J Biol Chem, 1997 Jan, 272:4, 2050-2

 17) Galanin regulates prolactin release and lactotroph
 proliferation; Wynick D; Small CJ; Bacon A; Holmes FE;
 Norman M; Ormandy CJ; Kilic E; Kerr NC; Ghatei M;
 Talamantes F; Bloom SR; Pachnis V

 Department of Medicine, Bristol University, Marlborough
 Street, Bristol BS2 8HW, United Kingdom; Proc Natl Acad
 Sci U S A, 1998 Oct, 95:21, 12671-6

 18) Psychological Well-Being Before and After Growth
 Hormone Treatment in Adults with Growth Hormone
 Deficiency; McGauley GA, Cuneo RC, Salomon F et al.;
 Hormone Research 1990;33 (suppl 4):52-54.

 19) Advances in recombinant Human Growth Hormone
 Replacement Therapy in Adults; Steve Grinspoon MD,
 Neuroendocrine clinical center.

 20) Conformational studies of a potent
 Leu11,D-Trp12-containing lactam-bridged parathyroid
 hormone-related protein-derived antagonist; Maretto S;
 Schievano E; Mammi S; Bisello A; Nakamoto C; Rosenblatt

 M; Chorev M; Peggion E ; Department of Organic
 Chemistry, Biopolymer Research Center, University of
 Padova, Italy; J Pept Res, 1998 Sep, 52:3, 241-8

 21) Evaluation of Urinary Profiles Obtained from People
 with Autism and Associated Disorders. Part 1:
 Classification of Subgroups;  Paul Shattock and Dawn
 Savery Autism Research Unit, University of Sunderland
 Sunderland SR2 7EE Subreference: Shattock P., Savery D.
 Urinary Profiles of People with Autism: possible
 implications and relevance to other research. Proceedings
 from conference Therapeutic Intervention in Autism:
 perspectives from research and practice held at the
 University of Durham April 1996. Published by Autism
 Research Unit and NAS, 309-326.

 22) Differential distribution of corticotropin-releasing
 hormone immunoreactive axons in monoaminergic nuclei of
 the human brainstem; Austin MC; Rhodes JL; Lewis DA
 ;Department of Psychiatry, Western Psychiatric Institute
 and Clinic, University of Pittsburgh School of Medicine,
 Pennsylvania 15213, USA.

 Neuropsychopharmacology, 1997 Nov, 17:5, 326-41

 23) The chemical characterization of melanin contained in
 substantia nigra of human brain; Zecca L; Mecacci C;
 Seraglia R; Parati E ; Istituto Tecnologie Biomediche
 Avanzate, CNR, Milano, Italy.

 Biochim Biophys Acta, 1992 Jan 16, 1138:1, 6-10

 24) Changes in the processing of pro-dynorphin end
 products in the substantia nigra during neonatal
 development. Sei CA; Dores RM ; University of Denver,
 Department of Biological Sciences, CO 80208.

  Peptides, 1990 Jan-Feb, 11:1, 89-94

 25)  Brainstem and cerebellar vermis involvement in
 autistic children; Hashimoto T; Tayama M; Miyazaki M;
 Murakawa K; Kuroda Y ;Department of Pediatrics,
 University of Tokushima School of Medicine, Japan J Child
 Neurol, 1993 Apr, 8:2, 149-53

 26) Galanin-immunoreactive synaptic terminals on basal
 forebrain cholinergic neurons in the rat; Henderson Z;
 Morris N; Department of Physiology, University of Leeds,
 United Kingdom;  J Comp Neurol, 1997 Jun, 383:1, 82-93

 27) Nerve growth factor inhibits sympathetic neurons'
 response to an injury cytokine; Shadiack AM; Vaccariello
 SA; Sun Y; Zigmond RE ; Department of Neurosciences,
 Case Western Reserve University,

 10900 Euclid Avenue, Cleveland, OH 44106-4975, USA;
 Proc Natl Acad Sci U S A, 1998 Jun, 95:13, 7727-30

 28) Magnetic resonance imaging in autism: preliminary
 report; Hashimoto T; Tayama M; Mori K; Fujino K;
 Miyazaki M; Kuroda Y Department of Pediatrics, University
 of Tokushima School of Medicine,

 Japan; Neuropediatrics, 1989 Aug, 20:3, 142-

 29) Brainstem involvement in high functioning autistic
 children; Hashimoto T; Tayama M; Miyazaki M; Murakawa
 K; Shimakawa S; Yoneda Y; Kuroda Y; Department of
 Pediatrics, University of Tokushima School of Medicine,
 Japan; Acta Neurol Scand, 1993 Aug, 88:2, 123-8

 30) Development of the brainstem and cerebellum in
 autistic children; Hashimoto T; Tayama M; Murakawa K;
 Miyazaki M; Yoshimoto T; Harada M; Kuroda Y;
 Department of Pediatrics, University of Tokushima School
 of Medicine; No To Hattatsu, 1994 Nov, 26:6, 480-5

 31) Development of the brainstem and cerebellum in
 autistic patients; Hashimoto T; Tayama M; Murakawa K;
 Yoshimoto T; Miyazaki M; Harada M; Kuroda Y ; University
 of Tokushima School of Medicine;  J Autism Dev Disord,
 1995 Feb, 25:1, 1-18

 32) Differential effects of the neuropeptide galanin on
 striatal acetylcholine release in anaesthetized and awake
 rats; Antoniou K; Kehr J; Snitt K; Ogren SO ; Department
 of Neuroscience, Karolinska Institute, Stockholm, Sweden;
 Br J Pharmacol, 1997 Jul, 121:6, 1180-6

 33) Effects of galanin on dopamine release in the central
 nervous system of normotensive and spontaneously
 hypertensive rats; Tsuda K; Tsuda S; Nishio I; Masuyama
 Y; Goldstein M; Department of Medicine, Wakayama
 Medical College, Japan; Am J Hypertens, 1998 Dec, 11:12,
 1475-9

 34) Hypothalamic and hypophyseal regulation of growth
 hormone secretion; Bluet Pajot MT; Epelbaum J; Gourdji
 D; Hammond C; Kordon C ; UnitÆe de Recherche sur la
 Dynamique des SystÄemes

 Neuroendocriniens (US59), INSERM, Paris, France; Cell Mol
 Neurobiol, 1998 Feb, 18:1, 101-23

 35) Effects of food deprivation on the GH axis:
 immunocytochemical and molecular analysis; Brogan RS;
 Fife SK; Conley LK; Giustina A; Wehrenberg WB ;
 Department of Biological Sciences, University of
 Wisconsin-Milwaukee, USA; Neuroendocrinology, 1997
 Feb, 65:2, 129-35

 36) Galanin: analysis of its coexpression in
 gonadotropin-releasing hormone and growth
 hormone-releasing hormone neurons; Hohmann JG; Clifton
 DK; Steiner RA ; Program for Neurobiology and Behavior,
 University of Washington,  Seattle 98195, USA; Ann N Y
 Acad Sci, 1998 Dec 21, 863:, 221-35

 37) Differences in brain metabolites between patients with
 autism and mental retardation as detected by in vivo
 localized proton magnetic resonance spectroscopy;
 Hashimoto T; Tayama M; Miyazaki M; Yoneda Y;
 Yoshimoto T; Harada M; Miyoshi H; Tanouchi M; Kuroda Y
 ; Department of Pediatrics, University of Tokushima
 School of Medicine, Tokyo, Japan;  J Child Neurol, 1997
 Feb, 12:2, 91-6

 38) Proton magnetic resonance spectroscopy of the brain
 in three cases of  Rett syndrome: comparison with autism
 and normal controls; Hashimoto T; Kawano N; Fukuda K;
 Endo S; Mori K; Yoneda Y; Yamaue T; Harada M; Miyoshi
 K ; Department of Child Neurology, National Center
 Hospital for Mental, Nervous, and Muscular Disorders,
 NCNP, University of Tokushima,  Japan; Acta Neurol
 Scand, 1998 Jul, 98:1, 8-14

 39) Drugs of abuse and stress increase the expression of
 GluR1 and NMDAR1 glutamate receptor subunits in the rat
 ventral tegmental area: common adaptations among
 cross-sensitizing agents; Fitzgerald LW; Ortiz J; Hamedani
 AG; Nestler EJ  Department of Psychiatry, Yale University
 School of Medicine, Connecticut Mental Health Center,
 New Haven 06508, USA; J Neurosci, 1996 Jan, 16:1,
 274-82

 40) Galanin receptor-mediated inhibition of glutamate
 release in the arcuate nucleus of the hypothalamus;
 Kinney GA; Emmerson PJ; Miller RJ ; Department of
 Pharmacological and Physiological Sciences, The
 University of Chicago, Chicago Illinois, 60637, USA; J
 Neurosci, 1998 May, 18:10, 3489-500