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Old 14-06-2010, 08:46 AM
Dingo Dingo is offline
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Join Date: May 2010
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[SIZE="4"]Part 3[/SIZE]

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) 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) (source) (source). 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 a protein called Osteopontin is closely associated with curve progression in children with AIS. OPN can be a marker for inflammation (source). 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.
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