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Dingo
06-13-2010, 04:59 PM
Dr. Alain Moreau is the director of the The Viscogliosi Molecular Genetics Laboratory of Musculoskeletal Disorders (http://www.chu-sainte-justine.org/research/nouvelle.aspx?ID_nouvelles=51533&ID_Menu=2546&ID_Page=2546) and the developer of the Scoliosis blood test. He was kind enough to share some of his valuable time with me to explain his revolutionary blood test and the latest thinking on Scoliosis. This interview was conducted over e-mail.

I moved question 19 near the top because it contains information that parents can use to potentially help a child living with Scoliosis. The rest of the interview is in order.

Part 1

Question 1) What attracted to you to the field of Scoliosis research?

Dr. Moreau) I have had a long standing interest in bone diseases. I was trained in bone molecular biology at the Shriner’s Hospital for Children in Montreal, which allowed me to be recruited at Sainte-Justine University Hospital Research Center 10 years ago, to lead a new laboratory dedicated to studying the causes of idiopathic scoliosis.

Question 2) How long have you studied Scoliosis?

Dr. Moreau) I have been actively involved in this field since 2000.

Question 19) Can you offer parents of children with Scoliosis any general recommendations on diet or lifestyle? Is there anything they should do or avoid?

Dr. Moreau) Right now, it is difficult to make any recommendation without knowing the functional and biochemical status of an asymptomatic child or a scoliotic patient. Having said that, there are a few things that could be considered:

There is no proven diet to avoid scoliosis. It is true that selenium is a known inhibitor of OPN, but this nutrient can be highly toxic at high doses, especially in children. Moreover, we have experimental evidence that shows that selenium will not work in the majority of IS patients due to their genetic make-up and the fact that we already have enough selenium in our diet in North America.

Reducing exposure to mycobacteria could be a good way to reduce the risk and I would start by cleaning all shower heads in the house on a monthly basis or even changing them annually since they represent an important source of mycobacteria (Opportunistic pathogens enriched in showerhead biofilms (http://www.pnas.org/content/early/2009/09/11/0908446106). Feazel LM, et al., Proc Natl Acad Sci U S A. 2009 Sep 22; 106(38): 16393-9. Epub 2009 Sep 14). A second thing to consider is that personally, I would remove the fish tank (aquarium) from the room of my own daughter because mycobacteria are always present in such environments. Again, I would like to stress the point that you won’t catch scoliosis by taking a shower or having a gold-fish in your home! The general idea here is to reduce the exposure to specific environmental factors to decrease risks. In order to do that, we will need to work together with parents and monitor OPN and sCD44 blood levels regularly to identify all potential environmental factors. Some patients will be more sensitive while other will be more resistant to the same environmental factors, so this is a new area of research. Only time will tell if such measures will have positive impacts, but we need to start somewhere.

Dingo
06-13-2010, 05:01 PM
Part 2

Question 3) Your team in Quebec is developing the world’s first Scoliosis blood test. What can parents expect from this test?

Dr. Moreau) First of all, I would like to clarify the nature of our scoliosis blood tests since we have developed two distinct and complementary tests.

Functional scoliosis test: The first test is a functional assay performed with blood cells obtained from 10 ml of blood (equivalent to 2 tea-spoons). As you know, we have previously discovered that many cell types obtained from patients suffering from idiopathic scoliosis (IS) display a differential response in the transmission of melatonin signals. This is possible because melatonin receptors are present in most if not all cell types including blood cells. In other words, the test measures how the cells respond to melatonin. Three distinct responses among IS patients were obtained allowing their classification into three functional subgroups. It should be noted that two distinct methods were performed to determine the functional classification of IS patients, the first using the measurement of cAMP, an intracellular messenger (Moreau et al Spine 2004 & Azeddine et al CORR 2007) and more recently using a more accurate technology called cellular dielectric spectroscopy (Akoume et al Spine 2010), giving both the same functional classification. This functional test has the added advantage of being performed on asymptomatic kids (boys and girls) as well to predict their risks of developing scoliosis. Moreover this functional blood test is also superior because it can be performed without prior knowledge of specifically mutated genes causing IS since we are measuring a function. To better understand the usefulness of this functional assay, I often use the example of how cystic fibrosis (CF) is diagnosed. CF is a monogenic disease, which means that it is caused by mutations in a single gene (CFTR) that plays a role in the transport of chloride ions. Today, there are about 1500 mutations known to affect the function of this gene. CF however, is initially diagnosed using a functional test measuring the level of chloride ions in sweat after provoking perspiration at the surface of the skin. Then, if you are positive for CF and depending on which part of the globe you are from, specific mutations will be tested, since it is not clinically and economically relevant to test for all possible mutations. For instance in Quebec, we would test for the 6 most prevalent mutations for our pediatric population.

What can a parent expect from this functional test? This functional test is performed only once and it reflects the genetic predisposition or susceptibility of developing scoliosis. It can be performed at any age (although we prefer not to test babies).

According to the functional subgroup in which the patient is classified, we can determine the following:


A risk-score to establish the susceptibility of developing scoliosis among asymptomatic kids and to predict the risk of disease progression for those at an early stage of the disease. Parents need to keep in mind that this functional test, like any genetic test, cannot assess with 100% certainty if their child will or will not develop scoliosis because the etiology of IS involves a crosstalk with the environment. In other words, kids with a great genetic predisposition (high risk) may develop a severe scoliosis if they are often exposed to specific environmental factors. Inversely, the same kids with a limited environmental exposure could develop a mild scoliosis or none at all.
The risk of developing specific co-morbidities (osteoporosis, anxiety, depression, etc.) which are known to be associated with IS. This aspect is unique to our test and we are in the process of validating whether or not some functional subgroups are more often associated with the risk of developing an early onset of osteoporosis. In that case, knowing a child’s functional subgroup could delay or prevent the development of osteoporosis by increasing his/her bone mass using exercise, diet and medication (which are proven and already available). In the same way, testing scoliotic adults could improve their health outcome and prevent complications simply by knowing which functional subgroup they belong to.
In the long term, this functional classification will be essential for the development of tailored pharmacological treatments (personalised medicine). This will reduce possible side-effects and better define the best treatment for a given patient to stop curve progression and eventually to prevent scoliosis when combined with an early screening using this functional test. We are conducting tests to identify potentially useful therapeutic agents, but parents and patients must be aware that these drugs won’t be tested in clinical trials that soon since we are just now beginning this phase of our research.


Biochemical scoliosis test: The second scoliosis predictive test is a biochemical one where two proteins called Osteopontin (OPN) and soluble CD44 (sCD44) are measured in the blood. Our clinical data in Montreal, Milan and Hong Kong clearly demonstrated that plasma OPN elevation is associated with IS onset and disease severity since all surgical cases (Cobb angle ≥ 45°) exhibit the highest values when compared to mild scoliosis and healthy control subjects. Conversely, sCD44 is a protective molecule that can prevent OPN from triggering scoliosis or spinal deformity progression by binding free OPN. This explains why IS surgical cases exhibit the lowest sCD44 values when compared to mild scoliosis cases and healthy controls subjects. OPN is not only a biochemical marker, it is the key player causing IS onset and it is responsible for spinal deformity progression. It is true that OPN and sCD44 are not disease-specific but when the observations of the effects of both are combined it does appear they become highly specific for IS. These data will be published in the upcoming months.

What can a parent expect from this biochemical test? First, this biochemical test must be combined with our functional test to predict the risk of developing scoliosis and spinal deformity progression. Secondly, the biochemical test will be used to monitor at regular intervals the following:


Risk of disease progression over a given period of time since plasma OPN and sCD44 levels are determined by individual genetics as well as by specific environmental factors. This represents the main advantage of this test since it monitors the impact of the environment on IS progression.
Effectiveness of bracing, physical therapy or pharmacotherapy because OPN is the molecule triggering scoliosis onset and inducing spinal deformity progression. Therefore, any treatment decreasing OPN levels is expected to have a beneficial impact.
Measurement of plasma OPN and sCD44 levels will allow contribute to determining the contribution of environmental factors known to trigger high OPN levels. Interestingly, OPN is a multifunctional cytokine that responds to many stimuli such as mycobacterial infections, drugs, diet, exercise, and biomechanical changes. It would be too long to go into detail for each of these factors but there are several papers demonstrating that OPN expression and synthesis can be increased or decreased in response to external factors. This aspect cannot be considered by genetic tests.
Elimination those factors or reducing the exposure to such factors may greatly reduce the risk of spinal deformity progression. For instance, this approach has been proven effective for the treatment of other diseases like asthma. There is no treatment for asthma but drugs are available to treat acute crisis as well as to reduce the number of attacks. However, reducing exposure to allergens (pet, dust, carpet, chemicals, and wooden stoves) has been shown to be very effective in controlling asthma. It is anticipated that regularly monitoring OPN and sCD44 blood levels will help parents and patients to work with us in the identification of those environmental factors.


Question 4) Do you know when your test will become available?

Dr. Moreau) This is a good question since I have previously predicted that the tests would be available in 2008-2009 and we are now in 2010! The main reason for this delay is it took us more time than expected to complete the clinical trial in Montreal, and launch clinical trials in Italy (Milan) and Hong Kong (China) to demonstrate the universality of our scoliosis blood tests in different pediatric populations. It is worth mentioning that the biochemical tests performed in Milan and Hong Kong were performed by others and yet still confirmed the validity of our own clinical data in Montreal. I can assure you that we are putting forth our best efforts to put our tests on the market as soon as possible.

Question 5) Can your tests be used for juveniles as well as adolescents? What about infantile Scoliosis?

Dr. Moreau) The aforementioned tests were validated in juveniles and adolescents. In regards to infantile scoliosis, we do not know at this point since we did not yet test this form of scoliosis, as infantile scoliosis is such a rare disease in North America. In principle, the tests should work but we need to assess such possibilities in Europe where the cases are more frequent.

Dingo
06-13-2010, 05:03 PM
Part 3

Question 6) Can you foresee a day when it will become practical for medical professionals to use your test to screen large populations of children for Scoliosis?

Dr. Moreau) We already have the capacity using our robotic platform to screen hundreds of samples/patients per day in Montreal. Secondly, our tests have been specifically designed to screen large populations of children. Our partner in Milan (Italy), Dr. Marco Brayda-Bruno has received a first grant from the Italian government for a pilot project to screen 1200 school children for scoliosis using our tests.

Question 7) How will manufacturers of braces and medical devices use your test to build better products?

Dr. Moreau) Monitoring plasma OPN and sCD44 levels should be considered as a clinical tool to evaluate bracing efficacy and even treatment compliance. Since both molecules, OPN in particular, are known to be modulated by biomechanical forces, which make our biochemical tests the ideal tool for clinicians and physical therapists to evaluate whether or not bracing and/or physical therapy are really efficient. Secondly, it is anticipated that evaluation of plasma OPN and sCD44 levels in combination with our functional assay will identify scoliotic children for whom a specific brace could represent a better therapeutic option vis-à-vis others. In the same vein, a better selection of patients might improve their health outcome not only by choosing the best brace but by intervening at an earlier stage or by the identification of children having a higher risk of spinal deformity progression for which a minimally invasive surgery with fusionless devices could be a possible option. In addition, better selection of patients might reduce the need to prescribe a brace in a child having a low or non-existing risk of progression, thus reducing the psychological impacts of wearing a brace as well as financial costs to patients.

Question 8) In 2008 you stated, “We are now, for the first time, in the exceptional position of being able to foresee the eradication of the disease in the very near future with the development of the first drugs within ten years' time.” That’s very exciting! How do you think Scoliosis treatment will evolve over the next 20 years?

Dr. Moreau) It is anticipated that a new continuum of care will emerge with the arrival of early scoliosis diagnostic/prognostic tests. Prevention will be possible using biochemical assays for periodic monitoring of OPN and sCD44 levels and will increase our awareness of environmental factors exacerbating the risk of developing scoliosis. The discovery of OPN and how it acts to trigger scoliosis onset will surely lead to identifying useful therapeutic agents that can prevent scoliosis or stop its progression over the next 20 years. However, more immediate impacts will probably come from our functional classification of IS patients for the prevention of serious co-morbidities like osteoporosis or depression in some scoliotic patients. One third of IS patients become osteopenic and often develop osteoporosis during their thirties. We believe that our functional test is the only tool that can be used to identify at an early stage those patients at risk of developing osteoporosis and could potentially be used to prevent it or stop its progression using proven nutraceutical and pharmacological therapies available on the market.

Question 9) In 2004 you published a landmark study (source (http://www.ncbi.nlm.nih.gov/pubmed/15303021)) that found that children with progressive AIS shared a central nervous system disorder called Melatonin Signalling Dysfunction. In healthy children the presence of Melatonin lowers the level of a molecule called cAMP. In children with MSD this system is broken. Is there evidence that indicates where the physical “break” in the nervous system is located? Is it in the brain, spinal cord or somewhere else?

Dr. Moreau) We reported in 2004 that melatonin signalling defect (MSD) is caused by an aberrant chemical modification (called phosphorylation) affecting the activity of small proteins called G inhibitory proteins (Gi) through the transfer of phosphate group on serine residues. The alpha subunits of these small Gi proteins are all impaired in IS. The Gi proteins which are normally coupled to melatonin receptors belong to a large family of membranous receptors encompassing about 150 different members normally coupled to Gi proteins while others are coupled to Gs or Gq proteins. This means that all GPCR receptors coupled to Gi proteins are affected in IS and not only those specific to melatonin. Indeed, all tissues exhibiting Gi-coupled receptors are affected by such impairment but we don’t yet know if IS results from a specific tissue, like the nervous system or is the summation of all affected tissues. To answer that question, revisiting animal models will be necessary to specifically inactivate Gi signalling in a tissue specific manner.

Question 10) Do you know at what age MSD manifests itself? Is it something that children are born with or is it triggered during childhood or even adulthood? Is MSD something the body has the ability to repair?

Dr. Moreau) It is most likely that children are born with the Gi-signalling defect but its clinical manifestation (disease onset) is induced later, around puberty, because estrogens play a key role in exacerbating such a pre-existing condition. In other words, during infancy, the pool of Gi proteins is so abundant that it is impossible to inactivate all Gi proteins by phosphorylation because the proteins are renewed so quickly. However, it has been reported that estrogens induce a significant decrease in the production of Gi proteins, allowing their full inactivation in IS patients during puberty. This phenomenon can easily be demonstrated in vitro and explains the following: (1) the greater incidence of IS during puberty and (2) why girls are more affected in number and severity than boys. The delay observed in the first menstrual cycle of IS girls may play a rather protective role and should be seen as a compensatory mechanism to protect the body against scoliosis. Unfortunately, the body doesn’t have the ability to correct this signalling defect.

Question 11) Identical twins are not 100% concordant for Scoliosis (source (http://www.ncbi.nlm.nih.gov/pubmed/18670329)) (source (http://www.ncbi.nlm.nih.gov/pubmed/17426641)) (source (http://www.ncbi.nlm.nih.gov/pubmed/9306532)). Has any research been conducted that tells us if identical twins are 100% concordant for Melatonin Signalling Dysfunction?

Dr. Moreau) We are in the process of attempting to verify that. More importantly, in families exhibiting several IS cases, we have demonstrated that all affected family members belong to the same functional subgroup indicating that they share the same set of genes predisposing them to scoliosis, independently of their curve pattern or severity. Therefore, it is possible that discordant identical twins will display the same potential (genetic predisposition) but the development of scoliosis in one twin will be triggered by his/her exposure to specific environmental factors. For instance, identical twins do not necessary like the same things: one may prefer sports while the other is more sedentary, and similarly for their diets, with one preferring to eat pasta while the other one fish! Thus, they are experiencing different environments even if they stay under the same roof!

Question 12) Scientists have produced evidence that heredity plays a role in Scoliosis. However it’s not clear as to what degree genetics are involved. In some diseases like Cystic Fibrosis or Sickle Cell Anemia heredity is the direct cause of the disease. In other diseases like Multiple Sclerosis or Type 1 Diabetes genes play a role but an environmental component is also required. Are there clues that suggest whether MSD is triggered solely by heredity or alternately heredity in combination with an environmental component?

Dr. Moreau) We have solid evidence that IS is caused by both genetics and the environment. This is why genetic tests won’t work because they cannot simultaneously consider the environment.

Question 13) According to your patent (http://www.wipo.int/pctdb/en/wo.jsp?WO=2008119170&IA=CA2008000595&DISPLAY=DESC) a protein called Osteopontin is closely associated with curve progression in children with AIS. OPN can be a marker for inflammation (source (http://atvb.ahajournals.org/cgi/content/short/27/11/2302)). Does this suggest that curve progression is induced by a type of chronic inflammation?

Dr. Moreau) Osteopontin (OPN) is a multifunctional cytokine involved in normal and pathophysiological conditions. We have discovered a new facet of this molecule and I don’t think we should associate curve progression with chronic inflammation.

Dingo
06-13-2010, 05:04 PM
Part 4

Question 14) When mice don’t produce Osteopontin Scoliosis doesn’t occur. The following quote is from your patent, “OPN-knockout mice do not develop a scoliosis (NS) even if they are in the same genomic background (C57BI6/J)”. What does this tell us about OPN and Scoliosis?

Dr. Moreau) This experiment indicates that OPN is required to trigger scoliosis onset. It is worth mentioning that bipedal surgeries (amputation of forelimbs) performed on C57Bl6 mice, which are naturally deficient in melatonin synthesis, induce scoliosis through an acute condition (the surgery) resulting in an elevation of OPN levels (since wound healing is a naturally inflammatory process), which cannot be decreased in absence of melatonin because melatonin is a powerful OPN inhibitor. The same phenomenon occurs after a pinealectomy (removal of the pineal gland, which is the main source of melatonin) in chickens. The fact that treatments of pinelactomized animals with pharmacological doses of melatonin prevent scoliosis has nothing to do with a lack of melatonin but is rather associated with the property of melatonin to repress the production of OPN. Having said that, I do not recommend the use of melatonin because (1) melatonin may trigger many side effects including the promotion of dormant tumours and (2) genetic predisposition toward scoliosis may affect how the cells respond to melatonin and so far the results published by my colleague Dr. Machida are not at all convincing about the usefulness of melatonin.

Question 15) Can Osteopontin stay elevated even after skeletal maturity?

Dr. Moreau) Osteopontin levels decline in healthy females at around 15 years of age and typically remain low during adulthood. Interestingly, in most of IS patients, OPN levels decline during puberty, which may explain why spinal deformities progressing toward surgery occur only in less than 1% of IS patients. It is also worth mentioning that elevation of OPN has been detected in adult pathologies like cancers (mesothelioma, bone metastases associated with breast or prostate cancers), cardiac conditions, Parkinson’s diseases, etc but the presence of other factors like sCD44 protect these patients against the development of scoliosis.

Question 16) High levels of Osteopontin are associated with a variety of autoimmune diseases and cancers (source (http://en.wikipedia.org/wiki/Osteopontin)). Does this suggest that children or adults with Scoliosis may have an increased susceptibility to other disease processes?

Dr. Moreau) It may be premature to make such a claim. However the opposite may be true since scoliosis is a clinical feature (phenotype) often associated with many syndromes and pathological conditions.

Question 17) Most adolescents with Scoliosis have small curves that don’t progress significantly. Osteopontin is known to increase in the presence of bacterial infections (source (http://ajp.amjpathol.org/cgi/content/abstract/157/1/37)). Could some of these small curves be the artifacts of childhood disease?

Dr. Moreau) As mentioned previously, many factors can stimulate the production of OPN, including some bacterial infections, especially those with mycobacteria. For most healthy individuals exhibiting no genetic predisposition for scoliosis, OPN is a protective cytokine that helps fight, among others, mycobacterial infections. It that case, elevation of OPN won’t trigger scoliosis because other factors like sCD44 are there to counteract the negative effect of OPN on scoliosis. In children having a genetic predisposition for scoliosis, exposure to mycobacteria and other environmental factors could induce scoliosis onset. Having said that, I want to clarify to parents and patients that scoliosis is not an infectious disease!

Question 18) In 2003 Dr. Vert Mooney, a spine surgeon from California released a study that found that Torso Rotation Strength training was beneficial for children with Scoliosis (source (http://www.medxonline.com/downloads/articles/measuredresistanceinscoliosis.pdf)). Since that time two small studies produced similar results (source (http://www.ncbi.nlm.nih.gov/pubmed/17108439)) (source (http://www.ncbi.nlm.nih.gov/pubmed/18600146)). Here is a short news video of a young girl doing TRS (news video (http://www.wcsh6.com/news/health/story.aspx?storyid=92954&catid=8)). Does your research shed any light on why this kind of strength training might be helpful?

Dr. Moreau) I cannot comment about the validity of these studies because it is difficult to actually demonstrate the degree of effectiveness of any method or device to prevent scoliosis or spinal deformity progression, because the natural history of most IS patients indicates that they are non-progressors. In other words, this method like any other should be challenged by performing clinical trials only with individuals presenting a high risk of progression. Such a selection will be possible using our scoliosis blood tests.

mamamax
06-13-2010, 07:49 PM
Excellent posting Dingo! My gosh - kind of in awe on this one. Need some more time to go through all this but your efforts to contact Dr. Moreau and prepare such an in depth posting with references, is just - outstanding. Literally. You've set the standard and raised the bar at the same time! Thanks!

rohrer01
06-13-2010, 09:16 PM
Very interesting interview.

flerc
06-13-2010, 09:42 PM
I'll finish to read it tomorrow, but great post Dingo!

mamamax
06-14-2010, 05:30 AM
With a condition such as scoliosis, looking for the cure seems to also involve looking for a cause that has been around since the beginning of time. We have often wondered about the OPN/bacterial/viral/genetic-familiar predisposition; the possible implications; and the possible cure. The compelling evidence offered by Dr. Moreau, is very exciting and I look forward to what may unfold within my lifetime. I have to say, I went to sleep last night, more hopeful for future generations.

As an adult - always facing the possibility of progression, I found your question #13 interesting. While Dr. Moreau makes it pretty clear that he does not think, at this time, that inflammation (due to OPN) may be a trigger ... other information found in this interview found me pondering the potential of mild/chronic hidden infections (http://en.wikipedia.org/wiki/Infection) (both viral and bacterial). Interesting that the same virus that can cause measles, can also cause chronic infection, which would in turn cause chronic inflammation. Something to ponder in the adult patient. The implication of what these things relative to those with a genetic/familiar predisposition to scoliosis may hold, remains to be seen in the future. And thanks to Dr. Moreau, the future looks a bit brighter.

This is all very exciting. Thank you Dingo for stepping up to the plate, and using your best skills to get this information and pass it along to us. I have been wrong to think that there is no hope, or that there has been no active research with any substance. Deepest gratitude.

elizabeth1st
06-14-2010, 10:05 AM
Is it possible to receive a pdf copy of your information?
Thank you

foofer
06-14-2010, 12:47 PM
I've read this a few times and each time I'm absorbing a little more, not having the science aptitude and all. (I was absent that decade).

Thanks so much for taking the time and energy to be in touch with this doctor and posting it for all of us. I'm thinking back to a time when I was 11 or 12 and somehow managed to get extremely ill with septicemia blood poisoning from a staff infection which they think started with a scraped knee that I ignored. At the time, my GP thought I had a typical infection but cultured it. She thought the high fever (105.5) and illness were unrelated. My mother gave permission for me to try an experimental antibiotic that was never approved by the FDA. It healed me overnight and later the results came out. Strange story. I've often wondered about that episode and what long term damage it may have caused.

Plus, we always had fish tanks and turtles, etc. in my room! Sheesh! Used to love to play with the turtles...

Dingo
06-14-2010, 01:25 PM
I'm glad you guys enjoyed the interview. Many thanks go out to Dr. Moreau. His work will make a huge difference in the lives of children around the world. We are lucky to have a brilliant person like Dr. Moreau on our side.

Speaking of showerheads...

This is from the NewScientist
Shower heads make a perfect home for bugs (http://www.newscientist.com/article/dn17786-shower-heads-make-a-perfect-home-for-bugs.html)


His advice is to not use shower heads made of plastic. "If it has little crusty deposits, throw the sucker away. Have a bath."

I assume metal is superior to plastic because it conducts heat and kills bacteria and other pathogens. As Dr. Moreau said it will take research to determine if exposure to harmful bacteria can trigger curve progression. However using a clean showerhead is an inexpensive, healthy decision that could probably benefit almost everyone. I checked and my shower has a very old... very plastic showerhead.

Here is some information about Mycobacterium

Wiki: Mycobacterium (http://en.wikipedia.org/wiki/Mycobacterium)


Mycobacteria are widespread organisms, typically living in water (including tap water treated with chlorine) and food sources. Some, however, including the tuberculosis and the leprosy organisms, appear to be obligate parasites (http://en.wikipedia.org/wiki/Obligate_parasite) and are not found as free-living members of the genus.

Because Mycobacterium enjoy moist environments I guess it's also time to examine how we store toothbrushes at our home. :eek:

mamamax
06-14-2010, 05:16 PM
Seems logical Dingo ... I'm sitting here wondering if I should have the tap water checked!

Honestly, Moreau's work is just too exciting! Here's an excerpt from a story in the AAOS Journal (http://www.aaos.org/news/bulletin/nov07/clinical3.asp):



We are also working on pharmacologic treatments to prevent or slow the progression of the disease, which could have an enormous impact. One day, we may be able to identify children who are at risk or still asymptomatic and be able to give them the correct treatment at the correct moment. I anticipate that in the early stages, patients will have customized pharmacotherapy, in conjunction with other treatments, to prevent and eventually reverse scoliosis.
One of those things that makes you feel like you are watching history unfold :-)

skevimc
06-14-2010, 06:49 PM
Dingo, have you come across any smaller articles that have done what the clinical trials are attempting to do, i.e. test for OPN in a random group of adolescents and 'predict' which ones will develop scoliosis?

I found the recent 2010 article on melatonin signaling dysfunction. But can't find anything directly related to OPN.

As I've mentioned before, I remain optimistically skeptical about this. My skepticism is not alleviated by the apparent lack of published data, despite the time and the data available. His patent application, originally submitted in 2007, has a cohort of 252 consecutive AIS patients, 35 healthy controls and 70 'at risk' subjects and OPN, sCD44 and hyaluorinc acid are measured. OPN values are elevated in the AIS group although the standard deviations are quite large. The differences do reach significance compared to the healthy controls. This is certainly enough data and enough time has passed since then to have a good chunk of follow-up. Does he have plans to publish this soon? I'm unfamiliar with how the patent process works.

I'm to the point where I'm tired of seeing all of these hints at this great 'eureka' moment for AIS coming from this line of research. Let's see it already! :)

At any rate... Great questions and his answers are interesting to read and process.

Dingo
06-14-2010, 10:41 PM
Skevimc

I can't wait to see the data too although I'm not necessarily qualified to evaulate it. Previous to the patent I was not aware that OPN was connected to Scoliosis. I always thought that Dr. Moreau was investigating Calmodulin (http://www.ejbjs.org/cgi/reprint/76/8/1186.pdf) because there is so much interest in that area. I haven't seen a study on OPN and Scoliosis, but I don't see everything so it could be out there.

In Part 2 of Moreau's interview he wrote that he was about to publish his data on OPN, CD44 and Scoliosis.


These data will be published in the upcoming months.

Dingo
06-15-2010, 08:39 AM
In Dr. Moreau's answer to question 11 he wrote this.


...in families exhibiting several IS cases, we have demonstrated that all affected family members belong to the same functional subgroup indicating that they share the same set of genes predisposing them to scoliosis, independently of their curve pattern or severity.

What he's talking about are the 3 types of Melatonin Signalling Dysfunction.

If you look at page 5 of his 2004 study on Melatonin Signalling Dysfunction (http://pico.sssup.it/files/allegati/2004_1469.pdf) you'll see a chart at the top. The chart shows how cAMP (http://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate) responds to increasing amounts of Melatonin. The bottom line represents the healthy control group. The other 3 lines represent the 3 subgroups or types of Melatonin Signalling Dysfunction.

In healthy children cAMP plummets as the level of Melatonin increases. In subgroups 2 and 3 cAMP goes down but nearly as much as it should. In subgroup 1 (the dark black line) cAMP actually goes up in the presence of Melatonin.

I don't know which subgroup has the highest risk of curve progression but I have to imagine it's group 1. The nervous system appears work almost in reverse for this group.

I should add one thing...

Dr. Moreau's evidence suggests that a child's nervous system will break in a particular way depending on what genes she has. However it doesn't mean that heredity breaks the nervous system. I asked him if identical twins were 100% concordant for MSD and he responded.


We are in the process of attempting to verify that.

That's an answer that I'm looking forward too. My guess based on studies like this (source (http://www.ncbi.nlm.nih.gov/pubmed/18670329)) is that twins won't be 100% concordant. Future studies will show that in most cases an environmental component is required to trigger MSD just as an environmental component is required to trigger Multiple Sclerosis (http://www.sciencedaily.com/releases/2010/04/100428142256.htm) and so many other diseases. Time will tell but that's my strong suspicion.

rohrer01
06-15-2010, 09:02 AM
I wonder if that's why I get restless leg when I take melatonin? It rarely, if ever, puts me to sleep. I don't respond to drugs in a predictable way, either. It's very frustrating for both me and my doctor.:rolleyes:

Dingo
06-16-2010, 10:28 AM
I think it's fascinating that exposure to harmful bacteria could potentially drive curve progression in genetically susceptible children.

Interestingly enough scientists are developing a urine test to detect Autism in children. It measures the by-products of gut bacteria.
Autism Finding Could Lead to Simple Urine Test for the Condition (http://www.sciencedaily.com/releases/2010/06/100603091641.htm)


The researchers suggest that their new understanding of the makeup of bacteria in autistic children's guts could also help scientists to develop treatments to tackle autistic people's gastrointestinal problems.

Evidently children with Autism have a different balance of bacteria compared to non-autistic children. They aren't sure if this is a cause or consequence of Autism.

This made me wonder if children with Autism had a greater incidence of Scoliosis or perhaps more severe curves.

I did a google search of autism and scoliosis (http://www.google.com/#hl=en&source=hp&q=autism+scoliosis&aq=f&aqi=&aql=&oq=&gs_rfai=C0mi8EO0YTM_dHoi6Men86d8KAAAAqgQFT9B7hWw&fp=f11974faf5e3db50) and I see that a lot of people are writing about it. But I don't know if research has been conducted to determine if the two are associated with each other.

Dingo
06-16-2010, 10:46 AM
If there are any smokers out there who have children with Scoliosis they may want to read this.

Smoking increases the production of osteopontin in the lungs (http://www.sciencecodex.com/smoking_increases_the_production_of_osteopontin_in _the_lungs)


They found high levels of osteopontin expression in patients with interstitial lung disease, whereas healthy smokers had lower levels, and healthy non-smokers produced no osteopontin. Osteopontin expression could be stimulated directly by nicotine treatment.

rohrer01
06-16-2010, 10:48 AM
I would be very surprised if there were a link between scoliosis and autism. It does make sense that ANY time the metabolism is affected by a disorder, that you would find differences in gut bacteria type and/or quantity. Do you know if there have been any studies correlating scoliosis with higher levels of gut bacteria or the proliferation of different kinds of bacteria? I apologize in advance if I missed this in your interview posting. I'd bet you would find a difference in gut bacteria when comparing obese and thin people, too, due to slower/faster metabolisms. That's just my hypothesis.

rohrer01
06-16-2010, 10:55 AM
If there are any smokers out there who have children with Scoliosis they may want to read this.

Smoking increases the production of osteopontin in the lungs (http://www.sciencecodex.com/smoking_increases_the_production_of_osteopontin_in _the_lungs)

I would be careful here. They did not say what delivery method of nicotine treatment was used. This article also focused on the deliterious effects of osteopontin accumulation in the lungs. It said nothing about scoliosis.

Dingo
06-16-2010, 05:16 PM
Rohrer01


Do you know if there have been any studies correlating scoliosis with higher levels of gut bacteria or the proliferation of different kinds of bacteria?

I don't think research has been done on that. We'll have to wait for the blood test and then quite a few years of testing before we know.

Scientists will have to sift through all of the potential environmental factors that can lead to a surge of OPN and figure out which one's matter to kids with a genetic susceptability to Scoliosis.

Dr. Moreau mentioned bacterial infections as a trigger. Interestingly OPN surges after surgical procedures because it's part of the healing process.


It is worth mentioning that bipedal surgeries (amputation of forelimbs) performed on C57Bl6 mice, which are naturally deficient in melatonin synthesis, induce scoliosis through an acute condition (the surgery) resulting in an elevation of OPN levels (since wound healing is a naturally inflammatory process), which cannot be decreased in absence of melatonin because melatonin is a powerful OPN inhibitor.

Right there you'd think that children with Scoliosis should take Melatonin. But unfortunately it won't work because the nervous system is dysfunctional (http://pico.sssup.it/files/allegati/2004_1469.pdf) and Melatonin can't get it's job done.

Dingo
06-16-2010, 05:51 PM
Obesity appears to increase the level of OPN in fat tissue.

Plasma osteopontin levels and expression in adipose tissue are increased in obesity (http://www.ncbi.nlm.nih.gov/pubmed/17595250)


CONCLUSIONS: These findings represent the first observation that plasma OPN and mRNA expression of OPN in omental adipose tissue are increased in overweight/obese patients with the latter being further elevated in obesity-associated diabetes. Moreover, weight loss reduces OPN concentrations, which may contribute to the beneficial effects accompanying weight reduction. Measurement of OPN might be useful for evaluating the outcomes of various clinical interventions for obesity-related cardiovascular diseases.

rohrer01
06-16-2010, 08:12 PM
Rohrer01

Right there you'd think that children with Scoliosis should take Melatonin. But unfortunately it won't work because the nervous system is dysfunctional (http://pico.sssup.it/files/allegati/2004_1469.pdf) and Melatonin can't get it's job done.

Adults, too. ;) Like I said, melatonin wires me.

flerc
06-17-2010, 06:07 AM
Hi Dingo, probably I'm not interpreting right, but I think that answer to question 15) implies that the only cause to progression in adults is a high level of OPN. That is say, if would be possible that someone of 20 years old and 5 º or 0º, develop a high level of OPN, she could reach 70º at 50 years old. Gravity force has nothing to do with progression?, someone with 80º and normal level of opn are free of progression?.
I think that progression should to be caused by some kind of problem with joints, ligaments, vertebras, discs, muscles, tendons, internal organs, fascias...
Do you know which of all of this is affecting OPN?

Regards

Dingo
06-17-2010, 08:41 AM
Flerc

Dr. Moreau's work shows that OPN drives curve progression. When OPN is blocked Scoliosis doesn't occur in mice. I'm not sure if this rules out all other causes of curve progression.

However even if other factors play a part it's important to keep in mind that OPN is reduced after succesful bracing or fusion. So it's not only part of the problem but it provides feedback as well.

So for instance let's say eating avacados drove curve progression. Eating an avacado might not directly increase OPN but it would make a curve grow worse. As the curve got worse OPN would likely rise in response.

Think of it this way. OPN is not only an engine but it's also a speedometer. I believe this is because it performs multiple jobs inside the body. For instance it's involved in bone remodeling, the immune system, inflammation, etc.

PNUTTRO
06-17-2010, 11:44 AM
The test has great sensitivity and but little specificity.

There is nothing about this test that would make me feel better after having it done.

The dot plot on page 607 (figure 3) [Spine. 2010 Jun 1;35(13):E601-8] shows that most controls and patients fall into the range of 85-150. These are means of 3 independent tests for each individual. They state that the variation was "typically less than 10%. So a person with a score of 100 (is actually representative of a range from 95-105). If you get a score of 100-120, this test tell you nothing about if you are a patient or a control. More than 50% of the whole population is in this range.

Sorry, I wouldn't think my kid is out of the woods based on this test. It has zero predictive value in my mind.

Even if I got a score of 30, then it still means that I am going to do all the same stuff that I was planning to do anyway. Watch and wait. It doesn't change anything. If you got a score over 200, do you have enough confidence in the test to just do nothing, or are you going to watch for the scoliosis anyway?

Same thing with the genetic test. The doctors are not changing their treatment plans based on a Scolioscore. Parents are [NOT] going to change their observations of their kids.

flerc
06-17-2010, 12:09 PM
Dingo, does it occurs in adult mice too? It’s unknown which is the exact effect it produces?
I think it should be so difficult it can affect all the suspected as guilty factors for the progression in an adult in the same way. If you are not sure, could you ask it to Dr. Moreau?

Thanks for all!

rohrer01
06-17-2010, 01:00 PM
I think I would have a hard time believing that OPN drives curve progression. I would be more willing to believe that OPN rises as a response to curve progression. The reason I say this is because I had a "stable" curve for 20+ years. I have documented evidence that my curve progression occurred in conjunction with chiropractic treatment. OPN certainly was not the driving force here. In my case, anyway, adhesions holding the curve in place were probably broken as well as stretching of the ligaments during the adjustments. This resulted in weakening of the spine. Would I expect my OPN levels to rise, probably, especially if OPN is released due to an inflamatory response. BUT, maybe things work differently in children/adolescents with IS.

flerc
06-17-2010, 01:40 PM
May be it is not the only one primary cause, but the most frequently primary/original cause. Sastre (Fed Machine) explains that scoliosis appears in rabbits when cartilagues suffer a traumation. And then, the curve begins to be reduced during growth with the Fed machine (adapted to rabbits). In this case Opn was not the primary cause, but may be the traumatism lead to an increase of Opn and curve increases and then decrease with Fed… who knows?
But if it exists some way to reduce Opn (as seems to be applied in mice) different to reducing another cause, and progression stops, then it should to be one cause and not only an indicator.
Dingo, do you know how was Opn reduced in mice?

rohrer01
06-17-2010, 03:30 PM
Flerc,
If OPN is produced as a response to inflamation and then, once present, acts to drive progression, one would think that prolotherapy, as mentioned in your other thread, would be unsuccessful if not outright dangerous in the scoliotic patient. The whole purpose of the prolotherapy is to induce inflamation as a means to promote healing. Just a thought.

PNUTTRO
06-17-2010, 04:33 PM
I think I would have a hard time believing that OPN drives curve progression. I would be more willing to believe that OPN rises as a response to curve progression.

I agree but for different reasons.

jrnyc
06-17-2010, 05:05 PM
i dont buy it...and i dont subscribe to the bacteria cause...many people dont, whether they write in or not..
including patients with scoli...and doctors...
furthermore, if anyone checked up on folks who are exposed to lots of bacteria when children, they might find that those people do not develop scoli!
just sayin'...

jess

flerc
06-17-2010, 06:11 PM
jrnyc, did you send to me a PM some days ago?

jrnyc
06-17-2010, 07:01 PM
no...i did not...one time i disagreed with something you wrote...you accused me of "attacking" you...and you said you would "block" any posts by me...so no, i certainly did not

flerc
06-17-2010, 07:05 PM
Flerc,
If OPN is produced as a response to inflamation and then, once present, acts to drive progression, one would think that prolotherapy, as mentioned in your other thread, would be unsuccessful if not outright dangerous in the scoliotic patient. The whole purpose of the prolotherapy is to induce inflamation as a means to promote healing. Just a thought.

Great roher01!, the conclusion is right if assumptions are true.
Can we be sure at least than OPN is produced as a response to inflamation?
what more produce Opn except the progression itself?
Once scoliosis is triggered, mycrobacterias can produce Opn?

rohrer01
06-17-2010, 07:18 PM
I don't subscribe to bacterial, viral causes in MOST IS cases. If they were caused by a pathogen, other than what caused the original germ line mutation, it wouldn't be idiopathic. For example, polio causes scoliosis in some people. Of course, we should all be clean for our own health, but I have known plenty of filth-weasels that didn't have scoliosis. However, that doesn't mean that OPN is not involved somehow. It would be awesome if we could "clean up" and get rid of idiopathic scoliosis, but we all know it's not that easy.

PNUTTRO,
I have a limited education to draw on compared to you (B.S. in Cell and Molecular Biology). I make my own conclusions based on what seems logical to me and from personal experience. I have experienced that I react differently to most medications than would be expected. For instance, melatonin as I had mentioned earlier. I also react unpredictably to muscle relaxants and other meds. That is too bad because I suffer horribly from muscle spasms. I would be interested to know what your reasons are. I do see the flaw, as you mentioned, with being in a range or "normal". But, with that said, I think the medical profession has trouble with many tests in general that measure quantities of substances in the blood for that very reason. As individuals we "generally" fall into a category within normal ranges for any given substance, but what if we are one that is an outlier and that is perfectly "normal" for us? I would like to see human studies that show what happens when OPN is medically reduced, not by fusion or bracing. Obviously OPN plays important roles in function that have nothing to do with scoliosis.

flerc
06-17-2010, 07:20 PM
no...i did not...one time i disagreed with something you wrote...you accused me of "attacking" you...and you said you would "block" any posts by me...so no, i certainly did not
I did not remember to say I would "block" any posts of no one, in fact I did not know that PM can be blocked. Any way thanks for this response.

flerc
06-17-2010, 07:59 PM
Flerc

Think of it this way. OPN is not only an engine but it's also a speedometer. I believe this is because it performs multiple jobs inside the body. For instance it's involved in bone remodeling, the immune system, inflammation, etc.
Dingo do you know which are all these jobs?

rohrer01
06-17-2010, 08:07 PM
Something I missed earlier. Dingo mentioned that the forelimbs of mice were removed causing OPN to rise. These mice then developed scoliosis. How can it be determined that it was the OPN that caused the scoliosis and not muscle/ligament/nerve damage and the fact that the mice had to adapt to being bipedal when they, in fact, are not supposed to be? Could pain have been a driving factor also? I'm sure that their post surgical pain was not even addressed. I don't think this particular test proves anything about OPN function other than it is elevated after trauma.

flerc
06-17-2010, 08:45 PM
Something I missed earlier. Dingo mentioned that the forelimbs of mice were removed causing OPN to rise. These mice then developed scoliosis. How can it be determined that it was the OPN that caused the scoliosis and not muscle/ligament/nerve damage and the fact that the mice had to adapt to being bipedal when they, in fact, are not supposed to be? Could pain have been a driving factor also? I'm sure that their post surgical pain was not even addressed. I don't think this particular test proves anything about OPN function other than it is elevated after trauma.

rabbits of Sastre developing scoliosis because trauma on cartilages , remains always being quadrupeds

rohrer01
06-17-2010, 08:58 PM
rabbits of Sastre developing scoliosis because trauma on cartilages , remains always being quadrupeds

Which cartilage?

flerc
06-17-2010, 09:25 PM
http://www.sastre-roca.com/metodofed.html
Sure of vertebras : Descomprimir los cartílagos neurocentrales y epifisarios inhibidos.
Probably of discs too:
Modificar la orientación patológica de las fibras del anillo fibroso del disco intervertebral.
I'm looking for the article..

PNUTTRO
06-18-2010, 11:19 AM
. But, with that said, I think the medical profession has trouble with many tests in general that measure quantities of substances in the blood for that very reason.

I disagree. Most blood tests are very good at screening people that will require further examination.

My biggest problem with any test for scoliosis to date is that NONE of them significantly change the clinical outcome for anyone. For most people, their curve won't progress. For the remaining people, you always end up with surgery. Everyone gets x-rays.

The most important factor is prediction of progression and Moreau's test doesn't do that. He doesn't even say that the patients with the lowest scores have the biggest curves.

Axial claims that Scolioscore is predictive of progression, but I don't believe it yet. The statistical contributions of 52 independent factors requires a HUGE population to reach significance. It is still hard to say.

p

skevimc
06-18-2010, 12:31 PM
The test has great sensitivity and but little specificity.

There is nothing about this test that would make me feel better after having it done.

The dot plot on page 607 (figure 3) [Spine. 2010 Jun 1;35(13):E601-8] shows that most controls and patients fall into the range of 85-150. These are means of 3 independent tests for each individual. They state that the variation was "typically less than 10%. So a person with a score of 100 (is actually representative of a range from 95-105). If you get a score of 100-120, this test tell you nothing about if you are a patient or a control. More than 50% of the whole population is in this range.

Sorry, I wouldn't think my kid is out of the woods based on this test. It has zero predictive value in my mind.

Even if I got a score of 30, then it still means that I am going to do all the same stuff that I was planning to do anyway. Watch and wait. It doesn't change anything. If you got a score over 200, do you have enough confidence in the test to just do nothing, or are you going to watch for the scoliosis anyway?

Same thing with the genetic test. The doctors are not changing their treatment plans based on a Scolioscore. Parents are [NOT] going to change their observations of their kids.

This is a good point. It would take quite a bit of conclusive data to have this dramatically change the treatment paradigm.

A serious problem I see with this is that OPN is ubiquitously expressed. The patient values and control values should not have a huge overlap. If so, there would be a lot of false positives and potentially ramp up anxiety in some patients.

What is the relationship of OPN and the menstrual cycle? What about during a growth spurt? The body uses inflammation to assist in remodeling, i.e. it's not always a bad thing. What role does OPN play in the immune system's response to bacteria? Does it play a role in anti-body production?

If a relationship exists with progression and stability, I would see this as more an effect rather than a cause. But as this is a relatively new avenue it will be interesting to learn more about as more data is published.

LindaRacine
06-18-2010, 01:22 PM
Something I missed earlier. Dingo mentioned that the forelimbs of mice were removed causing OPN to rise. These mice then developed scoliosis. How can it be determined that it was the OPN that caused the scoliosis and not muscle/ligament/nerve damage and the fact that the mice had to adapt to being bipedal when they, in fact, are not supposed to be? Could pain have been a driving factor also? I'm sure that their post surgical pain was not even addressed. I don't think this particular test proves anything about OPN function other than it is elevated after trauma.

Exactly!

--Linda

rohrer01
06-18-2010, 01:28 PM
I disagree. Most blood tests are very good at screening people that will require further examination.

My biggest problem with any test for scoliosis to date is that NONE of them significantly change the clinical outcome for anyone. For most people, their curve won't progress. For the remaining people, you always end up with surgery. Everyone gets x-rays.

The most important factor is prediction of progression and Moreau's test doesn't do that. He doesn't even say that the patients with the lowest scores have the biggest curves.

Axial claims that Scolioscore is predictive of progression, but I don't believe it yet. The statistical contributions of 52 independent factors requires a HUGE population to reach significance. It is still hard to say.

p
What I meant is that screening tests in general - even good ones - miss some people. An example of a very common test is the blood test they give women to predict whether their unborn child has Down's Syndrome. There is a very high false positive rate with this test creating extreme anxiety in many pregnant women. The only truly accurate way to know this is to do an amniocentesis.

I also agree with Skemvic about creating unneccessary anxiety in patients and parents with false positives. With that said, all of these tests are still in the trial phases as far as I've seen and are not available to the general population, at least not with any degree of frequency. Researchers have to start somewhere with their investigations. I'm sure as more is understood, the kinks will be worked out and better tests will be developed. It's good that there are people like you all who know what to look for as far as efficacy in these tests. Knowledge protects.

Pooka1
06-19-2010, 08:04 AM
I'm to the point where I'm tired of seeing all of these hints at this great 'eureka' moment for AIS coming from this line of research. Let's see it already! :)

I find it interesting that he announced that the test would be ready in a year certain and we are well past that.

He has been doing research for ~10 years which in the scheme of things is not long, at least compared to many others. I think announcing and missing the pub date by a mile is a rookie mistake that he likely won't repeat.

Now that brings us back to the question of WHY he missed the pub date. He is still at the stage of patent and press release which is to say very early in the process. And even if he does eventually publish somewhere, it seems to me that this work is so intrinsically complex, non-specific, uncontrollable, etc. that the results are quite likely to be false (or not useful). This is tough nut to crack but he is trying to his credit. If it was easy it would have been solved by now.

We will see.

Pooka1
06-19-2010, 08:09 AM
"We have solid evidence that IS is caused by both genetics and the environment. This is why genetic tests won’t work because they cannot simultaneously consider the environment." -- Dr. A. Moreau

I'm sure Ogilvie will see the error of his ways and remove Scoliscore from the market forthwith. Or not.

Pooka1
06-19-2010, 08:17 AM
This is a good point. It would take quite a bit of conclusive data to have this dramatically change the treatment paradigm.

A serious problem I see with this is that OPN is ubiquitously expressed. The patient values and control values should not have a huge overlap. If so, there would be a lot of false positives and potentially ramp up anxiety in some patients.

What is the relationship of OPN and the menstrual cycle? What about during a growth spurt? The body uses inflammation to assist in remodeling, i.e. it's not always a bad thing. What role does OPN play in the immune system's response to bacteria? Does it play a role in anti-body production?

If a relationship exists with progression and stability, I would see this as more an effect rather than a cause. But as this is a relatively new avenue it will be interesting to learn more about as more data is published.

This is a fraction of the total questions remaining to be solved that suggest Moreau has much more work to do. And even if it is published means it is more likely to be false than correct.

It is easier to send a man to the moon and return him safely than to solve scoliosis as we can see by the results to date. Biochemistry of medical problems is just intrinsically complex having arisen from billions of years of evolution.

Pooka1
06-19-2010, 08:19 AM
Something I missed earlier. Dingo mentioned that the forelimbs of mice were removed causing OPN to rise. These mice then developed scoliosis. How can it be determined that it was the OPN that caused the scoliosis and not muscle/ligament/nerve damage and the fact that the mice had to adapt to being bipedal when they, in fact, are not supposed to be? Could pain have been a driving factor also? I'm sure that their post surgical pain was not even addressed. I don't think this particular test proves anything about OPN function other than it is elevated after trauma.

Good work. This is one of dozens if not hundreds of reasons why this work is likely false.

And I wonder what PETA is doing about the bipedalized mice issue. This seems like a powder keg issue that probably doesn't even provide any relevant results for humans... a lose-lose scenario.

PNUTTRO
06-19-2010, 04:39 PM
Part 4

Question 14) When mice don’t produce Osteopontin Scoliosis doesn’t occur. The following quote is from your patent, “OPN-knockout mice do not develop a scoliosis (NS) even if they are in the same genomic background (C57BI6/J)”. What does this tell us about OPN and Scoliosis?

Dr. Moreau) This experiment indicates that OPN is required to trigger scoliosis onset. It is worth mentioning that bipedal surgeries (amputation of forelimbs) performed on C57Bl6 mice, which are naturally deficient in melatonin synthesis, induce scoliosis through an acute condition (the surgery) resulting in an elevation of OPN levels (since wound healing is a naturally inflammatory process), which cannot be decreased in absence of melatonin because melatonin is a powerful OPN inhibitor. The same phenomenon occurs after a pinealectomy (removal of the pineal gland, which is the main source of melatonin) in chickens. The fact that treatments of pinelactomized animals with pharmacological doses of melatonin prevent scoliosis has nothing to do with a lack of melatonin but is rather associated with the property of melatonin to repress the production of OPN. Having said that, I do not recommend the use of melatonin because (1) melatonin may trigger many side effects including the promotion of dormant tumours and (2) genetic predisposition toward scoliosis may affect how the cells respond to melatonin and so far the results published by my colleague Dr. Machida are not at all convincing about the usefulness of melatonin.

I wondered about this question and answer. Couldn't it be said that most mice don't get scoliosis, OPN KO or not? I can't find a reference of a OPN KO bipedal experiment.
Jun KO mice get scoliosis (Development. 2003 Jan;130(1):103-9 (http://www.ncbi.nlm.nih.gov/pubmed/12441295)).

The answer by Moreau doesn't answer the question either. It's a circular argument.

jrnyc
06-19-2010, 06:00 PM
Mickey will be very upset about all of this...but he says none of his family have any history of scoli! :)

jess

Pooka1
06-19-2010, 06:19 PM
I wondered about this question and answer. Couldn't it be said that most mice don't get scoliosis, OPN KO or not? I can't find a reference of a OPN KO bipedal experiment.
Jun KO mice get scoliosis (Development. 2003 Jan;130(1):103-9 (http://www.ncbi.nlm.nih.gov/pubmed/12441295)).

That's an interesting point. I'm sure if we had a panel of peer reviewers in this field that many such interesting points would emerge. What we have here is two people on forum who have some requisite background to comment substantively and then we have a few bunnies who would be wowed by patent nonsense were it suitably phrased and parsed.


The answer by Moreau doesn't answer the question either. It's a circular argument.

I'm trying to see what exactly he is saying... let's see...


Question 14) When mice don’t produce Osteopontin Scoliosis doesn’t occur. The following quote is from your patent, “OPN-knockout mice do not develop a scoliosis (NS) even if they are in the same genomic background (C57BI6/J)”. What does this tell us about OPN and Scoliosis?

Dr. Moreau) This experiment indicates that OPN is required to trigger scoliosis onset. It is worth mentioning that bipedal surgeries (amputation of forelimbs) performed on C57Bl6 mice, which are naturally deficient in melatonin synthesis, induce scoliosis through an acute condition (the surgery) resulting in an elevation of OPN levels (since wound healing is a naturally inflammatory process), which cannot be decreased in absence of melatonin because melatonin is a powerful OPN inhibitor. The same phenomenon occurs after a pinealectomy (removal of the pineal gland, which is the main source of melatonin) in chickens.

He seems to be saying the surgery itself induces the scoliosis in mice that can't synthesize melatonin. If that is supposedly relevant to humans then why doesn't surgery trigger scoliosis in humans? Also, in the mouse model, he is artificially INCREASING [OPN] and in the pinealized chicken model, they are artificially DECREASING melatonin. Are one or both mechanisms known to be causative (either proximal or near proximal) in IS in humans?


The fact that treatments of pinelactomized animals with pharmacological doses of melatonin prevent scoliosis has nothing to do with a lack of melatonin but is rather associated with the property of melatonin to repress the production of OPN. Having said that, I do not recommend the use of melatonin because (1) melatonin may trigger many side effects including the promotion of dormant tumours and (2) genetic predisposition toward scoliosis may affect how the cells respond to melatonin and so far the results published by my colleague Dr. Machida are not at all convincing about the usefulness of melatonin.


So trying to increase the melatonin level in kids through various means or even feeding it to them is a double-edged sword. And so is Selenium.

Is there anything suggested by this research that isn't a double-edged sword?

Pooka1
06-19-2010, 06:21 PM
Mickey will be very upset about all of this...but he says none of his family have any history of scoli! :)

jess

This business of bipedalizing mice is unconscionable absent some very strong proof of relevance to humans which appears to be totally lacking. I question the regulatory agencies.

jrnyc
06-19-2010, 06:43 PM
me too...mice and humans...the relevance is...?

but regarding Mickey...he is considering legal action as he sees all of this as slander directed at him and the entire mouse community! ;)

rohrer01
06-19-2010, 08:20 PM
This business of bipedalizing mice is unconscionable absent some very strong proof of relevance to humans which appears to be totally lacking. I question the regulatory agencies.

I was wondering what relevance cutting mouse arms off has. Would he get the same results if he cut their tails off? Or what about their ears?... My point is, if it's trauma causing OPN to rise, why cut off their arms? If he just wants to force them to walk upright like humans, then wouldn't banding their arms down give the same result? I know animal studies have to be done, but this is one reason I haven't gone into animal research. I just couldn't do it day in and day out not having a truly legitimate reason for carrying out such orders. I'm just a "bunny" you know. :p

jrnyc
06-19-2010, 08:23 PM
uggghhh!! i know research is needed to find cures...but i cant stand the thought of this...it's enough to make me want to join PETA!! i dont understand the necessity of it! results for animals cant just be automatically transferred to humans...and to me, this wasnt justified!
ughhh!

jess

rohrer01
06-19-2010, 08:42 PM
uggghhh!! i know research is needed to find cures...but i cant stand the thought of this...it's enough to make me want to join PETA!! i dont understand the necessity of it! results for animals cant just be automatically transferred to humans...and to me, this wasnt justified!
ughhh!

jess

Maybe it would be useful as a study for amputees.:confused:

Pooka1
06-19-2010, 08:43 PM
I have to wonder how much they would walk on their hind legs just because you cut off their front legs. Even if it is most of the time, has anyone shown any relevance whatsoever of any bipedalized quadruped to a human?

Humans are the only species that shows IS. That is one of the main reasons why an animal model is lacking for research as I understand it.

Love,
a bunny, a bipedal bunny.

Pooka1
06-19-2010, 08:48 PM
uggghhh!! i know research is needed to find cures...but i cant stand the thought of this...it's enough to make me want to join PETA!! i dont understand the necessity of it! results for animals cant just be automatically transferred to humans...and to me, this wasnt justified!
ughhh!

jess

You know, I think PETA has it's share of loonies but they have brought attention to abject cruelty towards animals at research labs. The situation with chimps and other primates is really grim last I knew. Maybe there are better regs now, I don't know.

I know some bio types who work with fish were were bellyaching about new regs at that time (several years ago now) that they had to keep track of every vertebrate individually. Well these guys had a bunch of tanks full of a bunch of fish which of course are all vertebrates. I am sure they could not keep track of each one individually and there must have been some slack cut for aquaculture I imagine.

But that aside, I suspect there needs to be far more regulation and enforcement of regs for lab animals.

flerc
06-19-2010, 10:18 PM
rabbits of Sastre developing scoliosis because trauma on cartilages , remains always being quadrupeds


Which cartilage?

I can not find the article in the net but I saved it in a doc file. In the Sartre's book will surely be able to find all of this in great detail, but he said: The unilateral intervertebral compression factors aggravate the bends. Without the presence of these compression factors, is unlikely that the scoliosis be formed.
But the trauma he provoked in rabbits, I beleive is the 4) of this article (first page): http://web.jbjs.org.uk/cgi/reprint/43-B/1/116.pdf
Radiation is the 5)!

jrnyc
06-19-2010, 11:44 PM
hey Sharon
hmmmm...i sincerely hope some of those lab researchers come back as animals in their next lifetime! lab animals!! research subjects!
i suspect alot of the "research" involves unnecessary experiments...
and...excuse me, but i dont see the importance of the "predictions" until and unless there is some way of prevention!! if i knew way back when that i had a risk of scoli...what? what would i have done differently...?
and...my sisters dont have it...where was their risk?

jess

mamamax
06-20-2010, 08:08 AM
I'm glad you guys enjoyed the interview. Many thanks go out to Dr. Moreau. His work will make a huge difference in the lives of children around the world. We are lucky to have a brilliant person like Dr. Moreau on our side.

Speaking of showerheads...

This is from the NewScientist
Shower heads make a perfect home for bugs (http://www.newscientist.com/article/dn17786-shower-heads-make-a-perfect-home-for-bugs.html)



I assume metal is superior to plastic because it conducts heat and kills bacteria and other pathogens. As Dr. Moreau said it will take research to determine if exposure to harmful bacteria can trigger curve progression. However using a clean showerhead is an inexpensive, healthy decision that could probably benefit almost everyone. I checked and my shower has a very old... very plastic showerhead.

Here is some information about Mycobacterium

Wiki: Mycobacterium (http://en.wikipedia.org/wiki/Mycobacterium)



Because Mycobacterium enjoy moist environments I guess it's also time to examine how we store toothbrushes at our home. :eek:

Dingo -

I look forward to Dr. Moreau's continued work. I cannot pretend to understand all that is involved, but I can see links ;-)

Pathogens (viral, bacterial, fungal, parasitic, prionic): The body contains many natural orders of defense against some of the common pathogens (such as Pneumocystis) in the form of the human immune system and by some "helpful" bacteria present in the human body's normal flora. However, if the immune system or "good" bacteria is damaged in any way (such as by chemotherapy, human immunodeficiency virus (HIV), or antibiotics being taken to kill other pathogens), pathogenic bacteria that were being held at bay can proliferate and cause harm to the host. Such cases are called opportunistic infection. http://en.wikipedia.org/wiki/Pathogen

Immune System: The job of your immune system is to protect your body from these infections. The immune system protects you in three different ways: http://health.howstuffworks.com/immune-system3.htm


It creates a barrier that prevents bacteria and viruses from entering your body.

If a bacteria or virus does get into the body, the immune system tries to detect and eliminate it before it can make itself at home and reproduce. Bacteria are completely independent organisms able to eat and reproduce - they are sort of like fish swimming in the ocean of your body.

If the virus or bacteria is able to reproduce and start causing problems, your immune system is in charge of eliminating it. A virus particle is nothing but a fragment of DNA in a protective coat. The virus comes in contact with a cell, attaches itself to the cell wall and injects its DNA (and perhaps a few enzymes) into the cell.

Once inside the body, a germ deals with the immune system at a different level. The major components of the immune system are:

* Thymus
* Spleen
* Lymph system
* Bone marrow
* White blood cells
* Antibodies
* Complement system
* Hormones

Individuals who have a suppressed immune system are quickly over powered by the organisms. The majority of chronic or persistent infections occur in individuals who have poor defense mechanism(s). http://en.wikipedia.org/wiki/Infection#Susceptibility_of_host

OPN Connection: Osteopontin (OPN) is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells, with varying kinetics. OPN is reported to act as an immune modulator in a variety of manners. http://en.wikipedia.org/wiki/Osteopontin#Role_in_immune_functions

So .... If one is looking for causative factors relative to scoliosis, the causations need to be something that has been around since time out of mind. Seems to me those things certainly could involve a compromised immune system (genetic/familiar pattern leading to a predisposition) along with pathogens. Why not? The common cold is attributed to over 200 different viruses. One gets a cold when the immune system cannot fight these off, or when the immune system is compromised.

Why couldn't there be a yet unidentified link between scoliosis, genetic/familiar weakened immune systems, and pathogens (viral, bacterial, fungal, parasitic, prionic)?

Pooka1
06-20-2010, 08:55 AM
[COLOR="RoyalBlue"]hey Sharon
hmmmm...i sincerely hope some of those lab researchers come back as animals in their next lifetime! lab animals!! research subjects!
i suspect alot of the "research" involves unnecessary experiments...

Yes regulation is the only hope for these poor unfortunate creatures. It has gotten better over the years but there will always be a ways to go. I never could have gone into that type of research.


and...excuse me, but i dont see the importance of the "predictions" until and unless there is some way of prevention!! if i knew way back when that i had a risk of scoli...what? what would i have done differently...?
and...my sisters dont have it...where was their risk?

Yes. This type of research on predicting whose curves will worsen, who are the one in a 1,000 who will need surgery, is only the beginning. If there are no good non-surgical treatments then there are no good surgical treatmnts... it won't change that one whit. That's why I think the surgeons will develop a non-fusion surgical treatment well before they solve scoliosis on a molecular level and actually develop a pharmacological therapy. I don't think the latter will happen in my lifetime. Technical/engineering solutions, like my example of sending men to the moon and returning them safely, are just easier than the intrinsic biochemistry of animals. That's what ~3 billion years of evolution gets ya.

jrnyc
06-20-2010, 09:07 AM
i dont know how anyone does that kind of research day after day...and i know you wouldnt want to work in that kind of a lab!

my husband believes there will eventually be a way to fuse with flexibility...some way to have something in the rods, a kind of metal joints or spots on the rods that can "bend"... that will allow for some degree of flexing motion... surgeons tell me it isnt possible now with the limited technology we have available...
my sister told me a friend had treatment for a broken knee that involved some kind of "scaffolding" approach, so the knee had flexibility to it... it was held in some kind of a new fangled casting...while it healed!
i never thought of an approach using pharmacology! but it is a fascinating idea...

i know i wont live to see the new treatments, but if we could look ahead 50 years or so, i bet it would be an amazing view! :)

have a good wkend
jess

Pooka1
06-20-2010, 09:14 AM
I recalled reading a paper that questions Moreau's hypotheses about OPN triggering scolisois. Over on Kalla's site, fixscoliosis.com (sic), he found the paper and excerpted the relevant passages. He appears to be the only one on that forum who actually understands this issue.

http://www.scoliosisjournal.com/content/4/1/24

Here is what Kalla correctly excerpted which questions Moreau's work and interpretation. I bolded certain passages for emphasis.


"Osteopontin and soluble CD44 receptor
Most recently, Moreau et al [19,20] reported mean plasma
osteopontin (OPN) levels to be increased in:
• patients with idiopathic scoliosis, correlating significantly
with curve severity, and
• "an asymptomatic at-risk group" (offspring born
from at least one scoliotic parent).
In contrast, mean plasma levels of soluble CD44 receptor
(sCD44) were significantly lower in patients with Cobb
angles of 45 degrees or more. Drawing on evidence from
mouse models, it was concluded that OPN is essential to
induce scoliosis formation and curve progression through
interactions with CD44 receptors, "thus offering a first
molecular concept to explain the pathomechanism leading to
the asymmetrical growth of the spine in idiopathic scoliosis."
[19].
We ask whether:
(1) in mice, the scoliosis of melatonin-deficient models
has another interpretation; and
(2) in the AIS subjects [19,20], the increased OPN levels
are secondary to bone remodeling.

Some melatonin-deficient mouse models of scoliosis -
markers of developmental stress?

Moreau et al [19,20] found all transgenic melatonin-deficient
C57Bl/6J mice [150] devoid of OPN or CD44 receptor
were protected against scoliosis, contrasting with wildtype
ones. May this be, not because OPN is essential for
scoliosis pathogenesis, but because OPN deficiency
reduces stress reactions in mice [260]?
For, in mice, circulating OPN plays a significant role in the
body's reaction to stress by regulating hormones of the
hypothalamic-pituitary-adrenal axis (HPA) [260] modulated
by leptin which activates the JAK/STAT pathway. Stressors
cause less up-regulation of the stress hormone corticosterone
in OPN-deficient mice [260]. This may be tested in
the model used for mice: (1) rendered bipedal at 3 weeks
of age, and (2) kept in tall cages to make them reach up
increasingly for food and water [150]. The developmental
stress hypothesis [261], if confirmed, suggests that OPN
deficiency through reduced corticosterone up-regulation
causes less stress-reaction damage to the neural development
of posture and so protects against the scoliosis. If so,
these transgenic mice findings [19,20] may not be relevant
to AIS pathogenesis.

Osteopontin and bone remodeling in mice

Osteopontin, a major non-collagenous bone matrix glycoprotein
originally isolated from bone - sialic acid rich,
phosphorylated and inhibitor of calcification - has a critical
role in bone remodeling which in OPN-knockout mice
was suppressed [262]. Hence, the interpretation under
item 11. above, and the evidence from Fujihara et al [262],
together raise caution about attributing a causal, rather
than a consequential, role to increased plasma OPN in AIS
pathogenesis."

So we have other researchers questioning EVERY major claim of Moreau and especially the "centerpiece" claim that OPN causes AIS. The bunnies were incorrectly wowed. Again.

None of this means that Moreau is necessarily wrong. It does mean that there are other, equally valid interpretations of the research to date, that Moreau's work hasn't settled any question, and that there is still no solution. This research area is a long, hard road and I admire the researchers who walk it.

jrnyc
06-20-2010, 09:23 AM
hmmmm...much ado about little, i say...but that's just my opinion...

jess

Pooka1
06-20-2010, 12:11 PM
So we have other researchers questioning EVERY major claim of Moreau and especially the "centerpiece" claim that OPN causes AIS. The bunnies were incorrectly wowed. Again.

Actually I think I as wrong on this point. In reading the article, I notice that Moreau's results about the melatonin signaling dysfunction (MSD) pathway has been confirmed and extended by other researchers. But given that, I wonder why they are not pushing on this door in terms of trying to develop a pharmacology treatment? Instead he is pursuing the OPN/sCD44 business. That's curious. Essentially he is going with a less proven and more questioned hypothesis to pursue and seems to be downplaying the MSD stuff which enjoys more agreement among researchers in the field. Maybe there is no obvious play with the MSD thing. Maybe it is known that it isn't causative or even a point of entry into the biochemistry to block scoliosis onset or progression... I certainly don't know one way or the other.

Pooka1
06-20-2010, 01:16 PM
As far as I can gather (which isn't far!), scoliosis induced in mice is either functional (as in all the bipedal experiments) and not structural as in IS or is caused by premature fusing as in the abstract for research on a knockout mouse strain (Jun) Pnuttro posted and therefore NOT relevant to IS in humans.

If that is correct, NONE of this mouse work is relevant or at least directly relevant. The mouse work is what Moreau is using for his main claim that OPN is causative of IS in humans as I understand this.

Anybody know?

skevimc
06-21-2010, 01:38 PM
I just wanted to make a comment in regards to animal research.

1. It's true that any results from animal studies should always be interpreted with caution as it relates to human studies. However, there are also a lot of similarities.

2. There are several organizations, government and private, that oversee and certify animal facilities. Every procedure must be justified and every facet of recovery of any surgery must be addressed, including pain reduction. To a certain extent, animals are more protected than humans.

3. Regulations are always changing in order to be as ethical as possible.

I won't argue or defend any other points really because I know this is a passionate issue and not the easiest thing for people to think about. But I can assure you that those in charge of protecting the animals as well as most of the scientists doing the work have a lot of respect and compassion for the animals they work with.

flerc
06-21-2010, 08:20 PM
skevimc, I hope would be true all you said.
I do not know how are the current regulations, I think that outcomes should to be anticipated and conclusions for each ones should to be elaborated. If none conclusion is enough important, the experiment should not to be allowed at least if the suffer will be great.
I really doubt that much resources would be destined to reduce the suffer..

foofer
06-22-2010, 08:12 AM
Do bunnies get scoliosis?

Pooka1
06-22-2010, 09:15 AM
Do bunnies get scoliosis?

Post of the Month Nomination

Very good.

tonibunny
06-22-2010, 09:23 AM
Do bunnies get scoliosis?

This one did :p

PNUTTRO
06-23-2010, 11:18 AM
skevimc, I hope would be true all you said.
I do not know how are the current regulations, I think that outcomes should to be anticipated and conclusions for each ones should to be elaborated. If none conclusion is enough important, the experiment should not to be allowed at least if the suffer will be great.
I really doubt that much resources would be destined to reduce the suffer..

U.S. Government Principles for the Utilization and Care
of Vertebrate Animals Used in Testing, Research, and Training (http://grants.nih.gov/grants/olaw/references/phspol.htm#principle)

Dingo
06-23-2010, 11:19 PM
Mamamax


Why couldn't there be a yet unidentified link between scoliosis, genetic/familiar weakened immune systems, and pathogens (viral, bacterial, fungal, parasitic, prionic)?

When Dr. Moreau wrote that exposure to harmful bacteria might be a factor in curve progression I wasn't surprised. Pathogens cause more harm to humans than all other environmental factors combined.

Exhibit A)
Malaria causes 250 million cases of fever and 1 million deaths annually (http://en.wikipedia.org/wiki/History_of_malaria)

Interest in pathogens began to increase after Australian scientists proved that Ulcers were caused by chronic bacterial infections (http://en.wikipedia.org/wiki/Timeline_of_peptic_ulcer_disease_and_Helicobacter_ pylori).

This was from a few days ago.
Gut-Residing Bacteria Trigger Arthritis in Genetically Susceptible Individuals (http://www.sciencedaily.com/releases/2010/06/100617120716.htm)

This was from last year.
High Blood Pressure Could Be Caused By A Common Virus, Study Suggests (http://www.sciencedaily.com/releases/2009/05/090514221915.htm)

No doubt heredity and lifestyle play a role in susceptability.

Dingo
06-23-2010, 11:29 PM
From Dr. Moreau's patent

OPN-knockout mice do not develop a scoliosis (NS) even if they are in the same genomic background (C57BI6/J)

From the interview

This experiment indicates that OPN is required to trigger scoliosis onset.

Evidently Scoliosis is not the only disease that OPN is involved with.

Genetically removing the osteopontin protein prevents lung diseases (http://www.news-medical.net/news/20090916/Genetically-removing-the-osteopontin-protein-prevents-lung-diseases.aspx)

When Does Being Obese Not Lead To Diabetes? When Mice Lack Osteopontin (http://www.sciencedaily.com/releases/2007/09/070907105629.htm)

Molecule linked to autoimmune disease relapses identified (Osteopontin) (http://biosingularity.wordpress.com/2006/12/03/molecule-linked-to-autoimmune-disease-relapses-identified/)

Osteopontin and the skin: multiple emerging roles in cutaneous biology and pathology (http://www.mdlinx.com/allergy-immunology/news-article.cfm/2843143)


OPN is secreted in autoimmune diseases such as lupus erythematosus, and influences inflammation of immediate and delayed type allergies and granuloma formation. The authors describe that OPN is overexpressed in psoriasis and propose a model to study OPN function in psoriatic inflammation. Through cytokine functions, OPN supports immune responses against Mycobacteria and viruses such as herpes simplex virus. OPN is also implicated in skin tumor progression. Overexpression of OPN influences invasion and metastasis of melanoma and squamous cell carcinoma cells, and OPN expression in melanoma is a possible prognostic marker.

ArabianFancy
08-05-2010, 04:37 PM
I have a 5 year old son that I am really concerned about. His sister is recovering from scoliosis surgery. Should I get rid of the fish tank in the living room? ANY other ideas of what I can do to decrease his chances of getting scoliosis? I do NOT want him to have to go through what she did!
Thank you.
Gina

Dingo
08-07-2010, 12:31 AM
ArabianFancy

Torso Rotation Strength Training For Scoliosis (http://www.scoliosis.org/forum/showthread.php?t=8976)

If your five year old already has Scoliosis you may want to consider strength training when he gets a little older. I believe a 7 or 8 year old can fit into one of these machines.

If your five year old doesn't have Scoliosis I wouldn't worry about it. The odds are good that neither he nor his children will suffer from Scoliosis.

Although genes may (or may not) increase the likelihood that a child will suffer from Scoliosis nobody knows for sure what triggers it. Identical twins are routinely discordant for Scoliosis. The largest and most recent twin study found relatively low concordance. If one identical twin had Scoliosis the other had it just 13% of the time.

Adolescent idiopathic scoliosis in twins: a population-based survey. (http://www.ncbi.nlm.nih.gov/pubmed/17426641)

Another thing to keep in mind is that although some families are hit hard by Scoliosis roughly 2 in 3 cases occur seemingly at random.