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Relationship of Bioavailability of Leptin with Curve Progression in Adolescent Idiopathic Scoliosis
 

AIS girls have been shown to have abnormal growth and development during their puberty. Leptin is known more recently as an important factor in neuroskeletal biology and involved in the onset of puberty, skeletal growth, energy, and body composition during puberty. It is highly likely that leptin could be a putative candidate mediating the abnormality in AIS. Hence, we found hypoleptinemia in AIS girls when compared with controls.

We hypothesizes that the bioavailability of leptin is associated with the curve progression in AIS girls. We propose to document the leptin and soluble leptin receptor level in circulation to understand the bioavailability of the leptin in AIS girls and its relationship with curve progression. Secondly, we will investigate the body fat composition and nutrition status of AIS girls and their association with leptin level to further understand the possible underlying mechanism. The information could provide important scientific evidence for the development of new diagnostic, prognostic tool and clinical treatment for the AIS patients.

Summary expected soon

Quantification de l’activité de la voie vestibulospinale et réticulo-spinale chez les adolescents ayant une scoliose
 
L’objectif de ce programme de recherche comporte deux volets. Dans un premier temps, nous vérifierons si une anomalie du système vestibulaire pourrait être un facteur expliquant l’apparition et la progression de la scoliose. Le système vestibulaire est souvent présenté comme le sens de l’équilibre. Il se situe au niveau de l’oreille interne. Nous stimulerons celui-ci et mesurons l'activité des muscles du dos et des membres inférieurs.

D'autre part, en collaboration avec l’équipe du Dr Moreau de l'Hôpital Sainte-Justine (Montréal, Canada), nous cherchons à déterminer si une anomalie du système vestibulaire pourrait être identifiée à partir d’un test sanguin. Les résultats de ce programme de recherche permettront de vérifier s'il existe un lien étroit entre la génétique moléculaire et l’anomalie vestibulomotrice chez les patients scoliotiques ayant une courbure sévère.

summary soon available

Summary expected soon

The objectives are to investigate the presence of M receptors in platelets and skeletal muscle,to identify if the increased levels of C concentration in platelets of AIS patients are reflected as gene expressions, to identify whether parallel findings are present in skeletal muscle cells, andto identify the differences in the gene expressions of C and M in the AIS population in comparison with a non-AIS population with spinal trauma.

As a pilot study to demonstrate the role of C in AIS we have used the pinealectomized chicken model, and formed 3 groups; control, receiving tamoxifen (T), and 3 F perazine (3FP), both C inhibitors. Our early results demonstrate a decrease in the incidence of scoliosis (40% in C, 31.8% in T and 34.8% in 3FP), although not significant yet.

A total of 17 patients undergoing posterior instrumentation and fusion for AIS and 9 patients undergoing posterior surgery for spine trauma have been enrolled in the clinical study. Blood and muscle tissue samples were obtained during surgeries. These samples are in the process of being analyzed for M and C receptors. Comparisons will be made between the study and control patients, and the expression in platelets and muscle.

In our study we have shown that asymmetry of the posterior Basicranium and, indirectly of the cerebellum, was present but of slight amplitude in all normal non-scoliotic subjects and those subjects suffering from SIA presented a pathognomic amplification of this human trait. The requisite measurements were made possible by the use of an original, and statistically validated new method for establishing a reference frame to measure these asymmetries.

By employing a new method of treatment of the MRI data and a modelling programme, we were then able to demonstrate that they were associated with malformations in the semi-circular canals, probably due to a common genetic origin as suggested by several authors. At the same time, we brought to light an anomaly which seems to be specific to scoliotic subjects: the connection between the lateral and posterior canal. If this discovery is confirmed in other studies, this anatomical particularity, as well as the analysis of the pattern of the basicranium, could serve as an index for screening subjects at risk.

We have also shown the impact of these anomalies upon the visuo-motor function resulting in ocular torsion. These neuro-physiological anomalies underline the importance of the vestibular system in the formation of scoliosis via space perception and body schema representation and this in agreement with the research done by Yamamoto (1983), Yamada (1984) and Burwell (2002).

This study has also shown that subjects suffering from thoraco-lumbar scoliosis were the most affected by these diverse anomalies. It therefore appears necessary to pursue this line of research, the idea being to discover a metamerisation of the rachis deformation linked to the localisation of vestibular anomalies projected upon the different vestibular nuclei and cortical fields.

Outside surgery, the means available for fighting scoliosis are primarily based upon the modification of proprioceptive inputs (braces and/or muscular correction). In a forthcoming publication we will present the first results obtained thanks to a specific concentration upon visual and vestibular influxes with adolescent subjects suffering from iodiopathic scoliosis as a complementary alternative to proprioceptive action.

Familial idiopathic scoliosis is a complex genetic disorder that has limited treatment options.  The goal of this research is to define the genes responsible for this disorder from a large sample of families with at least two affected first degree relatives.  This strategy is based on the high prevalence of the disorder within the general population (2-3%), and the wide variability of disease presentation.

A genomic-wide scan and statistical linkage analysis of the identified population (202 families, 1208 individuals) have suggested areas on chromosomes 1,6,8,9,16, and 17 with potential significance to scoliosis.  Fine mapping has verified areas on chromosomes 1,8, 9, and 16.  Stratification of the population by mode of inheritance and phenotypic criteria has resulted in areas on chromosomes X, 5, and 13 to be potentially significant within subgroups.

To narrow further the critical regions an approach utilizing high-density biallelic markers (SNPs) will be combined with disease association studies.  This step is essential in the identification of known genes and EST’s within the area of interest for further study.  Analysis of these areas will include screening methodologies followed by direct mutational analyses.  The rationale of this effort is to be able to identify at-risk individuals prior to the onset of curvature.  Secondarily, specific genetic groups of individuals may be stratified earlier into therapeutic protocols.  This may allow for earlier limited surgical intervention and avoid long-term bracing which, in many cases, results in an extensive surgical intervention once initial treatment has failed

summary soon available

Studies related to visual-vestibular functions indicate that idiopathic scoliosis patients had a lower gain and a larger phase lead in their vestibule-ocular reflex (VOR) compared to healthy age-matched controls (Herman et al. 1985). Gross qualitative VOR abnormalities are observed in about 60-65% of idiopathic scoliosis patients (Sahlstrand and Petruson 1979; Herman et al. 1985). In addition, several studies have showed abnormal nystagmus response to caloric testing in patient with idiopathic scoliosis, suggesting an oculo-vestibular problem (Sahlstrand and Petruson 1979; Yamada et al. 1984).

Results from these studies demonstrated that the vestibular apparatus and/or the reflex circuitry are altered in idiopathic scoliosis patients. To our knowledge no study has investigated if idiopathic scoliosis patients process vestibular signals as good as healthy age-matched participants. In this study, the participants sat in a completely dark room on a chair located at the center of a black cylinder. The chair was rotated around the vertical axis using a handle attached to the rear of the chair. T

he magnitudes of the whole-body rotation, pseudo-randomly selected, were either 10º, 20º or 30º. The participant’s head was immobilized using a mechanical device that held the chin stationary during chair rotation. During chair rotation, eye movements were attenuated by the fixation of a chair-fixed target positioned straight-ahead. After the chair rotation, the participants produced a saccade to shift the gaze to the position fixed before chair rotation (“vestibular memory-contingent saccade” paradigm, Bloomberg et al. 1988).

Participants had to process the vestibular signal cognitively and to memorize this signal during whole-body rotation to produce a saccade of equal magnitude but in the opposite direction to the whole-body rotation (Blouin et al. 1995; Blouin et al. 1997). Overall, results showed that idiopathic scoliosis patients had a lower cognitive vestibular gain compared to healthy control participants. The saccade performance was based upon a cognitive perception of the vestibular response to head rotation in space.

Study Design : This prospective study assesses the clinical course of idiopathic scoliosis with melatonin deficiency and the effect of exogenous melatonin on progressive scoliosis.

Objectives : To clarify whether serum melatonin levels in adolescent idiopathic scoliosis correlate with curve progression, and whether  exogenous melatonin treatment is effective in patients with decreased levels of endogenous melatonin in adolescent idiopathic scoliosis.

Summary of Background Data. Our experimental studies in pinealectomized chickens and rats suggest that lower levels of melatonin play crucial role for development of scoliotic deformity and that the restoration of melatonin levels by administration of supplement prevents the development of scoliosis.

Subjects and Methods : A total of 63 adolescents were studied; 38 with adolescent idiopathic scoliosis and 25 age matched control subjects. We divided the patients into stable (28 patients) and progressive (10 patients) groups based on the scoliotic curve measured radiographically at 3 to 6 month intervals. The level of melatonin was considered low if it fell below the mean – 2.0 standard deviation established in normal adolescents throughout the 24 hour period or nocturnal (0:00 – 6:00 hour) integrated concentration. The patients with low endogenous melatonin were treated with oral replacement (3mg / day before bedtime) monitoring the serum level yearly for a period ranging from 3 to 6 years.
In all subjects the melatonin levels showed diurnal variations; low during the day and high at night. Of 22 patients with a normal melatonin level, 10 of 15 treated with brace and 6 of 7 untreated patients had stable scoliosis, and the remaining 6 had a progressive scoliosis. Of 16 patients with as low melatonin level, 8 of 9 treated only with melatonin, and 4 of 7 treated with melatonin and brace had stable scoliosis. The remaining 4 had a progressive course. Of the 10 patients who had  progressive scoliosis, 9 had greater than 40 degrees of curve at the initial examination.
These findings suggest that melatonin deficiency play a role in the prognosis of idiopathic scoliosis by determining the degree of spine curvature. Melatonin supplement may help prevent the development of progressive scoliosis especially in mild cases showing less than a 40 degree curve.