Lutein free diet:Autistic children visual impairment

What is lutein?
Lutein is a yellow carotenoid pigment produced by plants, and found in macula, the small, central area covering the retina. Lutein is believed to protect the eye and optic nerves, as a filter and as an anti-oxidant. Lutein belongs to xanthophylls, a subgroup in the carotene family of plant secondary metabolism products, which consist of over 600 phytochemicals derived from C5 isoprene, known as the carotenoid pigments. These pigments give yellow, green or orange coloration to vegetables and fruits and they are precursors for Vitamin A. Lutein is naturally found in egg yolk, and several plants including some flowers, red peppers, collard greens, kale, leeks, peas, romain lettuce, mustard and spinach.
In the eye, lutein is the primary carotenoid present in the central area of the retina, called macula. Lutein is thought to act as a filter to protect the light-sensitive photoreceptor cells (cone cells) in macula from potentially damaging forms of light and light-originated free radical damages.



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The lutein free diet, a treatment option for autism. Review of lutein as it relates to autism. Copyright”2003 World Community Autism Program, publishing Max and Sandra Desorgher, Directors WCAP, S.A. Introduction In our previous work, we have described how the human immune system could have evolved to result in an immune system selection of lutein as a non-self pathogen. 113, 67In this article, we review the literature on lutein as it relates to autism and a lutein-free diet as a treatment option. Visual impairment: “Ten autistic children, 6 girls and 4 boys, underwent a complete ophthalmologic examination in the Department of Pediatric Ophthalmology at the Hospital La Timone, Marseilles, France. Their age ranged from 1 to 14 years (mean = 8.5 +/- 3.8). RESULTS: Refraction showed: • Hypermetropia (far-sighted) in 7 cases (70%); • Astigmatism (Unequal curvature of the refractive surfaces of the eye, hence a point source of light cannot be brought to a point focus on the retina, but is spread over a diffuse area) in 6 cases (60%) • Strabismus (deviation of the eye which the patient cannot overcome) was present in 6 cases (60%) CONCLUSION: Ophthalmologic findings in autistic children appear to be mainly unilateral or bilateral astigmatism and binocular vision troubles. They can lead to amblyopia (chronic visual disorders) with the risk of functional loss of vision. Early diagnosis of visual problems in autistic children is also essential in order to be able to propose adequate psychological and educational care for the children and their family.” [Ophthalmologic signs in children with autism; Denis D et al; 1997] “A comparison between the 15 blind children who had IQs over 70 and 10 sighted children group-matched for age and verbal ability revealed that a number of autistic-like features were more common in the blind. When the nine blind children who had IQs less than 70 were compared with nine group-matched autistic children, the picture that emerged was of substantial overlap in clinical presentation, despite subtle differences on clinical impression. Similar results were obtained when blind subgroups were reconstituted according to the children's non-autistic or autistic-like clinical presentation, rather than IQ.”17 These studies strongly point to a disturbance which could be anticipated in a metabolism with an abnormal immunogenetic (IoGc) relationship to lutein (xanthophyllic pigments) resulting in the ophthalmologic findings in the eyes of people with autism. Coupled with dietary information which strongly indicates many people and particularly young children with autism actively attempt to avoid dietary lutein sources, the theory that lutein is a potential causal factor in autism is strongly supported by the research. 67
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“Children with blindness due to retinopathy of prematurity (ROP)—who are at greatly increased risk of cerebral damage - have been noted to have a high rate of autistic symptoms, but systematic controlled studies have been lacking. A controlled population-based study was performed; one group was blind due to ROP (N=27) and the other was congenitally blind due to hereditary retinal disease (N=14). Fifteen of the 27 children with ROP had autistic disorder.”18 The controlled study clearly shows that a disease which is suspected to result from lack of lutein protection in the eye has a strong occurrence within the autism population. It is possible, if not probable, that the lutein disturbance goes further than just a lack of eye pigment protection for people with autism. 67 Additional reports provide information such as incidents of ‘delayed onset of visual maturation’ - children born blind who later develop visual acuity with onset of autistic symptomology. 103 Blindness ‘As early as 1964, Fraiberg and Freedman made the observation that "ego deviation" (as they termed this condition) was present in 25-30% of blind children. This of itself is a very alarming assertion which might have been expected to arouse considerable concern among parents, educators and doctors. Perhaps one reason that it did not give rise to widespread comment is the association between visual impairment and learning disability. It is, of course, hard to obtain accurate data on the frequency with which learning disability accompanies visual impairment, not least because visual impairment is greatly under-reported in children with severe and complex disabilities. However, given the relative rarity of conditions resulting in "uncomplicated" blindness, compared to the more frequent situation in which visual impairment is just one component of a more widespread disability (as can occur in prematurity, pre-natal infection, birth asphyxia, various syndromes, etc), one can give a conservative estimate that at least 50% of blind children might be expected to have learning disability. Looking at the relationship between learning disability and autism, Wing and Gould, in their large population-based study in Camberwell, found the triad of impairments which characterise autism in 56% of those with severe learning disability (IQ <50). It might therefore be surmised that since learning disability is a common accompaniment of visual impairment, and autism a common accompaniment of learning disability, the association between visual impairment and autism needs no further explanation or investigation. … Perhaps a partial answer to this problem lies in the question of whether the behavioural disturbance observed in visually impaired children is the same phenomenon as autism in the sighted, or whether we are observing a superficially similar end-point arising from two quite different processes. At this point it is necessary to take a step back and consider a fundamental question; namely, what is autism? Accepting that our knowledge of normal social development in blind babies is very sketchy, the next question to address is which social development processes can go wrong. It has taken a long time to reach an understanding that sighted autistic children do not have a global impairment in their social interactions, and this is a widespread source of confusion amongst both parents and professionals. In fact, very specific processes are affected:
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AUTISTIC CHILDREN ARE ABLE TO: Show attachment behaviors Show proximity seeking behaviors Recognize self/non-self in the mirror and recognize faces of other people AUTISTIC CHILDREN ARE POOR AT: Sharing and directing attention Imitation Recognition of affect To sum up the current state of knowledge, we have a poor grasp of how normal social development proceeds in blind children, and given the blind child's very different experience of the world, it is in some ways more remarkable that the process frequently succeeds than that it sometimes fails. Whilst we might make the assumption that the autistic-like picture observed in a proportion of blind children arises from the same core deficit as that in sighted autistic children, we do not yet have enough data on the range of normal social development in blind children to be able to prove this assertion, not to identify early markers of incipient disaster. The field of visual impairment and autism is extremely confusing and this paper has perhaps raised far more questions than it has answered. Nonetheless, although the "tidy-minded" doctor likes to take a cause-effect approach to developing treatment approaches, this is often not the way that medicine advances, with progress in appropriate treatment and remediation often preceding our understanding of causation. For this reason it is quite possible to attack the problem from both ends and hope that somewhere in the midst of the confusion we are able to advance our management of this difficult condition to the advantage of the children in our care.’ 78 Vision impairment as an established finding in autism The 1996 paper by Dr. Cass was unfortunately published just a year before the Denis paper ‘Ophthalmologic signs in children with autism’, 1997. Had this study been available when Dr. Cass was presenting her information then she might have had greater confidence in the 1964, Fraiberg and Freedman observation that "ego deviation" (as they termed this condition) was present in 25-30% of blind children. The current research includes that many children have overlapping blindness and autism and that a significant percentage of the sighted children with autism have some severe ophthalmologic signs. Embryogenesis Evidence exists which suggests that human rhodopsin activation is developing within the embryonic kidney cells or as these are forming. Vitamin A actions which occur in the mammalian eye are being determined during embryogenesis. 19Evidence correlates ‘retinal histopathology with functional changes caused by the rhodopsin Q64ter mutation. …Microscopic changes in the donor retinas correlated well with the abnormalities in visual function in the patient donor and other family members. Postreceptoral ERG defects may relate to the abnormal photoreceptor processes found in the inner retina.’42 These types of findings correlate well to scientific investigation which alludes to changes in the human genome, evolution of the human immune system and changes taking place which take us one step farther from plant life. ‘The number of pigments found in the different animals increases from man to fish.’ 45
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Beta-carotene is not Vitamin A The simple truth is vitamin A, not beta-carotene, is needed to prevent night blindness, to protect from vitamin A deficiency syndromes and protect from vaccine related injuries which are known to cause blindness and death. 47, 48, 49, 50, 51, 52‘Vitamin A deficiency is a major public health problem in the countries of the Sahel. It causes xerophthalmia and high rates of child mortality and it occurs mostly in underdeveloped regions. People of all ages may suffer from vitamin A deficiency but it is a particular problem in pre-school-age children. Each year, about 250,000 children throughout the world become blind due to vitamin A deficiency. Measles, pneumonia and diarrhea reduce the child's reserves of retinol and increase the dietary requirement for vitamin A. Improvement of social conditions is a radical approach to preventing vitamin A deficiency.’ 58 The most readily available, cheap, locally grown foods in Africa include and are primarily rich sources of both beta-carotene and lutein including corn (mealie meal), spinach, many fruits and vegetables and eggs. More expensive and less readily available foods include fish and dairy the primary food sources of vitamin A. Many types of cheap vegetable oils and cheap margarine products are also available whereas butter and healthy oils are significantly more expensive. Many nuts are grown in Africa but often these foods are exported and when they are sold in Africa they are sold at world market prices keeping them out of the reach of most families many of whom are actively employed in production and harvesting of these exported foods. Often migrant farm workers are working for less than minimum wages which are now set at the equivalent of 45 cents (US$) per hour (2003) in South Africa. Millions of people are living below the UN defined poverty level of $1.00 per day. Vitamin A deficiency ‘Vitamin A was first discovered in 1913. Its deficiency was soon associated in animal models and case reports with stunting, infection, and ocular changes (xerophthalmia) resulting in blindness. The ocular consequences dominated clinical interest through the early 1980s. A longitudinal prospective study of risk factors contributing to vitamin A deficiency and xerophthalmia revealed a close, dose-response relationship between the severity of mild preexisting vitamin A deficiency and the subsequent incidence of respiratory and diarrheal infection (relative risk [RR], 2.0-3.0) and, most dramatically, death (RR, 3.0-10.0). Subsequent community-based prophylaxis trials of varying design confirmed that vitamin A supplementation of deficient populations could reduce childhood (1-5 years old) mortality by an average of 35%. Concurrent hospital-based treatment trials with vitamin A in children with measles revealed a consistent reduction in measles-associated mortality in Africa of at least 50%. It is now estimated that improving the vitamin A status of all deficient children worldwide would prevent 1-3 million childhood deaths annually.’ 59The World Health Organization has made an error, nearly four decades ago, when they included recommendations in the food guide which were based on evidence that some people could produce vitamin A from beta-carotene precursor foods. 46Science has been trying to prove this for nearly four decades and the jury is still undecided. 1, 6, 8, 12, 16, 28, 29The expert witnesses don’t agree and Science is often misused to sway the public interest. 44Having made such a heinous error, the World Health Organization, has not yet come forth to acknowledge the mistake. ‘Nutritional blindness is loss of useful vision resulting from vitamin deficiency. Vitamin A malnutrition Xerophthalmia refers to all of the ocular manifestations of
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inadequate metabolism of vitamin A, nutritional blindness being the end result of the most severe cases. The estimated overall prevalence of nutritional blindness in Africa is very low, below the WHO levels of significance, although isolated clusters of locally high prevalence exist, usually in arid, sparsely-populated regions. The peak age group affected is 2-year olds, with most nutritional blindness having its effect before age 6 years. Xerophthalmia may be considered as a serious side effect of protein-energy malnutrition (PEM). When associated with corneal sequelae of xerophthalmia, PEM has an estimated overall mortality of 50%. Intervention programs, therefore, are more appropriately aimed at the broader condition of life-threatening PEM than at the specifically vision-threatening problem of xerophthalmia.’ 58 ‘Pupils attending 12 schools for the blind in Malawi, 3 schools in Kenya and 2 schools in Uganda were examined to determine the causes of severe visual impairment or blindness (visual acuity in the better eye of less than 6/60). A total of 491 pupils aged 3-22 years was examined. Visual acuity was measured in each eye using a Snellen E chart. …Corneal pathology, attributed to vitamin A deficiency and measles infection in the majority, was responsible for proportionally more severely visually impaired /blind (SVI/BL) in students in Malawi than in Uganda or Kenya’ 60 Vitamin A deficiency is not limited to the poorer nations: ‘Studies from Africa suggest that vitamin A supplementation may reduce morbidity and mortality rates associated with measles among poorly nourished children. We studied 20 children with measles in Long Beach, Calif., and found that 50% (95% confidence interval; 28% to 72%) were vitamin A deficient. This frequency among presumably well nourished American children supports evaluation of vitamin A status as a part of acute management of measles in the United States. 61‘Health conscious’ Americans with limited information on nutrition in public education have relied on the food guide pyramid for several decades. Fear of fats and cholesterol as well as inaccurate reporting of vitamin A bio-availability from pre-cursor beta-carotene foods has likely contributed to decreased intake of natural vitamin A foods and use of truly supportive cod-liver oil supplementation. Fish liver oil supplementation is the first recorded supplement used in the human diet with records identifying this practice in Ancient Egypt (Olsen, J). WHO: Edible vaccines, genetic modification of foods and beta-carotene Instead WHO continues with efforts to produce even more potentially population damaging interventions; supporting research into edible vaccines 62. ‘Vaccine-induced immunity against measles is less robust than natural immunity. Waning of immunity in vaccines may eventually require a revaccination of adults. Measles antigens expressed in plants have been shown to be antigenic and immunogenic both after invasive and oral vaccination. Strategies for the vaccination of adults, the potential of an oral measles vaccine produced in edible plants and the design of suitable antigens are discussed.’ 64 WHO is actively involved in genetic modification of foods to increase carotenoid production in plant foods and allowing mega-dosing of infants, children and study participants with precursor beta-carotene all in the name of science.’ 53A deficiency of vitamin A can result in tragic errors when the dietary source of vitamin A is identified to be present but it has been calculated from the dietary precursor beta-carotene. How many studies have provided false information based on the findings where carotenoids were considered adequate sources of essential fat
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soluble vitamin A? Research continues and it has been determined that supplementing vitamin A at the time of vaccination does not provide the hoped for change in vitamin A status. Research continues to find whole populations which cannot make vitamin A from carotenoids such as this study from Indonesia: ‘The subgroup that was most in need of vitamin A could not obtain it from plant foods.’ 75Marion Nestle PhD says it best: ‘The suggestion that “golden” rice, bio-engineered to contain ß-carotene, could have “a real impact on the health of children living in Southeast Asia” deserves critical scrutiny from nutrition professionals. This rice, although not yet available commercially, has become the “poster child” of the food biotechnology industry’s extensive public relations campaign to convince the public that the benefits of genetically engineered agricultural products outweigh any safety, environmental, or social risks they might pose. National magazines promote golden rice as a means to prevent the more than one million annual deaths and cases of blindness that occur among children in developing countries as a result of vitamin A deficiency. The creation of golden rice appears to confirm the belief that biotechnology is the key to solving world food and nutrition problems. . . . Consideration of basic principles of nutrition suggests that rice containing ß-carotene is unlikely to alleviate vitamin A deficiency. To begin with, the bio-availability of ß-carotene is quite low - 10% or less by some estimates. To be active, ß-carotene - a pro-vitamin - must be split by an enzyme in the intestinal mucosa or liver into two molecules of vitamin A. Like vitamin A, the pro-vitamin is fat-soluble and requires dietary fat for absorption. Thus, digestion, absorption, and transport of ß-carotene require a functional digestive tract, adequate protein and fat stores, and adequate energy, protein, and fat in the diet. Many children exhibiting symptoms of vitamin A deficiency, however, suffer from generalized protein-energy malnutrition and intestinal infections that interfere with the absorption of ß-carotene or its conversion to vitamin A. In numerous countries where vitamin A deficiency is endemic, food sources of ß-carotene are plentiful but are believed inappropriate for young children, are not cooked sufficiently to be digestible, or are not accompanied by enough dietary fat to permit absorption. In addition to doubts about cost and acceptability, biological, cultural, and dietary factors act as barriers to the use of ß-carotene, which explains why injections or supplements of pre-formed vitamin A are preferred as interventions. The extent to which the ß-carotene in golden rice can compensate for these barriers is limited. Vitamin A deficiency is undeniably the single most important cause of blindness among children in developing countries and a substantial contributor to illness and death from infectious diseases. Mortality rates are higher among children with even mild vitamin A deficiency, but fall by as much as 54% when vitamin A - not ß-carotene - is supplemented or injected. Because such intervention methods are expensive and difficult to accomplish in the field, and because so many children exhibit signs of generalized protein-energy malnutrition, food-based approaches to improving vitamin A status seem especially desirable. The addition of a one or two nutrients to an existing food does not constitute a food-based approach. Furthermore, the use of ß-carotene as a single-nutrient supplement itself raises questions. Although fruits and vegetables containing ß-carotene are demonstrably protective against disease, the results of clinical trials of ß-carotene supplements as a means to prevent cancer or cardiovascular disease have proved disappointing. Some laboratory studies support the idea that ß-carotene produces biological effects that
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might protect against cancer, but others suggest that it might be co-carcinogenic. Still others argue that ß-carotene is a pro-oxidant that may be harmful or beneficial, depending on circumstances. What all this means is that the short- and long-term effects of supplementation of ß-carotene as a single nutrient - distinct from the foods that contain it - are as yet uncertain. The complexity of the physiological, nutritional, and cultural factors that affect vitamin A status suggest that no single-nutrient added to food can be effective as a remedy for dietary deficiencies. Instead, a combination of supplementation, fortification, and dietary approaches is likely to be needed, along with a substantial commitment to improve socioeconomic status. Food biotechnology may yet lead to products that improve nutrition and health, but at the moment its benefits remain theoretical.’ 63Vitamin A vs. beta-carotene – what the research really says: What we do know is that vitamin A retinol levels may rise when carotenoids are ingested or given as supplements, in some people. This does not prove that carotenoids are being converted to retinol. Carotenoids compete for retinol binding receptor sites. ‘The most likely explanations for carotenoid interactions appear to be competition for incorporation into micelles, carotenoid exchange between lipoproteins in the postprandial state, and inhibition of provitamin A (beta-carotene) cleavage.’ 3Some populations studied have NO increase in vitamin A levels when given vitamin A precursor foods or supplements. 73, 74Major studies on the effectiveness of beta-carotene supplementation for cancer prevention called the CARET studies failed miserably and had to be stopped early. ‘The analyses of two major lung cancer prevention trials, beta-Carotene and Retinol Efficacy Trial (CARET) and Alpha-Tocopherol Beta-Carotene (ATBC), were also published this past year. Both found an increased incidence of lung cancer in individuals receiving beta-carotene.’ 54‘CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29,133 male smokers in Finland.’ 55‘Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.’ 56 Evolution of color R.A. Nicolaus in his review of the evolution of pigments in living species states that there is every indication that pigments are used less and less over time and that the most decreased levels of use are in humans. 45This trend in evolution towards limited use of pigments as well as Science which still includes that carotenoids are NOT essential to the human diet are well hidden from public attention. The health food industry, pharmaceutical companies and even food suppliers have been allowed to replace the accurate labeling of beta-carotene with the vitamin A description without industry regulation. Beta-carotene has gradually and deliberately become synonymous with vitamin A in the public eye and indeed in some medical literature and product representation and through misrepresentation of the Science some doctors rapidly assume or are erroneously taught that beta-carotene can replace essential vitamin A. 44
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‘Physicians are accustomed to making decisions based on information regarding the prevalence of disease, symptoms, physical signs, laboratory test results, and the risks and benefits of alternative treatments. If nutritional assessment and therapeutics are to become more common components of medical practice, significant barriers in each of these areas must be overcome. Even rudimentary dietary assessment is often missing from physician education. Dietary assessment tools that are readily available and that have demonstrated usefulness are largely unknown. In addition, many nutritional interventions have not been formally investigated in randomized, controlled trials, and thus their cost-effectiveness remains unknown. We present one approach to these issues by discussing the construction of a decision model examining strategies for vitamin D and calcium screening. The application of medical decision making techniques to problems in clinical nutrition illustrates how findings from research studies may be used to determine the risks, benefits and costs of alternative population based health related nutrition policies which can then be applied by physicians in their daily interactions with patients.’ 111Evolutionary stress Not only is the human population showing signs of evolutionary stress but so are the animals in our food chain. ‘Pale-bird syndrome (PBS), defined as the failure of birds to realize the color potential of their diet, has been demonstrated to be caused by malabsorption or by hyperexcretion of carotenoids’ 65 ‘Birds hatched from breeders fed lutein had significantly lower relative liver weights than chicks of the other treatments, whereas birds hatched from the breeders fed beta-carotene and canthaxanthin had significantly lower spleen weights than the control. These experiments suggest that carotenoids may not be effective in increasing neonatal immune response when they supplement practical breeder diets.’ 66 Carotenoid toxicity72 Carotenoids can be toxic and even result in fatalities. Aplastic anemia and Canthaxanthin retinopathy have been reported. 70, 71‘Tanning pills,’ commonly available by mail order or sold in tanning salons are reported to have caused aplastic anemia, which led to death in a healthy young woman. A 20-year-old woman was hospitalized with headaches, fatigue, a general feeling of not being well, easy bruising, and weight loss four months after beginning the use of canthaxanthin-containing tanning pills. She had noticed the onset of fatigue and easy bruising about two weeks after beginning the pills. Canthaxanthin can remain in the body for long periods of time. It has been found in blood several months after use was discontinued. It may accumulate in the retina of the eye, and has been reported to cause hepatitis (inflammation of the liver) with itching and hives.” 71“As reported earlier, crystalline yellow-glistening deposits in the retinal inner layer were identified in 22 of 53 patients treated with PHENORO (containing 10 mg beta-carotene and 15 mg canthaxanthin per capsule) for various light sensitive dermatoses at cumulative doses of canthaxanthin of up to 178 g for up to 12 years. 14 of the 22 patients with deposits could now be investigated again, 5 years after discontinuation of treatment. There was an extensive reduction of the number of deposits, confirming other reports which have demonstrated that the formation of the crystalline deposits is reversible. Analysis of serum samples revealed significant concentrations of canthaxanthin, resulting from the intake of this carotenoid via food.” 70
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Something is wrong ‘A north Wales-based supermarket chain has stopped selling eggs with artificially coloured yolks after its chairman began keeping free-range birds and realised the colour was false. Deeside-based Iceland - the first supermarket chain to ban genetically modified foods - has now removed chemical colourants from its fresh egg range. Chairman Malcolm Walker said he discovered the myth behind the bright yellow yolk while rearing his own chickens. ‘Something was wrong’“I keep eight or nine hens at home just as I grow my own vegetables,” he explained. “I became worried about the eggs when I noticed the yolks were different colours. I had even thrown ones with lighter coloured yolks away as I thought something was wrong.” Mr Walker consulted Iceland's egg buyer about the issue just eight weeks ago and discovered the difference in colour was a totally natural occurrence. Damaged eye retinas“I found, to my horror, we have been dyeing eggs for 25 years in Britain by putting commercial dye in hens’ feed.” The shade of yellow of an egg's yolk depends on what a hen has eaten in the 10 days before laying it. Commercial animals are fed on high protein pellets which can contain three artificial chemicals to create an even yellow yolk. Of the three artificial colours used Iceland claim some 30% contain Canthaxanthin (E161g). This substance was formerly used in artificial tanning pills, but withdrawn when it was suggested its use could damage the eye's retina. Customer reaction not positiveAlthough eggs stamped with the egg industry's Lion code do not contain this, Iceland says another 30% of eggs on sale in Britain which are not Lion branded could contain the chemical. Iceland admits that initial customer reaction on testing panels to the paler yolks was not positive. But when shoppers heard the story behind the change in colour they wanted the more natural product.’ 68 European Commission The additives: carotenoid sources of canthaxanthine and lutein from substances such as marigold flowers and sunflowers makes egg yolks appear more yellow‘The additive makes egg yolks appear more yellow. The European Union has limited permitted levels of a food additive given to salmon and poultry, which may damage the eye. The chemical, canthaxanthin, is added to feed. It makes salmon appear more reddish, and chicken skin and egg yolks appear more yellow. But research has suggested that a build up of pigments can damage the retina. The level of the chemical allowed in salmon feed is to be cut by over two thirds. Limits will be even stricter in the feed for laying hens. Officials say the restrictions will not have any impact on the quality of farmed salmon or supermarket eggs.AssessmentsThe European Commission said levels of the chemical should be reduced from a maximum of 80mg per kilogram to 25mg per kilogram of feed for fish and poultry, and 8mg per kilogram for laying hens. All EU members will have to enforce new regulations by the end of the year. Commissioner David Byrne said: “Scientific assessments have shown that a high intake of canthaxanthins produces an accumulation of pigments in the retina, affecting the sight. The use of this feed additive is purely cosmetic.” Extreme consumptionA spokeswoman for the UK's Food Standards Agency (FSA) told BBC News Online: “What the EU has been looking at is the very extreme consumption of products
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containing canthaxanthin.” But it's something that's related to long-term exposure rather than acute. “Eating products with low levels of canthaxanthin is not something that people need to be worried about.” She said the FSA wanted to see levels of canthaxanthin in fish flesh, rather than in the feed measured, and labelling of products so consumers could see how much canthaxanthin they contain.’ 69 Lutein in human milk ‘Approximately 5-7% of all infants are born prematurely, and birth before 37 weeks is the most common cause of neonatal mortality, morbidity and long-term disability. Premature infants are poorly equipped for life outside the womb, and oxidant stress has been implicated in the aetiology of visual impairment in these infants, who are often exposed to increased O2concentrations and high light intensity in neonatal units. …Little information is available on blood lutein and zeaxanthin levels in neonates. Levels of lutein in human milk are two to three times higher than those of beta-carotene, whereas their concentrations in the mothers’ blood are approximately the same. Human milk is the main dietary source of lutein and zeaxanthin for infants until weaning occurs. The biochemical mechanisms which mediate the transport of the macular carotenoids into the eye are not known, but tubulin has been identified as the major carotenoid-binding protein, and may play a role in the physiology of the macula.’ 21 Kanner … Early research in autism began with two well-known doctors who followed similar paths. The results of their work have become known today as Autism/Asperger syndrome(s). Swiss psychiatrist Eugen Bleuler first introduced the term autism in 1911. Autism and autistic stem from the Greek word ‘autos’, meaning self. The term autism originally referred to a basic disturbance in schizophrenia, in short, an extreme withdrawal of oneself from the fabric of social life, but not excluding oneself. 76If we were to concentrate on this aspect solely then we would likely agree that even a typical child will exhibit extreme withdrawal from the fabric of social life when they are not well. When we, as humans, fall injured or sick, then our symptoms - pain, weakness, nausea, delirium, stomach ache, muscle contractions, breathing difficulties and the like - force us to withdraw from social life. Kanner reported his findings in an article entitled ‘Autistic Disturbances of Affective Contact’. Out of the 11 cases he reported, eight mentioned an unusual relationship to food, or feeding difficulties in early childhood. From another recent review from the Journal of Abnormal Child Psychology June, 2001 ‘Does DSM-IV Asperger's Disorder Exist?’, we can see that ‘dislike of certain foods’ has been set apart from the diagnostic criteria and is included as an associated feature. From ‘Autistic Disturbances of Affective Contact’ Kanner states “Since 1938, there have come to our attention a number of children whose condition differs so markedly and uniquely from anything reported so far, that each case merits - and, I hope, will eventually receive - a detailed consideration of its fascinating peculiarities. Kanner Case 1 - Donald T: He was breast fed, with supplementary feeding, until the end of the eighth month; there were frequent changes of formulas. ‘Eating,’ the report said, ‘has always been a problem with him. He has never shown a normal appetite.
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Seeing children eating candy and ice cream has never been a temptation to him . . .At mealtime, repeating something that had obviously been said to him often, he said to his mother, “Say ‘Eat it or I won't give you tomatoes, but if you don't eat it I will give you tomatoes,’” or “Say ‘If you drink to there, I'll laugh and I'll smile,’” Case 4 - Paul G: He vomited a great deal during his first year, and feeding formulas were changed frequently with little success. He ceased vomiting when he was started on solid food. He would express his desire for candy by saying, “You want candy.” Case 5 - Barbara K: was referred in February, 1942, at 8 years, 3 months of age. She nursed very poorly and was put on bottle after about a week. She quit taking any kind of nourishment at 3 months. She was tube-fed five times daily up to 1 year of age…She began to eat then, though there was much difficulty until she was about 18 months old. Since then she has been a good eater, likes to experiment with food, tasting, and now fond of cooking…In camp last summer she was well liked, learned to swim, is graceful in water (had always appeared awkward in her motility before), overcame fear of ponies, played best with children of 5 years of age. At camp she slid into avitaminosis and malnutrition but offered almost no verbal complaint. Throughout all these procedures, in which, often after several repetitions of the question or command, she complied almost automatically, she scribbled words spontaneously: ‘oranges’; ‘lemons’; ‘bananas’; ‘grapes’; ‘cherries’; ‘apples’; ‘apricots’; ‘tangerine’; ‘grapefruits’; ‘watermelon juice’; the words sometimes ran into each other and were obviously not meant for others to read. Case 6 - Virginia S: They remember that she loves candy so much and says ‘Chocolate,’ ‘Marshmallow,’ also ‘Mama’ and ‘Baby.’ Case 7 - Herbert B: He vomited all food from birth through the third month. Then vomiting ceased almost abruptly and, except for occasional regurgitation, feeding proceeded satisfactorily…He persistently refused to take fluid in any but an all-glass container. Once, while at a hospital, he went three days without fluid because it was offered in tin cups … He very frequently brought blocks and other objects to his lips. Case 8 - Alfred L: For the first two months, the feeding formula caused considerable concern but then he gained rapidly and became an unusually large and vigorous baby. He did a good deal of ‘worrying’: He frets when the bread is put in the oven to be made into toast, and is afraid it will get burned and be hurt . . .When infantile thumb sucking was prevented by mechanical devices, he gave it up and instead put various objects into his mouth. On several occasions pebbles were found in his stools. Shortly before his second birthday, he swallowed cotton from an Easter rabbit, aspirating some of the cotton, so that tracheotomy became necessary. A few months later, he swallowed some kerosene ‘with no ill effects’. Case 10 - John F: The father said: ‘The main thing that worries me is the difficulty in feeding. That is the essential thing, and secondly his slowness in development. During the first days of life he did not take the breast satisfactorily. After fifteen days he was changed from breast to bottle but did not take the bottle satisfactorily. There is a long story of trying to get food down. We have tried everything under the sun.’ John was born September 19, 1937; his birth weight was 7½ pounds. There were frequent hospitalizations because of the feeding problem. No physical disorder was ever found, except that the anterior fontanelle did not close until he was 2½ years of age. He suffered from repeated colds and otitis media, which necessitated bilateral myringotomy. . . Mild obsessive trends were reported, such as pushing aside the first spoonful of every dish. Discussion: Our patients . . . anxious to keep the outside world away, indicated this by the refusal of food. Donald, Paul (“vomited a great deal during the first year”),
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Barbara (“had to be tube-fed until 1 year of age”), Herbert, Alfred, and John presented severe feeding difficulty from the beginning of life. Most of them, after an unsuccessful struggle, constantly interfered with, finally gave up the struggle and all of a sudden began eating satisfactorily.” 77Biomedical intervention: Novel noninvasive optical techniques being developed may facilitate studies of ocular carotenoids distribution in the human eye and be adapted for use in early screening to identify at risk infants. 20Pigments, colors, vibrations – Autism a disturbance in energy metabolism ‘The pterins, neopterin and biopterin, occur naturally in body fluids including urine. It is well established that increased neopterin levels are associated with activation of the cellular immune system and that reduced biopterins are essential for neurotransmitter synthesis. It has been suggested that some autistic children may be suffering from an autoimmune disorder. To investigate this further we performed high performance liquid chromatography analyses of urinary pterins in a group of pre-school autistic children, their siblings and age-matched control children. Both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values. This supports the possible involvement of cell-mediated immunity in the etiology of autism.’ 105Research continues and ‘Evidence for the presence of pteridines in iridophores, leucophores, and xanthophores in a wide variety of vertebrate chromatophores, and argument that the chemical and functional distinction between pterinosomes and reflecting platelets is not as clear-cut as previously believed. Observations indicate that: (1) Pteridines may, either alone or in conjunction with purines, form pigment granules that reflect light, (2) these pigment granules are highly variable ranging from fibrous pterinosomes to typical reflecting platelets and may be colored, reflect white light, or be iridescent, and (3) many “leucophores” probably contain typical pterinosomes and presumed associated colorless pteridines and are therefore more closely related to erythrophores and xanthophores than to iridophores with which they are usually classified. We propose that the classification of pigment cells should be modified to reflect these facts.’ 22 ‘The fundamentally diverse vertebrate pigment cells, melanophores, xanthophores, and iridophores, contain pigmentary organelles known, respectively, as melanosomes, pterinosomes, and reflecting platelets. Their pigments are melanins, pteridines, and purines. Mosaic pigment cells containing more than one type of organelle have been observed and mosaic organelles containing more than one type of pigment have been discovered. It is proposed that the various pigment cells are derived from a stem cell that contains a primordial organelle of endoplasmic reticular origin. This primordial organelle can differentiate into any of the known pigmentary organelles.’ 23 Finding the truthThe health food industry has obviously already expanded it’s marketable products range to include lutein supplements based on some reports that there is a possibility that macular degeneration is directly related to levels of dietary lutein and no doubt is finding this to be profitable, and at the same time research scientists continue to spend a lot of research dollars trying to prove the theory. Some people, including medical
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people, have been convinced by the early reports. The ongoing research continues and the difficulty of finding a truth that satisfies the demand for scientific proof and settle the dispute is still in the research stages: Human eyes ‘Biochemical research has demonstrated that lutein and zeaxanthin, the two macular carotenoids, are bleachable pigments. Further, evidence suggests that exposure to UV light can degrade plasma carotenoid levels in vivo. The present study investigated the effects of exposure to normal levels of light on the levels of lutein and zeaxanthin in the retina. …The results suggest that lutein and zeaxanthin levels in the eye are unaffected by light and oxidation throughout the day. This justifies current research methods in which Macular Pigment Optical Density (MPOD) measures are made regardless of the time of day. However, significant between-day variance indicates that multiple MPOD measures may be necessary to evaluate lutein and zeaxanthin levels in the retina accurately.’ 29‘Thus a final characterization of the macular pigment shows that it is composed of three carotenoids: lutein, zeaxanthin and meso-zeaxanthin. Our identification of the non-dietary meso-zeaxanthin as a component of the macular pigment dramatically emphasizes the lack of understanding of xanthophyll metabolism by humans…Despite the remarkable concentration of carotenoid present in the macula, the dimensions of this tissue are such that only nanogram amounts of carotenoids are present. The concentration in liver [10] and serum is three orders of magnitude lower. …The difference in macular pigment density between AMDs (Age related macular degeneration) and controls tends to decrease from the inner to medial to outer regions, raising the possibility that the disease itself may be partly responsible for a preferential loss of lutein and zeaxanthin in the macula. …From these data, we conclude that very low carotenoid levels in the retina are associated with an increased incidence of AMD. However, this association may not be causal. It could be, for example, that processes which lead to AMD are also responsible for the retina's sluggishness in accumulating carotenoids.’ 1‘Prospects for future research in the study of macular pigment require new initiatives that will probe more accurately into the localization of these carotenoids in the retina, identify possible transport proteins and mechanisms, and prove the veracity of the photoprotection hypothesis for the macular pigments.’ 32 ‘Xanthophyll epoxides such as neoxanthin, violaxanthin and lutein 5,6-epoxide, are more abundant than epoxy-hydrocarbon carotenes in a number of vegetables and fruits that humans consume. To determine whether xanthophyll epoxides are also absorbed by humans, lutein 5,6-epoxide (taraxanthin) and zeaxanthin 5,6,5'6'-diepoxide (violaxanthin) were chemically prepared, dissolved in corn oil and orally administered to three human subjects. Analysis of plasma for carotenoids within 9 h after a single oral dose of either violaxanthin or taraxanthin failed to show any violaxanthin, taraxanthin or any of their metabolites.’12Sex, eye color and age are reported as significant factors in macular degeneration:
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‘Sex differences in protection of the retina by MP (macular pigment) and in the relationship between the retina, blood and diet could be a factor in the incidence of retinal diseases, especially age-related macular degeneration.’ 13‘Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older individuals worldwide. The disease is characterized by abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium. Although drusen deposition is common in older individuals, large numbers of drusen and/or extensive areas of confluent drusen represent a significant risk factor for AMD. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptor cells of the neural retina. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade.’ 2 It is safe to say that science just does not yet understand carotenoid metabolism in humans. This is not limited to beta-carotene or lutein but would include also sources of other carotenoid pigments as well as pterin and porphyrin substances and food dyes (pteridines) and as yet unidentified substances which get into the human food chain through animal and plant foods we ingest, environmental toxins and degradation products produced in our own bodies when these substances are stored or eliminated. There is a lot of research being carried out and a lot more to come. Science has limitations and funding is a major limitation. Curiosity, interest, intrigue and obsession drive some people to delve deeper into the mass of information and peek into microscopes looking for answers. Obstacles are overcome as scientists discover the laboratory is not always environmentally suited to studying how some bacteria produce pigmented substances in light or in darkness, in aerobic or anaerobic conditions. When a large funding organization has an interest in the findings then studies are funded. When no funding institution has an interest the scientist obsessed by his own curiosity and need to know seeks answers on his own. Some of the greatest scientific discoveries have been made by people with an obsessive need to find the truth. Lutein pigment may be one of the defining substances which elucidate the uniqueness of each individual, used in the immunogenetic development of the embryo to result in defining characteristics of eye color, pigmentation, circadian rhythm and brain function. Research continues: ‘This is a biographical sketch of my research and its related personal episodes with respect to brightly colored pigmentation in lower vertebrates. It includes a brief story of the studies on; (a) pterinosomes as a specific site of pteridine deposition in xanthophores or erythrophores of fish and amphibians, (b) a mosaic phenotype of chromatophores occurring in the reptiles and its implication for their developmental origin and differentiation mechanisms, (c) erythrophoroma as a tumor of erythrophores in goldfish, (d) the pluripotentials of erythrophoroma cells for expression of neural crest-derived characters in vitro, (e) pigment disorders occurring in hatchery-raised flounders and (f) recognition of pigment cell types by murine tyrosinase genes transfected into an orange-colored variant of medaka fish. Some of the personal affairs associated with the history of the Japanese community
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for pigment cell research were described to illustrate the background of these studies.’ Matsumoto30 Pterin metabolism Equally as difficult as carotenoid metabolism is the understanding of pterin metabolism in humans. Conditions of unconjugated pterin metabolism which co-occur with autism include Tuberous Sclerosis, Phenylketonuria, Down’s Syndrome, metal toxicity (lead and aluminum), confusional states, dystonia and depression, as well as conditions with some similarities to autism diagnosed in the adult and aging human population – Alzheimers and Parkinson’s disease. 104The co-occurrence of genetic conditions which involve unconjugated pterin metabolism and eye disorders including blindness co-occurring with autism encourage further study of lutein and pterin - pigment metabolism in the autism population. Substantial evidence exists to suggest that autism is an evolution which has occurred or been exacerbated through use of vaccination. 67 We have very little understanding of the causes of these disease states and even less understanding when they co-occur with autism. ‘Three novel pteridines have been isolated from the urine of patients with a new variant of 6-(L-erythro-1',2'-dihydroxypropyl)-5,6,7,8-tetrahydropterin (tetrahydrobiopterin) deficiency, showing hyperphenylalaninemia. From the results of high performance liquid chromatography, oxidative degradation, and gas chromatography-electron impact mass spectrometry, their structures were identified as 7-(D-erythro-1',2',3'-trihydroxypropyl)-pterin (7-neopterin), 7-(L-erythro-1',2'-dihydroxypropyl)-pterin (7-biopterin), and 6-oxo-7-(L-erythro-1',2'-dihydroxypropyl)-pterin (6-oxo-7-biopterin). The ratio of biopterin to 7-biopterin in the patients' urines was 1:1, and after oral loading with tetrahydrobiopterin, 7-biopterin excretion rose parallel to biopterin. This finding suggests that 7-substituted pterins may be formed endogenously by a yet unknown isomerization reaction. The cause of hyperphenylalaninemia is still unclear. The activities of the enzymes involved in tetrahydrobiopterin biosynthesis and regeneration were found to be normal in the patients, and no effect of 7-biopterin on these enzymes was observed in vitro. However, compared with the normal cofactor, tetrahydrobiopterin, the Km values of tetrahydro-7-biopterin for phenylalanine hydroxylase and dihydropteridine reductase are 20 and 5 times higher, respectively.’ 84 ‘A novel pterin intermediate, in addition to the expected 4a-hydroxytetrahydro-biopterin (4a-OH-BH4) and quinonoid dihydrobiopterin, was generated during catalytic turnover of tyrosine hydroxylase (TH) with tetrahydrobiopterin as the cofactor. Based on chromatographic, spectroscopic and stability properties its structure is proposed to be similar to the product formed by the non-enzymic conversion of synthetic 4a-OH-BH4 [Bailey, Rebrin, Boerth and Ayling (1995) J. Am. Chem. Soc. 117, 10203-10211]. This compound was tentatively described as a 4a-adduct of a side-chain hydroxy group, i.e. the O2', 4a-cyclic-tetrahydrobiopterin (4a-Cyc-BH4). The intermediate generated in the TH reaction has a UV spectrum which is similar to that of 4a-OH-BH4, but elutes with a longer retention time (tR = 1.69 min compared with 1.06 min) on reversed-phase chromatography. Its conversion into quinonoid dihydrobiopterin is catalysed by pterin-4a-carbinolamine dehydratase (EC 4.2.1.96), although 4a-OH-BH4 is the preferred substrate for that enzyme. A precursor-product relationship was demonstrated between 4a-OH-BH4 and the
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putative 4a-Cyc-BH4 intermediate. The apparent stability of this compound is dependent on pH as well as on the nature of the buffer ions. At pH 8.0 a large amount was generated in Hepes and Tris, but little in phosphate buffer. At pH 7.0 in Hepes (standard assay conditions) and Tris buffer the putative 4a-Cyc-BH4, but no 4a-OH-BH4, was observed. None of the intermediates was observed at pH 6.0. The accumulation of these intermediates in the absence of dehydratase has important implications for the assay of TH and phenylalanine hydroxylase activities, and is also compatible with a possible physiological role of the dehydratase in the synthesis of catecholamines in vivo.’34 Disturbance in pigment, pterin and carotenoid metabolism To further contribute evidence of disturbance in pigment, pterin and carotenoid metabolism we can look at Incontinentia pigmenti (IP) (usually lethal prenatally in males) research for Hypomelanosis of Ito (HI)or incontinentia pigmenti achromians has a heavy co-occurrence rate with autism. 67‘Patients with the depigmentation disorder vitiligo lack the capacity to synthesize the melanins from L-tyrosine via the essential activity of tyrosinase. The aim of this study has been to examine both the supply of the substrate (L-tyrosine) and the regulation of tyrosinase in the epidermis of subjects with vitiligo. Patients with this depigmentation disorder have a 3- to 5-fold increase in GTP-cyclohydrolase I activity leading to an excessive de novo synthesis of (6R)5,6,7,8 tetrahydrobiopterin (6-BH4). Continuous production of 6-BH-4 leads to: (1) an accumulation of the non-enzymatic byproduct 7-tetrahydropterin (7-BH4) in the epidermis, and (2) increased synthesis of the catecholamines in keratinocytes, leading to an excess of norepinephrine in both the plasma and urine of these patients. In vitiligo, the time-dependent production of 7-BH4 is caused by decreased 4a-hydroxytetrahydrobiopterin dehydratase activity; the essential enzyme for recycling and maintaining normal levels of 6-BH-4. In the epidermis and in cultured melanocytes, 7-BH4 is a potent competitive inhibitor of phenylalanine hydroxylase (Ki = 10(-6) M) and its accumulation in the epidermis of patients with vitiligo blocks the supply of L-tyrosine from L-phenylalanine. 4a-hydroxytetrahydrobiopterin dehydratase has a dual function as the activator/dimerization catalyst for the transcription factor hepatocyte nuclear factor I (HNF-I). HNF-I binds to a 16-base inverted palindrome which seems to be present on the promoters of both the tyrosinase and phenylethanolamine-N-methyl transferase (PNMT) genes. Therefore, defective 4a-hydroxytetrahydrobiopterin dehydratase in vitiligo influences not only the supply of L-tyrosine but also the transcription of the tyrosinase gene in melanocytes. Furthermore, a similar transcriptional regulation of the PNMT gene in keratinocytes offers a possible explanation for the accumulation of norepinephrine in these patients.’ 35 Vitiligo and its associated phenomena of abnormal tryptophan metabolism, C4Q-null allele, elevated Indole-acroloyl-glycine and pellagra-like photodermatotic conditions are found in autism. Immune, pigment, pterin, tryptophan and brain activity come together ‘Sepiapterin reductase (SPR) is the enzyme that catalyzes the final step of the synthesis of tetrahydrobiopterin (BH4), the cofactor for phenylalanine hydroxylase, tyrosine hydroxylase (TH), tryptophan hydroxylase, and nitric oxide synthase (NOS). Although SPR is essential for synthesizing BH4, the distribution of SPR in the human brain has not yet been clarified. In the present study, we purified recombinant human SPR from cDNA, raised an antibody against human SPR (hSPR), and examined the
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localization of SPR protein and SPR activity. Human brain homogenates from the substantia nigra (SN), caudate nucleus (CN), gray and white matters of the cerebral cortex (CTX), and dorsal and ventral parts of the medulla oblongata (MO) were subjected to Western blot analysis with anti-hSPR antibody or with anti-TH antibody. Whereas TH protein showed a restricted localization, being mainly detected in the SN and CN, SPR protein was detected in all brain regions examined. SPR activity was relatively high compared with the activity of GTP cyclohydrolase I (GCH), the rate-limiting biosynthetic enzyme of BH4, and was more widely distributed than GCH activity. Immunohistochemistry revealed SPR immunoreactivity in pyramidal neurons in the cerebral CTX, in a small number of striatal neurons, and in neurons of the hypothalamic and brain stem monoaminergic fields and olivary nucleus. Double-staining immunohistochemistry showed that TH and SPR were colocalized in the SN dopamine neurons. Localization of SPR immunoreactive neurons corresponded to monoamine or NOS neuronal fields, and also to the areas where no monoamine or NOS neurons were located. The results indicate that there might be a BH4 biosynthetic pathway where GCH is not involved and that SPR might have some yet unidentified function(s) in addition to BH4 biosynthesis.’ 36 Cell death, beautiful colors Brightly colored Fall foliage excites the human traveler and many tourism dollars are to be obtained entertaining the naturalists and fun seekers. The beautiful coloration associated with Fall, Halloween parties and ending with Thanksgiving in the USA are the signs of cell death in the plant which is readying to drop the no longer needed dead and dying foliage. Unconjugated bilirubin (UCB), cell death and disease presentation are being studied. ‘Mitochodrial membrane, with release of intermembrane proteins, has been strongly implicated in cell death. …The pathogenesis of bilirubin encephalopathy and Alzheimer's disease appears to result from accumulation of unconjugated bilirubin (UCB) and amyloid-beta (Abeta) peptide, respectively, which may cause apoptosis. …In this study, we further characterize UCB- and Abeta-induced cytotoxicty in isolated neural cells, and investigate membrane perturbation during incubation of isolated mitochondria with both agents. …Apoptosis was assessed by DNA fragmentation and nuclear morphological changes. …Toxicity occurs through a mitochondrial-dependent pathway, which in part involves opening of the permeability transition pore. Furthermore, membrane permeabilization is required for cytochrome c release from mitochondria …mitochondria is a pharmacological target for cytoprotection during unconjugated hyperbilirubinemia and neurodegenerative disorders...’ 43Developmental patterns in the fish: ‘In the zebrafish, the peripheral neurons and the pigment cells are derived from the neural crest and share the pteridine pathway, which leads either to the cofactor tetrahydrobiopterin or to xanthophore pigments. The components of the pteridine pattern were identified as tetrahydrobiopterin, sepiapterin, 7-oxobiopterin, isoxanthopterin, and 2,4,7-trioxopteridine. The expression of GTP cyclohydrolase I activity during the first 24-h postfertilization, followed by 6-pyruvoyl-5,6,7,8-tetrahydropterin synthase and sepiapterin reductase, suggest an early supply of tetrahydrobiopterin for neurotransmitter synthesis in the neurons and for tyrosine supply in the melanophores. At 48-h postfertilization, sepiapterin formation branches off the de novo pathway of tetrahydrobiopterin synthesis. Sepiapterin, via 7,8-dihydrobiopterin and biopterin, serves as a precursor for the formation of 7-
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oxobiopterin, which may be further catabolized to isoxanthopterin and 2,4,7-trioxopteridine. Neither 7, 8-dihydrobiopterin nor biopterin is a substrate for xanthine oxidoreductase. In contrast, both of these compounds are oxidized at C-7 by a xanthine oxidase variant form, which is inactivated by KCN, but is insensitive to allopurinol. The oxidase and the dehydrogenase form of xanthine oxidoreductase as well as the xanthine oxidase variant have specific developmental patterns. It follows that GTP cyclohydrolase I, the formation of sepiapterin, and the xanthine oxidoreductase family control the pteridine pathway in the zebrafish.’ 37‘Carotenoid compositions of the flesh, skin, and ovaries were determined in sexually maturing and immature Arctic charr (Salvelinus alpinus) fed diets supplemented with astaxanthin (optical isomer ratio (3S,3'S):(3R,3'S; meso):(3R,3'R); 1:2:1). Astaxanthin comprised 64-79% of the flesh carotenoids, and the 3',4'-cis and 3',4'-trans glycolic isomers of idoxanthin, present in a 1:1 ratio, represented 20-35%. The flesh of the sexually maturing charr contained relatively more idoxanthin than that of sexually immature fish (20 vs 35% of total carotenoids), possibly being indicative of a higher metabolic turnover of astaxanthin in the latter. The relative proportions of flesh carotenoids were unaffected by sex. The relative carotenoid composition of ovaries was similar in sexually maturing and immature females. The 3',4'-cis and 3',4'-trans glycolic isomers of idoxanthin (ratio 0.7:1) were the major carotenoids (56% of total), followed by crustaxanthin (20%), and astaxanthin comprised less than 5% of ovarian carotenoids. Three glycolic isomers of crustaxanthin were detected (3,4,3',4'-di-cis-:3,4-cis-3',4'-trans-:3,4,3',4'-di-trans-glycolic isomer ratio 2.6:3.1:1) in the ovaries. Sex and maturity status had no apparent effect on the relative composition of skin carotenoids. The skin carotenoids consisted mainly of diesters (82-87% of total carotenoids) and monoesters (7-13% of total carotenoids). Saponification revealed that astaxanthin comprised 85% and idoxanthin 10% of total carotenoids, and minor amounts of tunaxanthin-, lutein-, and zeaxanthin-like metabolites were also present. Maturity status seems to be more important than sex in determining the relative carotenoid composition of the tissues of Arctic charr, with astaxanthin and its metabolites being selectively accumulated in different tissues.’ 40 ‘Apparent astaxanthin (3,3'-dihydroxy-beta,beta-carotene-4,4'-dione) digestibility coefficients (ADC) and carotenoid compositions of the muscle, liver, whole kidney and plasma were compared in Atlantic salmon (Sa...
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