There's a Battle Being Fought Between the ScoliScore Folks and the ICONS Folks

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A group of 320 consecutive patients with IS were compared with 120 healthy control subjects and 82 asymptomatic offspring, born from at least one scoliotic parent, who are considered at risk of developing this disorder.

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Mean plasma OPN levels were significantly increased in IS patients and correlated with disease severity, with average values of 743+326ng/mi and 975+389ng/mi for moderated (10-44 degree) and severe (>45 degree) spinal deformities, respectively, when compared to the healthy control subjects.

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I think Dr. Moreua used healthy children who had parents with Scoliosis to make his point a little stronger. This risk factor didn't translate into high levels of OPN. Only the group with Scoliosis had high OPN. The higher the OPN, the more severe the curve.

I'm curious to know if high levels of OPN continued well into adulthood or if they slowly shifted back to normal after skeletal maturity.

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Mean plasma OPN levels were significantly increased in IS patients and correlated with disease severity, with average values of 743+326ng/mi and 975+389ng/mi for moderated (10-44 degree) and severe (>45 degree) spinal deformities, respectively, when compared to the healthy control subjects.

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I don't know, but this sounds to me that this test also is just showing the magnitude of a scoliotic process, that has already occurred based on the size of the curve magnitude. Where is the predictive value in this?

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The genetic test doesn't tell parents if their daughter is susceptible to Scoliosis. It tells parents if their daughter who ALREADY HAS Scoliosis is susceptible to curve progression.

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This seems okay to me. There are people in ballet who believe that most people with hyperextended joints in ballet have at least a minor case of scoliosis, and from my experience, it does seem to have some basis in fact. But most of these cases aren't anything to worry about, they can't even be seen, so maybe the Scoliscore and it's predictive ability for curve progression would still be a good way to limit the need for the OPN test i.e. only the kids who have a high degree of progressing could get more in-depth testing during their growth.

I don't even have the information for either of these tests to be able to make a reasonable interpretation of the results and what it might mean, so I'm going to stop there, and hopefully the scientists will be figuring out what all this means. I just truly hope they keep an open mind either way and use whatever methods are best for the kids....including testing the Mynicycline and see if it has a positive effect on kids diagnosed with scoliosos. :)

Ballet Mom

I've talked to the team in Canada and I am no longer absolutely certain how the blood test works. However I know that it's not just one test.

The first blood test determines if the child (any age or gender) has the nervous system disorder that leads to Scoliosis. This test is taken once. Depending on the results each child is placed in one of 3 functional groups, low, medium and high risk. I'm nearly positive this test looks for Melatonin Signaling Dysfunction because in Moreau's landmark study children were placed into 3 groups. On page 5 it shows that out of 41 kids 7 were in the high risk group, 20 were in the moderate risk group and 14 were in the mild risk group. These ratios don't represent how a normal population of children with Scoliosis would be broken down because all 41 kids in this sample had their spine's fused.

The next test is given several times per year to determine if curve progression is likely. I had previously thought this test measured Calmodulin because so much interest was in that area. Now I'm thinking this part of the test measures OPN levels. If OPN rises curve progression is imminent, if it falls or goes back to the normal zone the curve should remain stable or maybe even regress. I dunno for sure.

We will know soon enough because these tests are going to be released in the USA sooner rather than later. :)

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The next test is given several times per year to determine if curve progression is likely.

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Is this a blood test? Good luck getting that several times a year from kids who aren't sick...especially young ones. :( And to have to continue throughout their growth years? Yikes! And having that test done several times a year from when they're three years old? It seems like the cost would be prohibitive. But, what do I know? But hey, good luck to them.

According to this paper, increased melatonin, increases osteopontin, and suppresses cAMP.

Melatonin is higher in younger animals, and causes differentiation and calcification of osteoblasts.

All it means is that bone cells are growing.

So, if the melatonin (or osteopontin, or cAMP) is high, maybe curve progression is simply a consequence of a fast rate of bone growth.

PNUTTRO

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increased melatonin, increases osteopontin, and suppresses cAMP.

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EEEEeeeee... that makes things a bit more complicated. Melatonin suppresses cAMP which in theory should be a good thing. Once again page 5 on this chart shows that children with Scoliosis don't inhibit cAMP properly in response to Melatonin.

I can't get to the study you listed. Does the study suggest that these hormones merely trigger and work together or are they suggesting that something like a Melatonin supplement would cause Osteopontin to shoot up?

For example I can take all the Vitamin B I want and anything over a normal level gets flushed. But if I ate iron supplements like candy my skin would turn orange.

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Originally Posted by Dingo

EEEEeeeee... that makes things a bit more complicated.

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A bit? A BIT???

This stuff is more intrinsically complex than landing a man safely on the moon and returning him safely to earth.

There is a reason why there are long-standing, unsolved medical dilemmas. And it's not for lack of a bunch of lay folks discussing it on a scoliosis forum. (I apologize for the preceding remark and for the fact it is a penetrating glimpse into the obvious.)

Half the battle is just getting to point where you begin to form some nascent sense of just how complex this stuff is (or it would have been solved by now). I don't think most of the players here have arrived at that point. Pnuttro obviously has as this is her field. And that's about it. I commend her restraint.

PNUTTRO

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So, if the melatonin (or osteopontin, or cAMP) is high, maybe curve progression is simply a consequence of a fast rate of bone growth.

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Height certainly does appear to be a risk factor for Scoliosis. I thought about it but I don't think it could be the cause. According to the study I just posted a couple of times a few messages back all children with Scoliosis have Melatonin Signaling Dysfunction.

So for whatever reason something has gone wrong and this ultimately leads to an increase in OPN.

Melatonin secretion is regulated by the activity of allylalkylamine N-acetyl transferase (AA-NAT) which is usually but not always [38], considered the rate-limiting enzyme in the synthetic pathway of melatonin [39, 40]. Recent studies suggest that estrogen suppresses the synthesis of AA-NAT protein [41, 42]. It is therefore assumed that melatonin secretion decreases in response to an increase in estrogen levels in adolescent women, as their markedly increased estrogen suppresses the synthesis of melatonin via AA-NAT activity. Judging from the results of recent studies which show that melatonin is a physiological factor that promotes bone formation [22, 26], there is a possibility that expression of the melatonin receptor in osteoblasts is upregulated to compensate for a decrease in melatonin action caused by the abrupt increase in estrogen levels occurring in adolescent women.

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Height certainly does appear to be a risk factor for Scoliosis.

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Probably just because they have a longer time to grow and develop a more severe curve. I have a friend who's daughter is in ballet and has just been officially diagnosed with scoliosis and she's under five feet tall......but she does have hyperextended joints! Luckily, she probably won't grow much more because her mom and dad are both quite short.

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Originally Posted by Ballet Mom

Probably just because they have a longer time to grow and develop a more severe curve. I have a friend who's daughter is in ballet and has just been officially diagnosed with scoliosis and she's under five feet tall......but she does have hyperextended joints! Luckily, she probably won't grow much more because her mom and dad are both quite short.

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I'm talking about a rate of growth, not a period of time.

Fig. 4. (A) Intracellular cAMP production induced by forskolin
was suppressed by melatonin in a dose-dependent manner (**:
p < 0.01). (B) The suppressive effect of melatonin was blocked by
treatment with luzindole or PTX (a: p < 0.01 vs 100 lM melatonin,
b: p < 0.01 vs 200 lM melatonin). Values are mean ± SE
from two independent experiments performed in triplicate.

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Originally Posted by PNUTTRO

I'm talking about a rate of growth, not a period of time.

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Sorry, PNUTTRO, I was responding to Dingo's comment. I wasn't even aware you were posting.



Heh, never mind....I realize he was responding to your comment....

Our daughter is involved in this study at Ste. Justine.
The 1st time the parents need to give a saliva sample and our daughter had blood taken. Only she will have blood taken each time she goes for x-rays, every 6 months or so.
This study may or may not benefit her, but it could help children in the future... who knows, maybe even our grandchildren someday!!

Osteopontin is triggered by and protects the body from bacterial infection.

Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection.

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We conclude that osteopontin expression correlates with an effective immune and inflammatory response when humans are challenged by a mycobacterial infection and that osteopontin contributes to human resistance against mycobacteria.

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Increased expression of osteopontin in the brain with scrapie infection

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Immunohistochemically, OPN was intensely immunostained in neurons of the midbrain at the time of scrapie infection initiation.

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Osteopontin Regulates Infection-stimulated Periapical Bone Loss

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these results are consistent with a model in which OPN is expressed at the site of infection, and acts to facilitate migration of neutrophils and macrophages out of the circulation into the area of infection. In the absence of OPN, reduced neutrophil or macrophage numbers and/or function may result in reduced bacterial killing. The increased bacterial load ultimately results in an increased inflammatory response and increased bone loss.

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Attenuated Host Resistance against Mycobacterium bovis BCG Infection in Mice Lacking Osteopontin

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When infected with Mycobacterium bovis BCG, mice lacking a functional OPN gene had more severe infections characterized by heavier bacterial loads and a delayed clearance of the bacteria.

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Originally Posted by Dingo

PNUTTRO



Height certainly does appear to be a risk factor for Scoliosis. I thought about it but I don't think it could be the cause. According to the study I just posted a couple of times a few messages back all children with Scoliosis have Melatonin Signaling Dysfunction.

So for whatever reason something has gone wrong and this ultimately leads to an increase in OPN.

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So if you have melatonin signaling dysfunction, how will more melatonin in your diet help?

PNUTTRO

Increased Melatonin cannot repair Melatonin Signaling Dysfunction.

However there is some non-definitive evidence that low Melatonin correlates with curve progression. Melatonin is an antioxidant and has anti-inflammatory properties. If it's helpful this might be why.

Personally I would not give my child Melatonin supplements unless the science was definitive. It's free to sleep in a dark room and that simple behavior probably boosts melatonin production to an optimal, natural level.

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Originally Posted by Dingo

Personally I would not give my child Melatonin supplements unless the science was definitive. It's free to sleep in a dark room and that simple behavior probably boosts melatonin production to an optimal, natural level.

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While I agree that its a good idea for good overall health, there is an inherent contradiction when you say that one needs to boost melatonin levels (by diet or dark rooms) when

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Originally Posted by Dingo

all children with Scoliosis have Melatonin Signaling Dysfunction.

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p

PNUTTRO

Melatonin Signaling Dysfunction doesn't mean that kids don't produce Melatonin.

One of Melatonin's jobs is to shut down the molecule cAMP. For whatever reason children with Scoliosis produce Melatonin but it doesn't do it's job and flush out the cAMP in bones.

I am guessing that this buildup of cAMP produces inflammation which elevates OPN. Melatonin doesn't do it's job and flush out cAMP but perhaps since it has anti-inflammatory properties this helps keep OPN levels down.

I dunno, I guess we'll find out soon enough.

Osteopontin is a huge, red flag for inflammation.

Osteopontin: A Multifunctional Molecule Regulating Chronic Inflammation and Vascular Disease

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Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases, and it is specifically localized in and around inflammatory cells. OPN is a secreted adhesive molecule, and it is thought to aid in the recruitment of monocytes-macrophages and to regulate cytokine production in macrophages, dendritic cells, and T-cells. OPN has been classified as T-helper 1 cytokine and thus believed to exacerbate inflammation in several chronic inflammatory diseases, including atherosclerosis. Besides proinflammatory functions, physiologically OPN is a potent inhibitor of mineralization, it prevents ectopic calcium deposits and is a potent inducible inhibitor of vascular calcification. Clinically, OPN plasma levels have been found associated with various inflammatory diseases, including cardiovascular burden. It is thus imperative to dissect the OPN proinflammatory and anticalcific functions.

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Fish oil is an effective, well documented anti-inflammatory. A few months after my son was diagnosed with Scoliosis I started giving him pharmeceutical grade fish oil supplements on the off chance that inflammation played a role. I'll never know for sure but I think that one might have paid off big time.

Hooray fish oil! :)

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Originally Posted by Dingo

PNUTTRO

Melatonin Signaling Dysfunction doesn't mean that kids don't produce Melatonin.

One of Melatonin's jobs is to shut down the molecule cAMP. For whatever reason children with Scoliosis produce Melatonin but it doesn't do it's job and flush out the cAMP in bones.

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Exactly my point. If you can produce melatonin, but not respond to it properly, then no amount of darkness or other method to increase melatonin will make your cells react differently.

PNUTTRO

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Exactly my point. If you can produce melatonin, but not respond to it properly, then no amount of darkness or other method to increase melatonin will make your cells react differently.

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Melatonin does a lot more than flush out cAMP molecules. Every other part of the system is working properly.

If Melatonin wasn't working at all I think that might turn fatal at some point.

METHOD OF DETERMINING RISK OF SCOLIOSIS

Bracing (if it's effective) and surgery lower OPN levels. If OPN levels don't drop a brace will be ineffective. GOLD! :)

[0014] In accordance with another aspect of the present invention, there is provided a method for assessing the efficacy of a brace on a subject having a scoliosis comprising measuring osteopontin (OPN) expression in a sample from the subject prior to and at least once after bracing the subject, wherein an increase in the OPN expression after as compared to prior to bracing the subject is indicative that the brace is ineffective.

[0015] In a specific embodiment, the determining the OPN expression after the bracing is performed at least one month after the bracing. In another specific embodiment, the determining the OPN expression after bracing the subject is performed at least 2 months after the bracing. In another specific embodiment, the determining the OPN expression after bracing the subject is performed at least three months after the bracing. In another specific embodiment, the determining the OPN expression after bracing the subject is performed at least six months after the bracing.

[00162] A distribution of 12 AIS patients was also performed across the predefined cut-off zones pre-operation and post-operation. Figure 15 shows 92% of the surgically treated patients had pre-operation OPN levels in the red-zone (>800ng/mL of plasma OPN level), while the remaining 8% were in the yellow zone (700-800ng/mL). No patients were in the green zone representing plasma OPN levels <700 ng/mL. This also shows a strong correlation between high OPN concentrations and the progression of scoliotic curves.

[00163] Panel B of Figure 15 show that red zone patients who were treated surgically experienced a decline in OPN concentrations in the blood. 75% of the surgically treated patients fell into the green and yellow zones (800 ng/mL or less).

Dr. Moreu is very direct that Selenium is low in children with AIS and supplements may be an effective treatment. I copied in all of the relevant paragraphs. There were several others that mentioned Selenium but they primarily talked about ways to administer it.

[0024] In accordance with another aspect of the present invention, there is provided a method of preventing or reducing scoliosis comprising administering to a subject having scoliosis a therapeutically effective amount of an osteopontin inhibitor (OPN) or a selenium rich diet, whereby scoliosis is thereby prevented or treated.

[00114] Any amount of a pharmaceutical and/or nutraceutical and/or dietary supplement compositions can be administered to a subject. The dosages will depend on many factors including the mode of administration. Typically, the amount of anti-scoliosis composition (e.g. osteopontin inhibitor or selenium compound) contained within a single dose will be an amount that effectively prevents, delays or reduces scoliosis without inducing significant toxicity "therapeutically effective amount".

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EXAMPLE 14 Comparison of selenium levels in AIS patients vs. healthy subjects

[00166] Selenium concentration was reported to be significantly decreased in plasma of AIS patients (42). Selenium and more specifically Se-methylselenocystein, an organoselenium naturally occurring in diet, are used to prevent metastasis in breast cancer as chemopreventive therapy by targeting OPN transcription (43-45).

[00167] Plasma selenium concentration was thus measured in pediatric populations (AIS vs. healthy controls) to determine whether or not low selenium levels correlate with higher OPN concentrations in AIS. Plasma selenium concentrations were determined by a fluorometric method using 2,3-diaminonaphthalene (DAN) (46, 47). Results presented in Figures 18 and 19 show a correlation between high OPN levels and low selenium levels in scoliotic and asymptomatic at risk children.

Brazil Nuts are the richest, natural source of Selenium available.

USAWEEKEND: Nuts

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Brazil nuts, a holiday favorite, are the food richest in selenium, a potent antioxidant linked to low rates of cancer and heart disease. If you ate only one Brazil nut a day, you would never be deficient in selenium, says Donald J. Lisk, at Cornell University. Gobbling more than a half-dozen Brazil nuts every day could add up to nausea-causing selenium toxicity, he cautions.

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Nut & Seed chart

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1 ounce of brazil nuts (6 nuts) contain 543.5mcg of Selenium

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Brazil nuts boost health

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One Brazil nut a day is enough to raise the average New Zealander's selenium intake to internationally recommended levels and eating two could lead to added health benefits, according to University of Otago researchers.

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Seeking selenium? Try Brazil nuts: study finds this rich food source of the antioxidant mineral is superior to supplements.(PREVENTION)

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A study in the February issue of The American Journal of Clinical Nutrition shows that Brazil nuts are better at raising blood levels of this essential trace mineral than supplements. In the study, one group consumed two Brazil nuts daily (about 100 micrograms, or mcg, of selenium); a second group took 100 mcg of a selenium supplement; and a third group received a placebo for 12 weeks. Those who ate Brazil nuts had substantially higher blood concentrations of selenium.

"The supplement raised [serum selenium] levels, but not as much as the nuts," says Kathy Isoldi, MS, RD, CDE, a registered dietitian at Weill Cornell Medical College. "It is believed that the food source offers a more bioavailable form of selenium."

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National Institues of Health: Selenium

Recommended Daily Allowance Of Selenium
The RDA recommends the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in each age and gender group.
1 - 3 years: 20mcg
4 - 8 years: 30mcg
9 - 13 years: 40mcg
14 - adult: 55mcg

Tolerable Daily Upper Intake Of Selenium
The Upper Limit is the maximum daily intake unlikely to result in adverse health effects.
0 - 6 months: 45mcg
7 - 12 months: 60mcg
1 - 3 years: 90mcg
4 - 8 years: 150mcg
9 - 13 years: 280mcg
14 - adult: 400mcg

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[0065] Mean plasma OPN concentration in patients with AIS were significantly higher (p-value <0.001) in patients with AIS having a Cobb's angle >45° (965 ± 414 nanograms per milliliter) than that in healthy controls (570 ± 156 nanograms per milliliter) and than that in AIS patients with a Cobb's angle <45° (799 ± 284 nanograms per milliliter). Diagnostic sensitivity and specificity of OPN for AIS was 84.4 percent and 90.6 percent respectively (cut-off value > 800 nanograms per milliliter). Subgroup analysis showed that 47.9 percent of children at risk had OPN values higher than 800 nanograms per milliliter as opposed to only 8.6 percent for the controls indicating that elevated plasma OPN levels precede scoliosis formation. There were no significant differences in mean plasma sCD44 levels and HA levels between all groups.

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The "at risk" group consisted of children without Scoliosis who had 1 parent with Scoliosis. Approximately 50% of these children had dangerously high levels of OPN. If OPN was only implicated in Scoliosis it wouldn't be as stunning. It seems implausible to me that half of the offspring produced by parents with Scoliosis would be saddled by heredity with a potentially fatal health time-bomb. I think this discovery might provide evidence as to what the environmental half of Scoliosis is.

This story comes to mind.
LA Times: Rats' virus holds clues to diabetes

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The BioBreeding, or BB, rat naturally develops diabetes at about 2 months of age, and researchers have attributed the disease to genetics. The new findings suggest that there is indeed a genetic susceptibility but that the precipitating event is a viral infection.

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Maybe they have a genetic predisposition to being infected with that virus whereas normal controls don't get infected or get over it.

It would be like the opposite situation where a small group of HIV patients overcome the infection, perhaps due to some genetic control. In the rats' case, they only get the infection and consequences due to having a different genetic make-up.

If most/all the rats of this type become diabetic at around 2 months then the virus must be common in the environment. If true, incidence of diabetes in this rat strain is under genetic control. Maybe people are the same way. My brother became diabetic and the rest of us did not, all living in the same environment.

Pooka1

It certainly could work that way. I'm really curious to see how this all turns out over the next few years.

I hope someone interviews Dr. Moreau and he offers an explanation for the high OPN levels in kids with and without Scoliosis. This is where a twin study would really be useful.

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It seems implausible to me that half of the offspring produced by people with Scoliosis would be saddled by heredity with a potentially fatal health time-bomb.

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I agree, I think it probably shows that half the kids have already been infected with a common childhood illness, such as chickenpox, that causes an exagerated immune response in those kids with the genetic predisposition. And, who knows, maybe the body "knows" that these kids with the lax ligaments are going to have problems with this viral antagonist in their bodies and so the immune system goes into overdrive trying to get rid of it before the damage is done and continues to react even more strongly as the damage (the scoliosis) is being done to it.

Like your very interesting article about the rats you posted, I think this theory definitely deserves some research into it. I think it is plausible. And perhaps just to see if Solodyn, which is an extended release version of minocycline, possibly has an effect on controlling the immune response, perhaps an interested surgeon could prescribe this acne drug to some willing patients and see if it has an immediate effect on them. It's not that dangerous a drug after all. And then if it works, a brace could possibly be used to redirect the growth after the abnormal immune response is done and straighten out the curve a bit? Who knows...I think it's a fascinating theory to be tested.

Or maybe the scoliosis starts slowly forming immediately, and so the immune response starts immediately.....which would, of course, be the ideal time to treat it. So possibly, kids could have had that Scoliscore test taken and then when they get chicken pox, and if they have a high probability of progressing, they could be immediately prescribed a drug afterwards, like Solodyn,that stops the formation of the curve before it even gets started! Wouldn't that be awesome! It's so exciting to think about. (And that way, it would only require one blood draw for the Scoliscore DNA test, which is MUCH more plausible in kids....or anyone else for that matter. I know I would have never been able to get my kids to submit to the blood draws such as that being planned with the Canadian group and (even if I could, I probably wouldn't have done it because of the stress and duress it would have caused them).....and listening to kids who ARE getting their blood drawn, it's not a very fun experience for any of them....or their parent, or the tech drawing the blood!

Actually, now that I think about it, I suppose the Scoliscore test could possibly be done with a saliva or other sample instead of a blood draw? If so, so much the better! :)

I did just find out that the Scoliscore test is a saliva based test, which is a huge bonus in my book!

http://www.news-medical.net/news/200...in-the-US.aspx

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Originally Posted by Ballet Mom

........ because of the stress and duress it would have caused them).....and listening to kids who ARE getting their blood drawn, it's not a very fun experience for any of them....or their parent, or the tech drawing the blood!

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Our daughter didn't mind it at all - in fact she asked the nurse when she was going to take the blood and it was already done!!! ...So not stressful in all situations!!