Wednesday, October 19, 2011

Piracetam

Piracetam used to the be "in" drug for children with T21. And today, a lot of parents give their child Piracetam and believe that it helps him or her. Although I know some who saw no difference. Here is a brief overview on its purported benefits and then an article that talks about its use in the DS community as not properly supported through research. (I'm not one to wait for double blind studies on the actual DS population, but it would be nice to have.)  I've also included my notes as Jett has been taking it for a month and has shown huge improvement! Not knowing that I'd see such a huge improvement, I started Jett on Neuroprotek at around the same time, so I'm sorting through which benefits to attribute to P & which to attribute to NP.

Benefits

Piracetam is said to promote the flow of information (or messages) between the right and left hemisphere of the brain. Dean and Morgenthaler claim that it can enhance memory, language and learning abilities. It may also prevent memory loss and learning difficulties caused by trauma. By its action on the brain membranes it is also thought to prevent seizures. Finally it may be used for the treatment of myoclonus (uncontrolled muscle twitching or jerking) and for the treatment of Dyslexia.

Piracetam, a derivative of the neurotransmitter GABA, is a racetam a category of cognitive enhancers that includes aniracetam, pramiracetam, oxiracetam, and others. Cognitive enhancers are also called noötropics. Piracetams effects on both nerve cells and on blood may be explained by the fact that it alters the fluidity of membranes of cells. Such a change in fluidity would affect the function of various proteins that float in these membranes proteins such as ion channels in nerve cell membranes, and metabolic enzymes in mitochondrial membranes. Cell membrane fluidity would also affect the ability of blood cells to pass through small veins and capillaries.

For more information, please go to http://www.riverbendds.org/index.htm, click the Medical Series folder on the left hand side, then Supplements & Drugs, and then Piracetam.

Research:
- Epilepsy: Koskiniemi M, Van Vleymen B, Hakamies L, Lamusuo S, Taalas J. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry 1998 Mar;64(3):344-348.

- Aphasia: Kessler J, Thiel A, Karbe H, Heiss WD. Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients. Stroke 2000 Sep;31(9):2112-2116

- Dyslexia: - Wilsher CR, Bennett D, Chase CH et al. Piracetam and dyslexia: effects on reading tests. J Clin Psychopharmacol 1987 Aug;7(4):230-237. "Piracetam-treated children showed significant improvements in reading ability (Gray Oral Reading Test) and reading comprehension (Gilmore Oral Reading Test)."

Source
http://www.henryspink.org/smart_drugs.htm

Piracetam improves mitochondrial dysfunction following oxidative stress. 
British Journal of Pharmacology.
147(2):199-208, ... 2006. Peer-Reviewed Professional Journals
· Keil, U., et al.
Department of Pharmacology, University of Frankfurt, Frankfurt, Germany.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615864/
Mitochondrial dysfunction including decrease of mitochondrial membrane potential and reduced ATP production represents a common final pathway of many conditions associated with oxidative stress, for example, hypoxia, hypoglycemia, and aging. Since the cognition-improving effects of the standard nootropic piracetam are usually more pronounced under such pathological conditions and young healthy animals usually benefit little by piracetam, the effect of piracetam on mitochondrial dysfunction following oxidative stress was investigated using PC12 cellsand dissociated brain cells of animals treated with piracetam.

Piracetam treatment at concentrations between 100 and 1000 muM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside (SNP) and serum deprivation. Under conditions of mild serum deprivation, piracetam (500 muM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. Piracetam treatment (100-500 mg kg(-1) daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Moreover, the same treatment reduced antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in aged mouse brain only, which are elevated as an adaptive response to the increased oxidative stress with aging. In conclusion, therapeutically relevant in vitro and in vivo concentrations of piracetam are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of piracetam's beneficial effects in elderly patients.
 

Some History of Piracetam and Down syndrome

Excerpt from a summary by Len Leshin, MD, FAAP
Full text:  http://www.ds-health.com/piracet.htm

Note: I'm not sure why, when Piracetam was tested, it didn't show impressive results. I do know that the parents in the study continued giving their child P. Why would they continue to pay for it and give it if they didn't see results? -Andi

Piracetam became a controversial topic in the mid-1990s when a parent group began advocating its use for Down syndrome. There was notable publicity due to two ABC news shows about it and internet advocacy on the part of the parent group. However, the company licensing it, UCB Pharma in Belgium, has discouraged its use in children with Down syndrome. In July 1998, UCB Pharma specifically denied all rumors that it will fund or has plans to fund any study with children with Down syndrome in the United States or elsewhere. Many advocates of its use in Down syndrome claim that UCB Pharma's reluctance stems more from economic motives than scientific; however, UCB Pharma has obtained "orphan drug" status for piracetam in the US, and is currently planning a controlled trial of piracetam and myoclonus in the US. If given approval by the FDA for myoclonus, UCB Pharma would have several years of exclusivity of the drug in the US.

I have listed below the studies that involve children with Down syndrome. I have a separate page for other research on piracetam.

Lobaugh NJ et al. Piracetam does not enhance cognitive abilities in moderate to high-functioning 7 to 13 year-old children with Down syndrome. Presented at the PAS/SPR meeting in San Francisco May 3, 1999; published in Archives of Ped and Adol Med, April 2001, 155(4):442-448.

"Piracetam, a drug reported to enhance cognitive performance in many neurobehavioural conditions, has become popular in the treatment of children with Down Syndrome (DS). However, reports of its efficacy in DS have been anecdotal, not from evidence-based studies. Some caregivers have noted no effect of piracetam, while others claim substantial improvement in cognitive functioning. To address the need for objective analysis, we conducted a double-blind placebo-controlled crossover study assessing the cognitive and behavioral effects of piracetam in children with DS. Patients and Study Design. Children with DS (n = 25, 13 males, 6.5 - 13 yrs) and their parents participated. The first phase of the study was a baseline cognitive assessment. Children were then randomly assigned to one of two four-month treatment arms: Piracetam. Placebo or Placebo. Piracetam. Children were retested at the end of the two treatment phases. Children received 80-100 mg/kg piracetam per day in capsules. Placebo was administered in the same manner. Test Battery. The test battery included 16 tasks assessing attention, learning, memory, verbal fluency, perceptual and spatial abilities, processing speed, fine motor skills, and executive function. Both standardized and experimental tasks were included. Secondary outcome measures were questionnaires completed by parents and teachers at each of the three phases. Results. Eighteen children (7 - 13 yrs) completed the study, 5 withdrew, and 2 could not complete the battery at baseline testing. The mean mental age for the final sample was 4.2 ± .7 years (Stanford Binet). The 16 tasks yielded 75 measures and the parent and teacher questionnaires had 80 and 24 items, respectively. Piracetam did not show significant effects over placebo on any outcome measure. All significant interactions (p's < 0.05) with drug order or the covariate were examined further to ensure drug effects were not being masked. That analysis did not alter the results. Piracetam administration was associated with CNS stimulatory effects: aggressiveness (n=4), agitation (n =3), sexual arousal, (including masturbation in public, n=2), irritability (n=1), and poor sleep (n=1). Conclusion. Piracetam has received a great deal of attention in the popular press purporting its efficacy in improving cognitive function in children with Down Syndrome. In this study, we were unable to substantiate these claims, even at doses associated with adverse effects. Neither cognitive nor behavioural measures demonstrated improvement under piracetam. Due to the serious adverse effects, it is unlikely that larger doses can be tolerated."
©1999 Pediatric Academic Societies

Fialho J Dromia and Piracetam: a useful association in the treatment of Down syndrome. Tempo Medico 30:944, 1977. (The original was published in Spanish; an English version was reprinted in a book whose specifics are unknown to me.) 26 children with DS between 3 months and 12 years were given Dromia (mixture of pyriglutine and 5-hydroxytryptophan) alone, and then a combination of Dromia and Piracetam. The children were then evaluated based on their muscle tone, motor development, mental development, speech, affective-social development, scholastic achievement and EEG trace. The author concludes that the combination of the two drugs caused an improvement in all aspects, but especially speech. There were no side effects noted. (Unfortunately, this is a terrible study. There were no controlled subjects, the investigator does not tell how he evaluated the above categories and does not say if the subjects, parents, or investigators were "blinded" as to which children were getting one or both drugs.)

An unpublished feasibility study was conducted in 1999 at the Kennedy Kriger Institute in Baltimore under the guidance of Dr. George Capone. Five school-aged children with DS were given piracetam and compared to five children with DS not on piracetam. The piracetam was given at 100 mg/kg body weight per day. After six months, the children were assessed for auditory verbal memory, auditory non-verbal memory, visual memory, and spatial working memory. There were no statistically significant differences in the two groups. It should be noted that this was a study that was set up more to prove to the NIH that the study was doable and deserving to be funded on a large-scale basis rather than to prove whether to not piracetam had any measurable effects. A lack of funds kept this study from being carried out to a point where the research could be published.

In 2002, Dr. Capone and his associates published their trial of piracetam on trisomy mice: The effects of piracetam on cognitive performance in a mouse model of Down's syndrome Physiology & Behavior 77: 403-409, 2002.

"Piracetam is a nootropic agent that has been shown to improve cognitive performance in a number of animal model systems. Piracetam is reported to be used widely as a means of improving cognitive function in children with Down's syndrome (DS). In order to provide a preclinical assessment of the potential efficacy of piracetam, we examined the effects of a dose range of piracetam in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for a region of mouse chromosome 16 with homology to human chromosome 21. Daily piracetam treatment at doses of 0, 75, 150, and 300 mg/kg ip was initiated in 6-week-old male Ts65Dn and euploid control mice. Following 4 weeks of treatment, mice were tested in the visible and hidden-platform components of the Morris water maze and were placed overnight in computerized activity chambers to assess effects on overall activity. Piracetam treatment was continued through the 4 weeks of testing. In control mice, 75 and 150 mg/kg/day piracetam improved performance in both the visible- and hidden-platform tasks. Although low doses of piracetam reduced search time in the visible-platform component in Ts65Dn mice, all piracetam doses prevented trial-related improvements in performance in Ts65Dn mice. The 300-mg/kg/day-piracetam dose was associated with a reversal of the nocturnal spontaneous hyperactivity in Ts65Dn. These data do not provide support for piracetam treatment for individuals with DS."

Advocates of piracetam have argued that choline must also be supplemented with piracetam to get any effect, thus explaining the results of the Toronto and Johns Hopkins studies. The main basis for this belief are the following studies:

Bartus RT et al. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging Summer;2(2):105-11, 1981. Rats given both choline and piracetam did better on a memory test than on choline or piracetam alone.
Platel A et al. Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Pharmacol Biochem Behav 21(2):209-12, 1984. Mice did better on memory of their environment with the combination of choline and piracetam than on either separately.
Mosharrof AH & Petkov VD. Effects of citicholine and of the combination citicholine + piracetam on the memory. Acta Physiol Pharmacol Bulg 16(1):25-31, 1990. Mice did better with memory retention with the combination of citicholine and piracetam than the compounds separately.
Friedman E et al. Clincal Response to choline plus piracetam in senile dementia: relation to red-cell choline levels. New Eng J Med 1981 Jun 11; 304(24): 1490-1. This is actually a "letter" rather than a full paper, and consisted giving 10 patients with presenile dementia piracetam and choline for 7 days in a non-controlled study. 3 of the 10 had "marked improvement" cognitively, but no description of the cognitive tests or whether the testing was blinded is mentioned. The 3 who responded had higher choline red blood cell levels than the 7 who didn't respond.

However, other studies show a lack of usefulness of the combination:

Ennaceur A & Delacour J. Effect of combined or separate administration of piracetam and choline on learning and memory in the rat. Psychopharmacology 92(1):58-67, 1987. Rats given choline alone did better than rats given piracetam alone on memory test, and rats given piracetam and choline together did worse than the other groups.
Growdon JH et al. Piracetam combined with lecithin in the treatment of Alzheimer's disease. Neurobiol of Aging 7:269-276, 1986. Piracetam was administered alone or with lecithin (phosphatidylcholine) in a double-blinded test. No effect was seen, with or without lecithin, on cognition or memory test scores.
Corona GL et al. Clinical and biochemical responses to therapy in Alzheimer's disease and multi-infarct dementia. Eur. Arch. Psychiatr. Neurol. Sci. 239:79-86, 1989. Patients with either AD or multi-infarct dementia were given either piracetam or piracetam with choline. This was not paired with placebos. Despite biochemical changes, there was no change in memory performance.

It should be noted that the maker of piracetam, UCB Pharma, has never incorporated choline as part of any of its research on humans with Alzheimer's disease or myoclonus.

Products

NooRacetam (Piracetam) 800mg $17.95 plus $6 shipping


Dosage

75 mg per kilo per day is the recommended dosage.  Is recommended to take with choline. (Body Bio PC is the brand of choice.) May cause hyperactivity so you may need to avoid at night. Piracetam tastes bitter so if you have to break open the capsules, you'll need to be a little creative when giving it. Jett takes it fine with a chunk of banana and a little bit of honey. If I add fermented ketchup to a mashed vegetable such as acorn squash or avocado, it works as well.

My notes on Jett's experience with Piracetam

Day one
Age: 20 months  
Dosage: Jett weighs 19.8 lbs which is 8.98 kilos. So he'd get 673 mg per day. One capsule is 800 mg. So I will give him 1/2 a capsule (400) in the morning and 6 hours later, give him a third of a capsule (266) and see how it goes. But for day one, I'm giving him 1/3 of a capsule in the am and 1/3 in the afternoon.
He's not on Prozac at the moment and we ran out of LC and EGCG and have a full bottle of Piracetam that I haven't tried so... I'll let you know what I see...
I take 840 mg of choline a day and Jett still breastfeeds, so I am assuming that he is getting some choline 3 times a day. (I did look this up and a study supports the fact that breastfeeding woman who supplement with choline have higher choline content in their breast milk.)
Cognition test: I wrote 6 words on the magnadoodle, one at a time and showed him what they were in the room:  bean bag, chair, cow (a picture), shoe laces, stool and umbrella. (Bean bag, shoe laces and umbrella are brand new words. The others he has seen this week.) Sometimes he wanted to write them as well after I wrote them (I mean that he made me hold his hand and he wrote them with me). Then I immediately wrote each one again and asked him where they were. He got them all right. I called my husband and stepdaughter into the room and although he was distracted and "talking" to them, he got them all right again. He's taking a nap now, but I'll try again when he wakes up to see if he remembers.
He did remember when he woke up and remembered all but one (bean bag) the next night. This test only proves that Piracetam doesn't seem to hurt his cognition. I can't say he did this because of it.
I'm excited because he's not on Prozac, LC or EGCG. Just ginkgo and vitamins (and Piracetam). Hopefully we can afford LC and EGCG again soon. He's not been hyper at all and he actually crawled around the house and played a lot on his own (w/out being irritable--being happily independent). I did read a lot of books to him and did some Little Reader and magnadoodle, as I mentioned. When I do a lot of that, he seems to feel happier and more independent. If I don't spend a lot of time with "lessons" he gets really irritable and whines for me to read to him.
Obviously, it's caused no sleep issues so far because he's taking a nap now.

Day two
I noticed by day two on Piracetam that it doesn't support the eyes as well as: LC, Prozac & EGCG since his eyes are crossing very badly. (Shows that the communication between the brain and eyes are not doing well.) We've ordered LC (yeah!!!) and should expect it in 3-5 days. But, his language is coming along nicely. Usually, off LC, he either stops talking or really regresses language wise, but yesterday he said a bunch of words, actually repeated after me. (Unfortunately one was "shut up" (I did say PLEASE, first...) which of course he repeated like twenty times with enthusiasm. And then it was the first thing he said this morning. I said, "Good morning, Jett." and he smiled and said, "Shut up!" Hopefully people will think it's cute... like Ann Hathaway in Princess Diaries...
I did also add Neuroprotek which he took before w/no side effects.
I showed Jett colors, but he didn't get them all right. I'll try again another day. Maybe the concept is more difficult than words?

Day three
I'm upping the dose to 1/2 in morning and 1/3 in the afternoon. Ooops... Jett was fed the last dose of Piracetam at 7pm! So, he didn't sleep very well at all. He didn't fall asleep until 2 am. Once he fell asleep, he was fine though. So, it looks like it takes about 7 hours to get out of his system... We won't make that mistake again!

Day four and five
He turned 21 months old on Nov. 25, 2011. These past two days he has been playing independently for very long periods of time! And instead of sitting and going "ehhhhhh" when he wants me to read a book, he takes the book, crawls over to me and hands it to me to read. He also has been more interested in his bath time and has been taking an hour long bath and not wanting to get out. For the first time. (He's always enjoyed bath time, he's just more engaged and for a longer period of time.) So, it appears to me that he's more focused with a longer attention span on the Piracetam and NeuroProtek (NP has a lot of the same things as ginkgo, EGCG and curcumin, so I think it's more the Piracetam). Any one else notice that on Piracetam?

Day six
Saturday, Nov. 26, 2011 I had to work (2-4 a month) and there was a "miscommunication" so Jett got 1/2 a capsule of Piracetam at 10am and then another 1/2 at 1pm. (I fixed the small bowls of supps, but my husband got the times wrong--I didn't write it down for him this time.) He seemed fine though and Kenny said that he didn't "give him any trouble" which means that Jett did a lot of independent play, was in a good mood, ate well and took almost a 2-hour nap. :D

Day seven
Sunday, Nov. 27, 2011 My mother came over and had Jett outside for his 30 minutes of sun. While outside, Jett stood up and walked behind a rolling toy car! She said that he took three steps! I took him outside an hour later and he took five steps! So I got my husband and stepson to see and take a video. I'll get my husband to upload it soon and will provide a link here. I'm excited!! I would love for him to walk soon! (As part of the ND program, I haven't initiated much walking because crawling is so important for brain development. I don't know if my mother "put him up to this" or if he thought of trying to walk behind the toy on his own... I do wonder how long he's been able to do this. I don't really think I'm supposed to encourage him to walk like this...) He has taken a couple of steps forward on his own just in this week, so maybe it was his idea? The average age of a child w/DS who can walk 10 feet with a push toy is 22 months and 11 months for a typical child. Jett did walk about 5 feet today. I'm not sure how much Kenny recorded. I don't think it would hurt for me to try this again tomorrow.

Day eight
I played Little Math for the first time and he LOVED. He shouted with protest when it was over. They counted to five really fast and he shouted out "six"! So funny because no one taught him any of that! (There is a Readeez song that counts to 12 very fast so he probably learned it that way.) He did it twice more when my husband played it later on in the day, so it wasn't my imagination.

Day 11/Dec. 1:
Jett's finally back on curcumin. Yeah! He said five recognizable words in front of the speech therapist today. I figure that's pretty good for an hour, right? (Horse was one.)  His walking is progressing as well. And he learned to read the names of some of his instruments: drum, tambourine, morocco and xylophone as well as shake and beat. He was very excited to learn these & would play each one when I wrote the name. He also loves to dance, bounce and shake. He wouldn't vocalize for "sing" but he did sway his arms from side to side and looked toward the computer where I play pandora.com (music).
When I wrote "together" he laced his hands together. I only showed him that word once a couple of days ago. But it's one of his favorite words, so it makes sense that he learned it immediately. When I wrote "chair" he pointed to the chair closest to him then he also pointed to the chair that was on the other side of him. These chairs look very different so he does understand what a chair is and not just the chair I showed him first. He remembered all the old words except bean bag--again! It's not a word we use a lot so maybe that's why? We worked on shapes yesterday and colors the day before but he didn't seem to either get them or be too interested so I didn't check today to see if he magically got them. I know that he knows star, though because he's said it a couple of times and will point to one.
Some meaningful words he said today were: Jett, yes, eyes, "S", "Ah" (for A-apple), "kuh" for book (upon request), "zzz" for buzz, shapes... that's all I can think of off the top of my head. He jibber jabbers constantly so I forget to remember all the stuff he says. His favorite book today is Mr. Brown Can Moo, Can You? He was having fun tonight pretending to read it out loud. He made a lot of noises but they didn't exactly match the word. I'll have to teach him those words tomorrow--he'll love that!
Oh, we did Little Reader in Chinese and he freaked out. He hated it! He rolled off my lap onto the floor he was so disturbed by it. I think it's because it was all too foreign to him and he LOVES reading English so much that it was not a pleasant experience. I'll have to try again later--once he's got a good grasp of the English language. (Learning another language is really good for the brain.)
I gave him the Piracetam a little after 5 so he fell asleep about an hour late (midnight). I have to remember that he won't fall asleep until 7 hours after the last dose -- so no later than 4pm.

Dec. 4
Discovered for sure that he knows and will verbally say ten letters of the alphabet. He says the sound, not the letter name. When I read the alphabet to him, I say "wuh" instead of "double-u", etc. He knows A, C, E, O, P, S, T, W, X and Z. (I found out the next day that he knew M as well.)
Yesterday, he spontaneously gave me a hug for the first time and my mother said he hugged her too. This afternoon, when he was supposed to be napping, he spontaneously gave me like 5 kisses on my nose. He never initiated kisses and hugs before. But he recently started to give me kisses from afar by making the smack sound.
Yesterday I also noticed that he put a lid on a container which I don't think he's done before.

Dec. 11
Okay, so now Jett can put in a puzzle piece for the first time. (It was the Melissa & Doug farm sound puzzle of the sheep.) And he wanted to put the shapes into the shape sorter, but was having difficulty so he had me come over. I set it up so he could succeed better (less choice of shapes, at the right side where the correct shape hole is, etc.) and he was able to do it better and better! He put them in himself! (He's not great at it yet, but he understood the concept and was interested and tried and did it!)
Yesterday, he spontaneously said, "A B C" while playing in the bathtub and my husband parroted him and then Jett said, "D!" He's started singing (ba, ba, ba) and has been singing with the Readeez version of the alphabet song. (I mean that he tries to, he can't actually sing the alphabet song.) I can tell that his brain is more organized... He went around and gathered all the parts of his floatable xylophone where each musical bar is on its own colored puzzle piece. So, he's picking through his toys and brings me a pile of his xylophone and says "together" (his version of the word) so that I will put it together for him! (Then he immediately ripped them apart so I'd do it again.)
He did something similar last night, he sorted out the red puzzle pieces from only one puzzle and just brought those to me.
I was unhanging socks that were dry and I dropped each one on his head as if it were raining socks and then I rolled the matching ones together into "sock balls." So he gathered the sock balls and we played catch for a while and then he gathered them and carried them all through his crawl tube and went back and got the ones he dropped, etc. And played with them for a good while, very creatively!
All this type of play is NEW NEW NEW! I don't know if it's the Piracetam or the NAET or what, but I'm loving this burst of amazing cognitive progress!
And his mood... he is smiling much more and seems to be an all around happier kid! His eyes are doing great as well. Very little crossing. Yes, we are still doing the neurodevelopmental exercises for his eyes. I'll have to ask around and see what other moms have seen in their child on Piracetam.
He also has been reading--out loud--words that I haven't specifically taught him, from his books. Like in the Hide and Squeak book, he read: Pup and the Mr. Brown book, he read: Hoo, Buzz, Pop, Klopp, Boom, and Grum... In a pig book, he read splash and like three other words. And in other books, I see him react to the words before I say them. Like a Barney books says pat your head and he's already doing it before I read it out loud.

Dec. 17
We have contact! Eye contact, that is! I didn't realize what little eye contact Jett had before, but today, he really held my gaze. Because of this, he parrots more--both verbally and "gesticularly." I'm rather animated with my hand movements when I talk and I see him copying me. Too funny. I always thought he was engaged, but the change has been amazing.
Also new--I had noticed that when I pointed, Jett looked at my finger or the end of my finger and not at the object to which I was pointing. This is significant because studies show that children who can follow where you point learn better. Jett just started looking at the object! I try this everyday so I can tell you that this is the first time he's done it!

Dec. 18
I've readded TriEnza enzymes to help w/Jett's bowel movements. Because of the uncomfortable nature of getting his stomach in order, he was very clingy and irritable all day and night. He had 2 BMs in one day--1 BM a week is "normal" for him, so this will take some time for him to adjust.
As I learn more about Neuroprotek, I'm thinking that I need to attribute all the elimination of Jett's borderline Autistic tendencies on it rather than the Piracetam. I don't know how much of the P to attribute the speech and cognitive advances, but I am quite pleased so far!

March 24
Jett's been off P and only on NP for months and he's still doing great! I'm going to reintroduce P along with BodyBio PC soon and see if I observe a difference. He's 24 months and has been putting together the Melissa and Doug stacking puzzle, the M & D wooden puzzles with the little red knobs, reading words out loud like "helicopter, enterprise, happiness" and has been repeating two-three words at a time instead of just one. He's also been playing appropriately with cars and has been showing me things (new behavior). He recently starting following my point to far away objects instead of just looking at the end of my finger. And now he points himself. Last week he pointed excitedly to a flock of birds flying overhead and said, "Birds! Birds!" He didn't point to anything except for things up close until about 3 weeks ago. (This is another autistic tendency that is going away.) And just today, he called out to a boy on a bicycle as he rode by. So, he's wanting to be more social. And the past two weeks he's been memorizing songs including "Itsy Bitsy Spider" and the ABC song. He hasn't gotten it perfect yet, but he's having fun with it. And he's been playing with stuffed animals and dolls--brand new behavior as well!

Related Posts

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Tuesday, October 18, 2011

Newborn baby boy with DS needs adoptive family

http://m.facebook.com/story.php?story_fbid=290395664323765&id=110555265641140&__user=782769331

Midwest Foster Care and Adoption Association just learned about an immediate private adoption of a Caucasian baby boy born this weekend with Down's Syndrome. We're seeking adoption studied/ready families interested in privately adopting this little guy. The adoption could be completed for a study ready family by the end of the year, making the family eligible for the federal adoption tax credit to cover the expenses incurred in the adoption. The cost will be $4-5,000.00 in attorney fees. Matched adoptive family declined placement upon learning of the baby's condition. Baby is otherwise healthy. Interested? Contact Lori@mfcaa.org.

Monday, October 17, 2011

Link Between Sleep Deprivation & Alzheimer's Risk

Very interesting... Our kids have a lot of sleep disturbances from apnea, lack of REM, congestion, etc. Wouldn't it be great if solving sleep problems would help reduce their risk of Alzheimer's disease? (I am working on a post about sleep and DS... along with 67 other half finished drafts!)
Study Suggests Link Between Sleep Deprivation, Alzheimer's Risk

Body seems to use brain's downtime to clear away disease-related material, researchers say


WEDNESDAY, Sept. 28 (HealthDay News) -- A new study shows that levels of amyloid beta, a byproduct of brain activity that is considered a marker for Alzheimer's disease, normally rise during the day and decrease at night.
While the finding is preliminary, it could suggest a possible link between sleep deprivation and people's risk for developing the brain-robbing disease, researchers say.
"We've known for some time that significant sleep deprivation has negative effects on cognitive [brain] function comparable to that of alcohol intoxication," Dr. Stephen Duntley, professor of neurology and director of Washington University's Sleep Medicine Center, said in a university news release. "But it's recently become apparent that prolonged sleep disruption and deprivation can actually play an important role in pathological processes that underlie diseases. This connection to Alzheimer's disease isn't confirmed yet in humans, but it could be very important."
The findings were released online in advance of publication in an upcoming print issue of Archives of Neurology.
According to the researchers, levels of the amyloid beta protein do seem to ebb and flow.
"In healthy people, levels of amyloid beta drop to their lowest point about six hours after sleep, and return to their highest point six hours after maximum wakefulness," Dr. Randall Bateman, associate professor of neurology at Washington University School of Medicine in St. Louis, explained in the news release.
"We looked at many different behaviors, and the transitions between sleep and wakefulness were the only phenomena that strongly correlated with the rise and fall of amyloid beta in the spinal fluid," he added.
Bateman and colleagues also found this pattern was most prevalent in healthy, young people and less pronounced in older adults who suffer from shorter or more disrupted periods of sleep.
They suggested the reason for this may be that the brain's low activity during sleep allows the body to clear amyloid beta through the spinal fluid.
Levels of amyloid beta in older adults with Alzheimer's appear to be constant, suggesting a possible link between lack of sleep and people's odds for developing the disease, the team said.
In conducting the study, the researchers divided study participants into three groups:
  • People aged 60 and older who tested positive for the presence of amyloid beta plaques in the brain.
  • People aged 60 and older who did not have amyloid beta plaques.
  • Healthy people ranging in age from 18 to 60 years.
Using a spinal tap, researchers monitored amyloid beta levels in the participants' spinal fluid every hour for up to 36 hours. During this time, they also videotaped the patients' activities and monitored their brain activity.
In the group with brain plaques, amyloid beta levels remained virtually constant. In the other two groups, however, the levels regularly rose and fell in snake-like waves. The highs and lows of this pattern were much more obvious in younger participants, and flatter in older people.
Although the participants' activities did not have an impact on changes in amyloid beta levels, peaks in their sleep and wakefulness consistently occurred before peaks and drops in amyloid beta levels.
The study authors said that more research is needed to explore how disrupted sleep in young people disrupts the normal ebb and flow of spinal amyloid beta, and how sleep aids may help maintain this wave-like pattern.
"It's still speculation, but there are tantalizing hints that better sleep may be helpful in reducing Alzheimer's disease risk," concluded Duntley. "We know from a number of studies that exercise enhances sleep, and research also has shown that exercise is associated with decreased risk of Alzheimer's. Sleep might be one link through which that effect occurs."
More information
The U.S. National Institute of Neurological Disorders and Stroke has more about Alzheimer's disease.
-- Mary Elizabeth Dallas
SOURCE: Washington University School of Medicine, news release, Sept. 26, 2011
Last Updated: Sept. 28, 2011
Copyright © 2011 HealthDay. All rights reserved.

http://consumer.healthday.com/Article.asp?AID=657319

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Sunday, October 16, 2011

Achieving Iron Balance with Diet


Source: http://www.irondisorders.org/diet/

If a person is iron deficient he or she will want to incorporate substances or foods that increase or improve iron absorption and avoid foods or substances that impair absorption. If a person has abnormally high body iron levels, he or she will want to consume foods or substances that lower the amount of iron absorbed. 

Substances that increase iron absorption:

Ascorbic acid or vitamin C occurs naturally in vegetables and fruits, especially citrus. Ascorbic acid can also be synthesized for use in supplements. Ascorbic acid enhances the absorption of nutrients such as iron.    In studies about effects of ascorbic acid on iron absorption, 100 milligrams of ascorbic acid increased iron absorption from a specific meal by 4.14 times.

Alcohol

Although alcohol can enhance the absorption of iron, no one is encouraged to drink alcohol as a means of improving iron status.  Moderate consumption of alcohol has known health benefits but heavy or abusive drinking, especially when in combination with high body iron levels increases the risk for liver damage, liver cancer and blood cell production. Approximately 20-30% of those who are heavy consumers of alcohol acquire up to twice the amount of dietary iron as do moderate or light drinkers, but alcohol abuse increased the risk of liver disease such as cirrhosis. A standard drink is defined as 13.5 grams of alcohol: or 12oz beer, 5oz wine, 1.5oz distilled spirits.  Moderate consumption is defined as two drinks per day for an adult male; one drink per day for females or those older than 65 regardless of gender.

Beta-Carotene

is one of more than 100 carotenoids that occur naturally in plants and animals. Carotenoids are yellow to red pigments that are contained in foods such as apricots, beets and beet greens, carrots, collard greens, corn, red grapes, oranges, peaches, prunes, red peppers, spinach, sweet potatoes, tomatoes, turnip greens and yellow squash. Beta-carotene enables the body to produce vitamin A. In studies of the effects of vitamin A and beta-carotene on absorption of iron, vitamin A did not significantly increase iron absorption under the experimental conditions employed. However, beta-carotene significantly increased absorption of the metal. Moreover, in the presence of phytates or tannic acid, beta-carotene generally overcame the inhibitory effects of both compounds depending on their concentrations. Like vitamin E, beta-carotene is an excellent anti-oxidant, but one should take any of these judiciously.  Studies have shown that taking vitamin A habitually in amounts of 25,000 IU can cause liver problems, and that taking supplemental beta-carotene can enhance the progression of some cancers. The best source of these nutrients is whole foods.

Additive iron

EDTA+fe and Ferrochel?are additive iron compounds and are emerging as candidates for fortification by major food manufacturers. Both additives were found to exceed absorption capabilities of the commonly used fortificant ferrous sulfate.
Hydrochloric acid

Hydrochloric acid (HCI) present in the stomach, frees nutrients from foods so that they can be absorbed.

Meat

Especially red meat increases the absorption of nonheme iron. Beef, lamb and venison contain the highest amounts of heme as compared to pork or chicken which contains low amounts of heme. It has been calculated that one gram of meat (about 20 percent protein) has an enhancing effect on nonheme iron absorption equivalent to that of 1 milligram of ascorbic acid.  A Latin American-type meal (maize, rice, and black beans) with a low iron bioavailability had the same improved bioavailability when either 75 g meat or 50 mg of ascorbic acid was added

Sugar

As part of the Framingham Heart Study, a National Institutes of Health project, investigators looked at the factors that increased iron stores such as diet and iron supplementation. Participants included more than six hundred elderly patients. Those who took supplemental iron along with fruit had higher iron stores, some as much as three times. No one is encouraged to consume sugar to improve iron absorption. Too much sugar can lead to other health problems, such as obesity and diabetes. Refined white sugar has no nutritional value except calories. However, eating fruits or adding honey or black-strap molasses to foods such as cereals can boost iron absorption and add nutrients that are lacking in refined sugar.

Nicotine Products

Smoking cessation gums can increase serum ferritin levels

Substances that impair iron absorption:

Medications that reduce the amount of acid in the stomach such as antacids or proton pump inhibitors can lead to hypochlorhydria (low stomach acid) or achlorhydria which is the complete absence of stomach acid.

Calcium (like iron) is an essential mineral, which means the body gets this nutrient from diet. Calcium is found in foods such as milk, yogurt, cheese, sardines, canned salmon, tofu, broccoli, almonds, figs, turnip greens and rhubarb and is the only known substance to inhibit absorption of both non-heme and heme iron. Where 50 milligrams or less of calcium has little if any effect on iron absorption, calcium in amounts 300-600 milligrams inhibit the absorption of heme iron similarly to nonheme iron. One cup of skimmed milk contains about 300 milligrams of calcium. When calcium is recommended by a healthcare provider, as is often the case for women trying to prevent bone loss, these supplements can be taken at bedtime. Calcium supplements are best taken with vitamin D and in a citrate rather than carbonate form.

Eggs contain a compound that impairs absorption of iron.  Phosphoprotein called phosvitin is a protein with a iron binding capacity that may be responsible for the low bioavailability of iron from eggs. This  iron inhibiting characteristic of eggs is called the “egg factor”. The egg factor has been observed in several separate studies. One boiled egg can reduce absorption of iron in a meal by as much as 28%

Oxalates impair the absorption of nonheme iron. Oxalates are compounds derived from oxalic acid and found in foods such as spinach, kale, beets, nuts, chocolate, tea, wheat bran, rhubarb, strawberries and herbs such as oregano, basil, and parsley. The presence of oxalates in spinach explains why the iron in spinach is not absorbed. In fact, it is reported that the iron from spinach that does get absorbed is probably from the minute particles of sand or dirt clinging to the plant rather than the iron contained in the plant.

Polyphenols are major inhibitors of iron absorption. Polyphenols or phenolic compounds include chlorogenic acid found in cocoa, coffee and some herbs. Phenolic acid found in apples, peppermint and some herbal teas, and tannins found in black teas, coffee, cocoa, spices, walnuts, fruits such as apples, blackberries, raspberries and blueberries all have the ability to inhibit iron absorption. Of the polyphenols, Swedish cocoa and certain teas demonstrate the most powerful iron absorption inhibiting capabilities, in some cases up to 90%. Coffee is high in tannin and chlorogenic acid; one cup of certain types of coffee can inhibit iron absorption by as much as 60%.   These foods or substance should not be consumed within two hours prior to and following your main iron-rich meal

Phytate is a compound contained in soy protein and fiber. Even low levels of phytate (about 5 percent of the amounts in cereal whole flours) have a strong inhibitory effect on iron bioavailability. Phytate is found in walnuts, almonds, sesame, dried beans, lentils and peas, and cereals and whole grains. Phytate compounds can reduce iron absorption by 50 to 65 percent.

Diet for Iron Balance

When iron is appropriately distributed throughout the body in hemoglobin, muscles, ferritin and elsewhere, your diet should be geared toward continued iron balance and disease prevention. Fresh fruits, vegetables, whole grains, adequate protein, limited dairy, limited fats and sugars form the basis for a good eating plan that will assure adequate iron and lower the risk of disease.


Healthy diet checklist will include:

Fresh fruits and vegetables which provide natural hydration and a supply of antioxidants

Whole grains which provide fiber needed to keep the digestive tract clean

Adequate protein which builds muscle

Limited dairy which can cause mucous in the intestines

Limited animal fats which can trigger free radical damage. Eat healthy fats found in olive oil, cold water salmon, avocados and nuts

Limit processed sugars which contain empty calories and trigger free radical damage.

Whenever possible, consume whole foods as opposed to “foods in a pill”. Our bodies are not geared to large doses that tax the liver and knock other nutrients out of balance.

Get at least 20 minutes of physical activity a day; walk or take at least 10,000 steps if you can.

NOTE: Individuals with hereditary hemochromatosis should not consume raw shellfish

Download Iron Content In Foods (206.92 KB)

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Saturday, October 15, 2011

Why supplement and monitor zinc?

Jett just tested low on zinc so I thought I'd do some research. OMG...  Needless to say, we are buying him zinc TOMORROW morning!!! It is absolutely ridiculous that this paper, The Role of Zinc in Down’s Syndrome by Eastland Roxanne, was written 10 years ago and that zinc isn't a mandatory supplement for everyone with DS. 

I just reviewed the (recently revised) Clinical Report on the Health Supervision for Children With Down Syndrome written by the American Academy of Pediatrics to see what they say about zinc. Guess how many times zinc is mentioned? ZERO. I'm going to rewrite the Guidelines for Treatment of DS myself. (Okay, so it's on my to-do list…) You are welcome to listen to the AAP, but I feel that us parents have our children's best interest at heart and seriously wonder about whomever is on the board that created our present guidelines. Of course, I will share my Guidelines with you! (I'm sorry, I am soooooooo angry right now!!) My notes are in italics.

Of course, once I supplement zinc and possibly copper, I have to add l-carnosine to protect his brain. (See Q's post at http://gotdownsyndrome.blogspot.com/2011/10/31-for-21-l-carnosine.html for an explanation.)

Excerpts from: The Role of Zinc in Down’s Syndrome
Eastland Roxanne 2001
Please find the full article as a pdf here:
http://www.dsrf-uk.org/library/documents/The_Role_of_Zinc_in_Downs_Syndrome.pdf


Conclusion
...The conclusions have been drawn from a critical review of all the research papers available on the subject of DS and zinc.

It appears that the majority of DS individuals are zinc deficient, and that they exhibit symptoms classically associated with zinc deficiency:

• Thyroid dysfunction
• Immunodeficiency
• Retarded growth
• Faulty DNA repair

Supplementation will raise DS zinc status to normal. Correction of zinc deficiency seems to:

• Improve thyroid function, though it is not clear yet what parameters are being affected
• Raise active thymulin levels and concomitantly lower inactive thymulin
• Possibly increase lymphocyte proliferation
• Possibly restore delayed hypersensitivity
• Improve neutrophil function
• Possibly normalise lymphocyte subset distribution
• Possibly minimise growth retardation
• Regulate DNA repair
• Regulate myeloid cell differentiation and apoptosis

There several possible reasons behind DS zinc deficiency, which are most likely to be working in some combination:


• Over-expression of genes
• Malabsorption
• Dysfunction of transport proteins
• Food choices
...As it is possible for too much zinc to suppress the immune system it would be wise to regularly test an immune parameter, such as lymphocyte proliferation, or to alternate periods of supplementation and periods without. It is possible that zinc therapy could benefit DS babies from birth, but at present it is not possible to recommend this as there is no evidence even as to its safety. It may be that the typical DS diet is low in zinc-rich foods, and it is vital to find ways of preparing such foods so as to appeal to a DS person and to educate individuals to incorporate such food in their diet.
It could also be sagacious to investigate such potential sources of malabsorption as food allergies, hypochlorhydria, and pancreatic insufficiency.

Dosage
The average adult daily intake of zinc from the diet is 10 mg. Evidence suggests this dietary intake will always be inadequate for patients who are at risk, like those who have Down's syndrome.
Zinc deficiency can result in many health problems and we believe it may be the root cause for the universal brain injury we see in Down's syndrome from a very early age. Medical research is needed to find the best treatment therapy. 25 mg per day of zinc may be needed to prevent zinc deficiency in young people and adults with Down's syndrome. Even higher doses (up to 60 mg per day) has been suggested for adults with DS. Babies and young children would get a much smaller dose rate based on body weight.In the autism community, the dosage is one mg per pound, plus twenty mg. This is the dosage I will go with until Jett's next blood draw. -Andi
Pumpkin seeds are high in zinc but can be hard to digest. I like soaked pumpkin seed butter.

For zinc products, please see the DS Day to Day amazon store.

(All of this is my addition. -Andi)

I'm researching these brands:

Gluten free and contains the amino acid methionine (L-methionine):

Life Extension Optizinc-- 30 mg - 90 Vegetarian Capsules
Vitacost L-OptiZinc® -- 30 mg - 200 Capsules is soy free


Has monomethionine:
Douglas Labs OptiZinc™Uses monomethionine. Other ingredients include cellulose, gelatin (capsule), and vegetable stearate. This product contains no yeast, wheat gluten, soy protein, milk/dairy, corn, sodium, sugar, starch, artificial coloring, preservatives, or flavoring.

Source Naturals OptiZinc® has monomethionine and 300 mcgs of copper and is soy free

Solaray-OptiZinc as Zinc Monomethionine and has 20 mgs of B6

---


Standard Process Zinc Many chiros carry this brand.



Eastland Roxanne 2001:

Zinc and its links with Down's Syndrome
...The importance of zinc is suggested by the many disease states found in DS that have also been observed in subjects with zinc deficiency. These include diabetes mellitus, dwarfism, hypogonadism, atherosclerosis, vitamin A deficiency night blindness, cirrhosis of the liver, myeloid leukaemia (Milunsky, 1970), and hyperthyroidism and hypothyroidism (Napolitano et al, 1990). Fabris et al (1993) cite the importance of zinc in the homeostatic networks found to be altered in DS, namely nervous, neuroendocrine and immune, and their interrelationship, plus a reduced turnover of this mineral, leading to the hypothesis that zinc deficiency could be implicated in at least some of the DS phenotype.
“Zinc forms part of the composition of at least 160 different enzymes. Indeed, zinc is the most widely used mineral in enzymes” (Graham and Odent, 1986).
It is vital for protein, essential fatty acid and carbohydrate metabolism, and for DNA synthesis, and can be used to detoxify lead and mercury (ibid.). The body only has a small pool of biologically available zinc, and a rapid turnover, meaning that deficiency signs appear very quickly (Passwater and Cranton, 1983).
 

Zinc status in Down's syndrome
It is this author’s opinion that taken as a whole the research to date indicates that it is likely that DS individuals have a low zinc status. Several papers reported normalisation of low zinc levels following zinc supplementation (Björkstén et al, 1980; Franceschi et al, 1988; Lockitch et al, 1989; Napolitano et al, 1990; Stabile et al, 1991; Licastro et al, 1992, 1993, 1994; Brigino et al, 1996; Trubiani et al, 1996; Bucci et al, 1999). This indicates a prevalence of zinc deficiency. If zinc status were already at an optimum level it is unlikely that homeostatic mechanisms would allow supplementation to raise zinc levels...
Importance of the Thyroid
Most investigators have found hypothyroidism in the DS population, with estimates of prevalence as high as 50% (Pueschel, 1990). This means that hypothyroidism is sometimes interpreted as being part of the ‘Down’s Syndrome Gestalt’, and that thyroid function should
be one system that is regularly monitored and treated as appropriate (ibid). ...Pueschel also states that failure to recognise thyroid dysfunction early enough can lead to further disturbances to
the central nervous system.
It should be noted that, although hypothyroidism is by far the most common thyroid dysfunction in DS and the one with which most researchers choose to work, a higher incidence than hyperthyroidism has also been reported (Pozzan et al, 1990). As certain parameters of thyroid function were universally found to be abnormal it is this author’s opinion that both hypo- and hyperthyroidism in DS could very well have the same root cause.
Function of the thyroid and thyroid hormones
The thyroid hormones regulate oxygen use and basal growth rate, cellular metabolism, and growth and development. There are two thyroid hormones under consideration in relation to DS (the third, calcitonin, is unrelated), T3 and T4. T4, also known as thyroxine, is manufactured in the thyroid from a glycoprotein, thyroglobulin, and is the inactive form. T3, triiodothyronine, is the active form and is made from T4. Reverse T3 (rT3) is also made from T4 but is inactive. This may be a mechanism for disposing of excessive amounts of T4.
Thyroid hormones are hydrophobic molecules which usually travel in the blood bound to a protein - specialised alpha globulin or albumin - and are inactive until released. A tiny fraction of the total T3 and T4 is free T3 and T4 (FT3 and FT4), and it is the concentration of free thyroid hormones that determines the effectiveness of these hormones. As they are lipophilic, the thyroid hormones are able to diffuse across plasma membranes and bind to receptors within the cell. This binding increases a receptor’s affinity for specific DNA sequences, controlling the rate of transcription of the appropriate gene. Secretion of T3 and T4 is stimulated by thyroid stimulating hormone (TSH, also known as thyrotropin), the secretion of which is stimulated in turn by thyrotropin releasing hormone (TRH). The release of TRH depends on blood levels of TSH, T3, glucose, and on the body’s metabolic rate.

Thyroid dysfunction in Down’s Syndrome
Research into thyroid function and zinc therapy in DS is still in its infancy and a clear picture has yet to form. The patterns that have emerged so far are that DS subjects exhibit:
• Elevated levels of TSH (Napolitano et al, 1990; Pozzan et al, 1990; Licastro et al,
1992, 1993; Sustrová and Strbák, 1994; Bucci et al, 1999)
• Reduced levels of rT3 (Lejeune, 1990; Licastro et al, 1992, 1993a)
• Normal levels of total T3 and total T4 (Franceschi et al, 1988; Napolitano et al, 1990;
Pozzan et al, 1990; Licastro et al, 1992, 1993a)
• Only a small percentage of disfunctional thyroids explained by antithyroid autoantibodies (Napolitano et al, 1990; Pozzan et al, 1990; Bucci et al, 1999)
The causes of these unusual ratios of hormones are as yet unknown. However, several authors make similar suggestions as to why TSH would be raised and T3 and T4 levels normal - i.e. why the thyroid has not been stimulated to release excess thyroid hormones. It is possible that there is some kind of dysfunction of communication between the hormone and its receptor.
Napolitano et al mention some kind of resistance syndrome, Pozzan et al posit the possibility of a less active TSH, and Sustrová and Strbák also put forward the idea, amongst others, of a hormone resistance. Licastro et al (1992) have a different approach, suggesting that there may be an increased rate of T4 degradation in the periphery, and that the body needs to secrete increased amounts of T4 to maintain a homeostasis.
Licastro et al (1992) put forward two possible reasons for the lowered amounts of rT3 found
in DS subjects: a decrease in formation T4 due to most of the T5 transforming into T3; or an increased conversion of rT3 into T2 (one of the precursors of T3 and T4). The latter is interesting as Lejeune states that excess SOD1 (discussed later) experimentally increases the transformation of rT3 into (inactive form) T2.
Sustrová’s and Strbák’s paper adds an interesting dimension to this picture as they separated their subjects by age into 3 groups: DS1 = 1-6 years, DS 2 = 6-15 years, and DS3 = 15-35 years. They found that all three groups had high TSH levels, high thyroxine binding globulin (TBH) levels, and low FT3 and FT4 levels. However, the T3 and T4 results told a more complicated story. DS1 had high levels of T3 and T4, DS 2 had high T3 and low T4, and DS 3 had T4 and T3 which were in lower concentration than the controls. Were the other researchers finding ‘normal’ levels of thyroid hormones because they were combining the high levels of the youngest subjects with the low measurements of the oldest? This could be true of Napolitano et al and Bucci et al whose DS subjects spanned the Sustrová’s and Strbák’s groups, though Bucci did find a significant inverse correlation between age and both T3 and FT3 levels. Licastro et al (1993a) fail to give the ages of the “children” in their 1993 paper - they could be as old as 17 or 18- but in their 1992 paper their DS subjects are 6-15 years old. Though this is the same age as the DS 2 group, Licastro et al (1993a) found normal T3 and T4 levels, thus contradicting Sustrová and Strbák. However, the idea that thyroid hormone production declines with age in DS people is worth further investigation and if true would beg many questions. Does TSH effectiveness decline? Does the ability of the thyroid to manufacture its hormones decline?
How could thyroid dysfunction be associated with the pathology of Down’s syndrome?
The thyroid hormones, along with insulin and human growth hormone, are responsible for accelerating body growth. It has been found that low rT3 levels could impair growth hormone stimulation (Lejeune), and that all DS children with elevated TSH exhibit more severe growth delay (Bucci et al). Increased weight gain often becomes apparent in many individuals with DS (Pueschel), a common symptom of hypothyroidism as the thyroid controls basal metabolic weight. Indeed Pueschel states that one cause of weight gain in DS is a decreased intracellular metabolic rate. Thyroid dysfunction interferes with the hypothalamic-pituitary-thyroid axis which modulates thymic activity, thus affecting immunity (Napolitano et al) and DS subjects are characterised by an unbalanced immune control including poor performance by the thymus (Serra and Neri, 1990). Both thyroid hormone deficiency (Barnes and Galton) and DS (Lejeune) are associated with mental retardation. Lejeune discusses the role of the thyroid in directing tubulin organisation, and points out that only three conditions exhibit neurofibrillary tangles: Alzheimer’s disease, hypothyroidism, and DS. It is interesting that many of the physical characteristics of cretinism (extreme thyroid deficiency during foetal or early life) correspond with those of DS such as enlarged tongue, open mouth, broad face and flat nose.
What role does zinc play?
Altered zinc levels have been observed in both DS subjects and in hypothyroid patients when compared to controls (Napolitano et al; Bucci et al), though the roles zinc plays are only beginning to be teased out.
Thyroid hormone receptors require zinc ions (Licastro et al, 1992; Sustrová and Strbák) which facilitate folding into their active shape (Bucci et al). Zinc is also required for binding thyroid hormone receptors to the target DNAs, called thyroid response elements (Licastro, 1992; Bucci et al). A zinc deficiency may require more of a hormone to be secreted in order that enough is taken up. Sustrová and Strbák suggest that if the pituitary receptors were affected, normal thyroid hormone concentrations would not inhibit TSH secretion. This author wonders whether TSH receptors are rendered less active by zinc deficiency, meaning more TSH must be secreted to maintain a normal level of T3 and T4.
Zinc is required by thyroid hormone deiodinase, which modulates the deiodination activity vital for the homeostasis of the thyroid hormones. Thyroid hormone deiodinase converts T4 to T3, and removes the iodine ions from excess T1 and T2 (thyroid hormone precursors) to be reused in the synthesis of more T3 and T4. Perhaps a zinc deficiency would affect the rate of conversion of T4 to rT3 via the deiodinising enzyme? It is impossible to ignore the connection between the function of the thyroid and of the thymus, especially when discussing the importance of zinc. There is a close correlation between zinc, the thymic hormone and the pituitary-thyroid axis. Thymulin - the thymic hormone - is associated with an improvement in thyroid function (Bucci et al) and each thymulin molecule contains a zinc ion (thymic function is discussed in more detail further on). Zinc may affect the action of the binding proteins that carry thyroid hormones, and this could interfere with the pituitary-thyroid axis (Napolitano et al). Zinc deficiency appears to affect the utilisation of thyroid hormones in the peripheral tissues (Licastro et al, 1992).


What effect does zinc supplementation have on thyroid function?
Every piece of research this author found which measured the effects of zinc supplementation on DS thyroid function found significant changes. However these changes were different in almost every case, and sometimes contradictory. Each piece of research supplemented the subjects by os, that is 1mg of supplement per kg body weight per day. Though most stated the use of zinc sulphate, some, such as Licastro (1992), did not make clear whether the measurement was of elemental zinc or a zinc compound. This would affect the amount of elemental zinc the children were receiving. This could be one of the reasons behind variations in results. 1mg per kg per body weight is a high dose when compared with the governmental Estimated Average Requirement for the normal population. Using growth charts for children with DS (Cronk et al, 1988) to estimate bodyweight a 1-3 year old would be given 12.5mg while the EAR is 3.8mg per day, and a 15 year old would be supplemented with 55mg instead of the EAR 7.3mg. In both their 1992 and 1993 papers, Licastro et al found that TSH levels returned to normal with zinc supplementation. Bucci et al note that it was the hypozincaemic DS subjects which exhibited high TSH and that they experienced a significant decrease after supplementation. Conversely, Napolitano et al found that TSH remained the same after 6 months supplementation and Sustrová and Strbák found that after a year of alternating three months with supplementation with three months off, ending on three months off, the TSH levels were found to rise. The only papers to measure rT3, both by Licastro et al, found a rise to normal levels after supplementation. These papers also found T3 and T4 remained the same while Napolitano et al found a rise in T3, and Sustrová and Strbák found a drop in T4. Napolitano et al found a drop in FT3 after zinc treatment, and Bucci et al found that FT4 levels reduced significantly, also reducing the FT4/FT3 ratio.


Immunodeficiency - The Thymus
“Patients with Down’s syndrome suffer from frequent infections and have an increased
mortality in infectious diseases compared to a normal population. Several laboratory studies
have demonstrated abnormalities of cell-mediated and humoral immune capacity and of
phagocyte function.” (Björkstén et al, 1980). As zinc is vital for the functioning of the
immune system (Meek, 1996) it makes sense to consider the role of zinc when questioning
why the DS immune system is weak, and how it can be supported. It has been found that
young animals and humans, when receiving insufficient zinc, exhibit:
• Rapid thymic atrophy
• Decreased production of thymic hormones
• Impaired lymphocyte proliferation after phytomitogen stimulation
• a) decreased number of, and dysfunction of, T-lymphocytes b) abnormal T-
helper and/or suppressor cell function
• Deficiency of natural killer cells
• Significantly reduced antibody and cell-mediated responses
• Delayed hypersensitivity reaction
• Decreased spleen and lymph nodes
• Generalised defective development of lymph tissue
(Franceschi et al, 1988; Stabile et al, 1991; Brigino et al, 1996)
The significance of the thymus
“The majority of immune alterations observed in DS subjects seem to depend on defective
thymic function.” (Fabris et al, 1993). This would include low levels of thymulin; a reduction
in and/or disruption to the subset division of, T-lymphocytes; a reduction in B-lymphocytes
(the proliferation of which is controlled by the T helper cells) and diminished delayed
hypersensitivity — all part of what is known as the adaptive immune system. Napolitano et al
(1990) claim that low zinc levels are responsible for the early atrophy of the thymus. One
obvious link between the thymus and low zinc status is that zinc is required to transport
vitamin A from the liver, and vitamin A is necessary for the growth hormone which
maintains the thymus (Meek, 1996).


The importance of functional assays
Before the effects of zinc supplementation on these parameters is considered, a ground-
breaking piece of research by Fabris et al in 1984 must be considered. Having realised that
plasma concentrations of thymic factors are not necessarily a reliable index of the functional
activity of the gland, the investigators measured the levels of active thymulin and the levels
of thymulin inhibitory activity in young DS subjects and in healthy controls. They then added
zinc sulphate in vitro and assayed again. The finding was that the DS individuals and the
normal subjects over 50 years old had an inverse correlation between plasma active thymulin
and thymulin-inhibitory activity. In normal people up to 20 years old thymulin levels were
highest of all those measured and thymulin-inhibitory activity was not detected in healthy
subjects until they reached 30. Conversely thymulin-inhibitory activity was high even in the
youngest DS children. In both the elderly people and DS subjects plasma zinc was below the
normal range for healthy adults. Once zinc sulphate was added to the plasma samples from
both these groups the active thymulin levels become the same as those found in healthy
young adults and the thymulin-inhibitory activity completely disappeared. These inhibitory
factors have not yet been identified, though some experiments suggest an anti-thymulin anti-
body is involved. However, as Fabris et al point out, this is highly unlikely in their work, as
there is a strict inverse correlation between the thymulin and the thymulin inhibitory activity,
which is reversed by the addition of zinc sulphate. Their interpretation is that the inhibitory
substance is in fact biologically inactive thymulin, which is still able to bind to thymulin
receptor sites, and that the thymulin is activated by zinc. This is a very neat assumption,
which accords with other research. Interestingly, though the DS active/inactive thymulin ratio
was completely corrected by the addition of zinc sulphate, in the normal subjects this was
only partial, suggesting that in physiological ageing other factors interfere with thymulin
turnover. The overall picture is that DS people’s thymuses do produce sufficient thymulin,
that insufficient zinc is available to activate it, and, importantly, simply measuring levels of
thymulin in the plasma was not telling the whole story. This paper plainly shows that
measuring levels and counting numbers is not the same as assaying what is biologically
available. In deed Lockitch et al acknowledge in their paper that “lymphocyte number and
subset distribution are relatively static indexes of immune system capability and that
functional assays such as in vitro antibody or interleukin production may be more sensitive
indicators for future studies.”

Does zinc improve the functioning of the immune system in Down’s syndrome?
Franceschi et al found that zinc significantly raised active thymulin and lowered inactive
thymulin, echoing Fabris’s findings, but Brigino found no increase in thymulin levels despite
normalised cellular zinc levels. These findings can not really be compared as Brigino used
only 5 subjects, all of whom presented with recurrent infections such as pneumonias and
chronic otitis media. It is quite possible that such conditions, which did improve with
supplementation, were utilising the extra available zinc. Franceschi et al used 18 subjects and
Fabris et al used 72, all off whom were basically healthy.
Zinc supplementation appears to increase lymphocyte proliferation (Stabile et al, Licastro et
al, Brigino et al), which may be because zinc is essential for cell division. This is because
DNA polymerase is the enzyme central to DNA replication, and cannot function without zinc.
The aforementioned three papers also all found a reduced incidence of recurrent infections.
Lockitch et al however, found no improvement in the frequency of infections. It is this
author’s opinion that the methods of assessing frequency of infectious episodes prior to and
after zinc supplementation were far too inexact to be useful. For example Licastro et al asked
parents to remember the number and type of infections their child had had the previous year
and Stabile et al give no indication how they collected the information. The parents in
Lockitch’s investigation were instructed in detail how to fill in an infection log, which lends
more credence to this research, but still relied on parental judgement on what would be
considered normal. Possibly more objective means of assessing day-to-day infectious status,
such as a daily temperature chart, should be investigated.
Other papers found improvements such as increased T-lymphocytes (Franceschi et al),
improved skin responsiveness (Björkstén), or improved utilisation of interleukin 2 (IL-2)
(Licastro et al), but until these tests are repeated it is not possible for this author to
confidently comment on their validity. Lockitch et al found no improvement in any of the
parameters they measured, and indeed found that lymphocyte proliferation decreased even
further. The researchers themselves suggest that “although low doses raise serum zinc values,
a much higher intake is needed to correct cellular deficiencies,” but Licastro et al propose the
possibility that “the zinc supplementation was given for a longer period (6 months in the
[Lockitch] study). Prolonged zinc administration (6 months versus [Licastro’s] 4 months)
might suppress immune functions. An excessive zinc intake has indeed been shown to
impair... lymphocyte [proliferation] in humans, polymorphonuclear migration response to the
chemotactic factors and granulocyte phagocytosis of opsonized bacteria.”

...

Immunodeficiency - Leukocyte Function
It has been found that the chemotaxis, phagocytosis, and other anti-foreign microorganism
actions of leukocytes are reduced (Fabris et al, 1993). Licastro et al (1993b, 1994)
investigated the ability of DS neutrophils to produce chemically active molecules, such as the
superoxide anion, when stimulated. They observed that chemical activity was low before
supplementation but after zinc therapy neutrophil reaction to a stimulus was normalised. The
authors point out that protein kinase C is believed to play an important role in the activation
of human neutrophils, including superoxide generation, and that the activity of protein kinase
C is regulated by zinc ions. Possibly the actual fault is an impaired activation of protein
kinase C because of a poor supply of zinc ion. Rates of infection amongst the subjects were
found to decrease with supplementation, but the same problems with this data apply as
previously discussed, especially the compilation of a record of each child’s infection history
for the year preceding the experiment from what the parents recalled.
Neutrophil chemotaxis was also found to be reduced in DS patients by about 30%, but
normalised after zinc therapy (Björkstén et al, 1980). Björkstén et al relate zinc enhancement
of neutrophil activity to possible membrane phenomena and also mention intracellular
activity, as leukocyte locomotion is very complex. Licastro et al (1993) also followed up their
subjects a year after ceasing zinc therapy and found that neutrophil activity had dropped
again, supporting their assumption that zinc had improved their functioning. Unfortunately
Björkstén did not follow up his subjects so a similar comparison is not available.
That zinc supplementation may improve neutrophil deadliness is very important in attempting
to understand how to reduce the incidence of infection in DS people. Further investigation to
expand understanding in this area could prove very fruitful, including investigation into the
role of protein kinase C and its relationship with zinc.

Maturation of blood cells
Differentiation is the process by which subsets of a family of cells are formed from parent, or
‘stem’ cells by the acquisition of specific functions. It is of particular importance in
haemopoiesis, the process by which blood cells are formed, and the consequent development
of T-lymphocytes. Differentiation is a gradual process with cells passing through various
stages before achieving maturity, and is stimulated by various growth factors. Apoptosis is a
mechanism of programmed cell death, which occurs as a response to an external factor or the
withdrawal of a growth factor. It is an important part of cell differentiation for both the
immune system and haemopoiesis as it culls excess cells to maintain a suitable subset balance. The enzymes concerned in breaking apart DNA fragmentation during apoptosis are
endonucleases.

Inefficient cell maturation

DS individuals have been found to have an unusual presence of immature myeloid cells
(found in the earliest stages of haemopoiesis) in peripheral blood circulation associated with
low levels of zinc plasma (Trubiani et al, 1996a, 1996b). Both pieces of research found that
six months of zinc therapy induced the disappearance of the immature myeloid cells, but the
authors offer different possible explanations:
• That zinc is required for the process of programmed cell suicide: “ The results here show that zinc therapy in Down’s patients induces cell death of undifferentiated and ineffective myeloid cells, recovering a mechanism related to cellular differentiation of the haemopoietic system”  (1996a)
• That zinc is required for normal cell differentiation: “Since leukocytes contain high
levels of zinc and this level varies with cell maturity, being lowest in the most
immature cells, we suggest that low plasma zinc levels in DS subjects could be
responsible for a reduced rate of myeloid differentiation resulting in accumulation and
in escape from the bone marrow of immature cells reaching the peripheral blood”
(1996b)
• These reasons are not mutually exclusive and most likely zinc supplementation is
supporting both processes (Trubiani et al, 1996a).

Inappropriate apoptosis

A paper was published the following year, by essentially the same researchers (Antonucci et al, 1997), which evaluated the presence of apoptosis in the peripheral blood cells in DS subjects before and after six months of zinc supplementation. It was found that there were signs of programmed cell death before the zinc treatment, which decreased in all the patients following supplementation. The authors state that endonucleases are inhibited by normal plasma zinc concentrations and suggest that in DS individuals low levels of plasma zinc activate the endonucleases. Zinc therapy would therefore inhibit the apoptotic process leading to a decrease in the number of apoptotic cells.

Meanings of these results
It would appear that programmed cell suicide is happening at an inappropriately high rate in
mature DS peripheral blood cells. This author believes that when combined with the
weakened cell maturation process discussed above these findings represent a serious decrease
in the numbers of healthy, efficient blood cells in circulation, and the apparent success in
treating this deficiency with zinc has important implications for supporting DS people’s
health. Murphy et al (1995) found that DS spleens are markedly missing T cells “suggesting
the inefficient release of mature T cells from the DS thymus to the DS spleen”. Could this
lack of mature T cells be related to a poor rate of stem cell maturation? Or to a rapid
destruction of healthy, mature cells by a high rate of apoptosis? Or both? How does this
confusion of the cell differentiation process relate to the 10 to 20 times higher risk DS people
have of developing myeloid leukaemia (Milunsky et al, 1970)? The question must also be
asked as to why these scientists found that zinc deficiency appears to reduce programmed cell death in immature cells and promote it in mature cells. It is unfortunate that at present one
group of investigators has done all the research and it is hoped that in the future other
scientists will pick up the baton.

DNA Repair
Premature ageing is a universal problem for DS people, including a far higher risk of
developing Alzheimer’s disease (Opitz and Gilbert-Barness, 1990). This observation suggests
a fault in the integrity of the DNA repair system. Chiricolo et al (1993) investigated whether
zinc supplementation affected the maintenance of DNA integrity by damaging lymphocyte
DNA with radiation in vitro, before and after four months of zinc supplementation, and
observing the rates of repair. The finding was that before supplementation the DNA damage
(which was normal) was repaired extraordinarily rapidly when compared with the cells from
normal children. The authors suggest that persistent oxidative stress may mean that DNA
repair enzymes are activated in higher numbers in DS, a possible explanation for the
increased rate of repair. It may even be that zinc deficiency contributes to this oxidative
stress. They also suggest that the high speed of repair is likely to mean more mistakes are
made and that “it could contribute to neurodegeneration and precocious ageing which are
both hall-marks of the system.” (Chiricolo et al). After the period of zinc therapy the damage
received by the DS lymphocytes was the same as before, but the rate of DNA repair was
significantly reduced, back down to a normal, and presumably more accurate, speed.
Thus the paper shows that zinc does not appear to have a protective effect against DNA
damage - at least not radiation damage - but rather modulates the speed of repair and so
probably its accuracy. The authors speculate that this is because four months of zinc therapy
was enough time to reduce the oxidative stress, but this author believes it is also possible that
zinc is a requirement for one or more enzymes which regulate DNA repair. Possibly this
could be investigated in vitro, without zinc supplementation in vivo, to observe the effect of
immediate availability of zinc ions rather than a slow build up of effects associated with a
gradual rise of zinc status to normal. Though this is only one paper it appears to be the first
that demonstrates a nutritional intervention apparently affecting DNA repair, and so is a
ground-breaking paper.


Growth Delay
“Growth retardation is a cardinal characteristic of Down syndrome” (Annerén et al, 1990). It
is not known what the underlying mechanism is responsible for the retardation of growth. DS
children have normal levels of human growth hormone (hGH) and low levels of
somatomedin C — also called insulin-like growth factor (IGF-1). IGF-1 is regulated by hGH
postnatally, and it appears that in DS there is a delayed, possibly incomplete, transfer from
foetal IGF-1 to the hGH regulated IGF-1 (Annerén et al, 1990). Growth is mainly restricted
between the ages of 6 months (when hGH starts to regulate growth) and 3 years. Some, but
not all, researchers have found that growth after this age is near to normal, just starting from a
smaller stature (Annerén et al, 1993). Napolitano et al (1990) found that the level of IGF-1
rose after zinc supplementation, especially in children over 7. Zinc levels diminish with age
in DS people, as with normal people, though this happens earlier in DS, so it is conceivable
that the results were more pronounced with older children as they had a greater need for extra
zinc. The effect of zinc supplementation
Strangely, despite the well documented link between zinc deficiency and growth delay
(Passwater and Cranton, 1983), this author found only one paper investigating the effects of
zinc supplementation on growth in DS children. Napolitano et al studied 22 DS children
whose growth velocity was calculated for the six months before the period of
supplementation and during the six months of therapy. They were supplemented by os, and
their rate of growth compared with special growth charts for DS children (Cronk et al, 1988).
It was found that 15 of the subjects moved into a higher centile in their growth charts and,
interestingly, that the children older than 7 years showed a greater differential in growth
velocities before and during supplementation than the children aged 4-7 years. This
particularly noteworthy when compared to the finding that suppressed growth occurs earlier.
Unfortunately, no children under 3.8 years were included. The results for children under 4
years, and over 10 years (girls) or12 years (boys) were considered separately to avoid
interference by first childhood and pubertal growth spurts.
This author considers that there could be huge potential for zinc therapy to minimise growth
retardation. Zinc is essential for DNA and RNA polymerase and thus for cell proliferation; it
is necessary for protein metabolism; and as it is essential for the functioning of hormone
receptors (such as protein kinase C) zinc is possibly required for hGH and/or any of the hGH
regulated growth factors to function efficiently. The results of Napolitano et al’s work are
encouraging, but need to be repeated with measurements of the foetal variant form of IGF-1,
and assays into numbers and activity of hGH binding sites in DS would be useful.  Further
research using younger children would be extremely valuable in illuminating the role of zinc
in hGH functioning, transfer to hGH regulated IGF-1, and growth delay. Napolitano et al
suggest the possibility that thymus hormones may have a role in regulating the secretion of
hGH in DS children. Considering the importance of the thymus and thymic factors already
discussed, this link raises many more possibilities.
 


Gene over-expression as a drain on zinc
Extra SOD-1 gene

The best known gene mapped to chromosome 21 is that for copper-zinc superoxide dismutase
(SOD-1), and it is estimated that 99% of DS people have three copies of this gene (de Haan et
al, 1997). Most researchers found an elevated level of zinc in the erythrocytes (Milunsky et
al, 1970; Nève et al, 1983, 1984; Purice et al, 1988) and as there is believed to be a 50%
increase in SOD-1 activity in DS subjects (Jeziorowska et al, 1988), it seems “highly
probable that the increase of red cell... zinc levels in trisomy 21 is partly attributable to the
increased SOD-1 activity” (Nève et al, 1983). Kadrobova et al point out that “adaptations for
permanent oxidative stress and changed biochemical functions in DS may lead to the
increased requirements of an organism for zinc” (1996). This means that it is highly likely
that DS people have an increased need for zinc as they use a larger percentage of that
available for manufacturing SOD-1. It also alludes to the effects of increased SOD-1 activity.The function of SOD-1
The task of SOD-1 is to remove the superoxide radical, but it performs only half of the
process of clearing up by transforming the free radical into a much less volatile free radical
called hydrogen peroxide. It is glutathione peroxidase (and possibly catalase) which finishes
the process by dismantling hydrogen peroxide, otherwise prone to forming the hydroxy
radical, the most destructive of the free radicals. While SOD-1 activity is elevated because of
gene dosage, glutathione peroxidase and catalase are only present in the normal quantities,
quite possibly leading to an accumulation of hydrogen peroxide which could result in
considerable oxidative damage.

Zinc as an antioxidant
As well as its role in the formation of SOD-1, zinc has an antioxidant effect in its own right,
and stabilises cell membranes (Kadrobova et al, 1996). It is possible that the permanent
oxidative stress of excess production of hydroxy radicals uses up a higher proportion of zinc
than is used for antioxidant activity in normal people. If oxidative stress were to be a drain on
zinc resources it could be expected that exercise would increase this load, as exercise
increases oxygen metabolism thus increasing the production of free radicals. Two pieces of
research look at the effects of exercise on the plasma and erythrocyte zinc levels. The first, by
Laires et al (1994) found that exercise did not change these measurements, but the period of
exercise was only twenty minutes rowing. As the paper reports that DS people find such a
length of time of concentrated exercise difficult, it is quite possible that many subjects either
did not complete twenty minutes, or did so in smaller sections. The second paper, by
Monteiro et al (1997), looks instead at the effects of aerobic exercise over the period of time.
The subjects’ regime was increased gradually until they were performing 25 minutes of
aerobic activity 3 times a week. After 16 weeks their plasma zinc and erythrocyte zinc levels
were compared with their starting values, and the plasma zinc was found to be significantly
lower. The authors suggest either an activated expression of antioxidant mechanisms or
elevated sweat loss as possible reasons. This author considers sweat loss less likely because
sweat, as well as having a cooling action, is a mechanism for excreting excess ions. There is
no evolutionary advantage to excreting a trace element that is already in short supply. There
is of course a possibility that DS people have a faulty sweat mechanism but this author found
no mention of this in relation to zinc status in any papers. Thus this author considers this
research supportive of the possibility that excess SOD-1 is placing a drain on zinc supplies.


Not all DS subjects express excess SOD-1
It should be added that some researchers have found that it is possible for the clinical features
of DS to exist without elevated levels of SOD-1 (Jeziorowska et al, 1988; De La Torre et al,
1996) — a reminder that “among numerous abnormalities reported in DS no finding except
for the extra chromosomal material is constant” (Jeziorowska et al). However it is this
author’s opinion that excess SOD-1 is likely to be a factor in the majority of DS people.

Over-expression of other proteins
Another known gene on chromosome 21 is that for the protein subunit S100ß. An increase of
this could also increase the requirements for zinc (Lejeune, 1990). According to Lejeune it is also possible that there is excessive adenosine formation, mainly produced by a zinc-
requiring enzyme, which could be another drain on the available zinc. Trubiani et al  (1996)
also mention other zinc binding proteins which appear to be over-expressed in DS subjects:
polymerase and various kinases which are necessary for cellular metabolism and
differentiation.

The possibility of malabsorption
A common explanation for nutritive deficiencies in subjects with a normal diet is that of
malabsorption, and several authors consider it a possible reason for low serum zinc in DS
(Bruhl et al, 1987; Kanavin et al, 1988; Licastro et al, 1993). Sylvester (1984) considers
malabsorption to be a significant reason behind low levels of nutrients. He states that the
shortages of some trace metals to which DS people are prone are lifelong, and points out that
their absorption from the intestines, measured using the xylose absorption test, has been
found to be reduced. Abalan et al (1990) measured the absorption in 4 DS patients by
microscopically examining their stools for meat fibres after a measured diet. The meat was
minced to negate the effect of insufficient chewing due to poor dentition – DS children are
prone to abnormalities of tooth formation, and to periodontal disease (Pueschel, 1990). The
finding was a high meat fibre count, strongly supporting the malabsorption hypothesis. As
Abalan et al point out, this test does not indicate what the cause of the malabsorption could
be, suggesting as possibilities pancreatic insufficiency, reduced intestinal absorptive capacity,
or other causes. This author would add hypochlorhydria, and food allergies as possible causes. In the wake of reports of a high incidence of coeliac disease in DS, Strong (1993) performed a study which found all of his ten subjects displayed raised IgE and IgG to one or more of 13 common food allergens. Though only a preliminary study this indicates a possible role of allergies in DS malabsorption. Both of these studies are small-scale, uncontrolled investigations; larger, controlled investigations would provide valuable data regarding DS absorptive status.
A cautious note is struck by Licastro et al who point out that some elements, such as copper and magnesium, are found in the normal range in DS, an argument against malabsorption as an explanation for low zinc levels.


Transportation
Zinc ions need to be bound to a carrier to travel in the bloodstream.
... It is also possible that carriers are transporting the wrong ions; the concentrations of heavy metals is beyond the remit of this paper, but it is known that cadmium, aluminium, and copper are zinc antagonists and can replace zinc ions.
This author believes that problems with transport proteins could play a role in DS low zinc status, and the way forward is to measure the activity of all the proteins known to be
involved.



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