In the first study of a large population of children with PWS treated with GH, beneficial effects were found with no adverse effects on the progression of scoliosis [321]. resistance in obesity and possibly in healthy females. The new Rabbit Polyclonal to MEF2C (phospho-Ser396) theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of thisdouble AMI-1 AMI-1 neuro-osseous theoryfor AIS pathogenesis in girls involvesselectively increased sensitivityof the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept =LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans. == Introduction == The autonomic nervous system through its hypothalamic neuroendocrine control of puberty, menarche and skeletal growth [1-3] contributes importantly to the pathogenesis of AIS [4-6]. Melatonin [7-13] and its signaling pathway dysfunction [14-20] and platelet-calmodulin dysfunction [21,22] detected in AIS subjects involve the autonomic nervous system. In AIS girls, autonomic nervous system activity was reported to be higher than controls [23]. Thedouble neuro-osseous theoryfor AIS pathogenesis in girls postulates developmental disharmony between somatic [24] and autonomic [25,26] nervous systems [27-29] expressed in the spine and trunk and exaggerated by hormones producing systemic skeletal overgrowth (preoperative girls) (Figure1) [30-45]. The theory predicates AIS pathogenesis in girls on dysfunction in one or both of two putativenormalmechanisms involved in trunk growth, each acquired in evolution and unique to humans, namely: == Figure 1. == Double neuro-osseous theoryfor the pathogenesis of AIS in girls. Disharmony in spine and trunk between the two nervous systems, autonomic (leptin-hypothalamic-sympathetic nervous system – LHS – concept) and somatic (escalator concept). The drawing of the girl shows three extraspinal sites where left-right skeletal length asymmetries have been detected in AIS subjects – ribs [30,31], upper arms [32] and iliac height [33,34]; the latter two asymmetries correlate significantly with adjacent spinal curve severity suggesting the presence of vertebral growth plate asymmetries [32,34-36]. Asymmetries are also found in tibial lengths [34,37], femoral anteversion [38,39], femoro-tibial correlations [40,41] but not tibial torsion [39,42]. There is some evidence suggesting a “primary” vertebral growth AMI-1 plate disorder in AIS [43,44] but this is controversial [45]. (1) Physiological trunk width skeletal growthdriven hormonally and supplemented by the sympathetic nervous system acting symmetrically [25,26,46-50]. (2) Physiological trunk postural mechanisms of the somatic nervous systemadapting normally to the growing and biomechanically changing skeletal framework [24,51,52]. There is preliminary evidence suggesting that the hypothalamus of some normal juvenile girls, but not boys, functions withcentral leptin resistance of the somatotropic (growth hormone/IGF) axis. This mechanism may AMI-1 limit the energy invested in female skeletal growth thereby conserving energy for reproductive development [50]. AIS in girls is viewed here as commonly resulting from increased central leptinsensitivityof hypothalamic sympathetic functions and, in some girls, of the somatotropic (growth hormone/IGF) neuroendocrine axis. These concepts provide an evolutionary and biological perspective [53] of energy homeostasis (bioenergetics) [54], particularly involving white adipose tissue storing excess energy as triglycerides, from which the double neuro-osseous theory is formulated. AMI-1 At the molecular level, disharmony between genes is established [55]. Gene variants that may impact the biology of AIS pathogenesis [56] are considered here.