Lateral bone density variations in the scoliotic spine

Adolescent Idiopathic Scoliosis (AIS) is the most common deformity of the spine, affecting 2-4% of the population. Previous studies have shown that the vertebrae in scoliotic spines undergo abnormal shape changes, however there has been little exploration of how scoliosis affects bone density distribution within the vertebrae. In this study, existing CT scans of 53 female idiopathic scoliosis patients with right-sided main thoracic curves were used to measure the lateral (right to left) bone density profile at mid-height through each vertebral body. Five key bone density profile measures were identified from each normalised bone density distribution, and multiple regression analysis was performed to explore the relationship between bone density distribution and patient demographics (age, height, weight, body mass index (BMI), skeletal maturity, time since Menarche, vertebral level, and scoliosis curve severity). Results showed a marked convex/concave asymmetry in bone density for vertebral levels at or near the apex of the scoliotic curve. At the apical vertebra, mean bone density at the left side (concave) cortical shell was 23.5% higher than for the right (convex) cortical shell, and cancellous bone density along the central 60% of the lateral path from convex to concave increased by 13.8%. The centre of mass of the bone density profile at the thoracic curve apex was located 53.8% of the distance along the lateral path, indicating a shift of nearly 4% toward the concavity of the deformity. These lateral bone density gradients tapered off when moving away from the apical vertebra. Multi-linear regressions showed that the right cortical shell peak bone density is significantly correlated with skeletal maturity, with each Risser increment corresponding to an increase in mineral equivalent bone density of 4-5%. There were also statistically significant relationships between patient height, weight and BMI, and the gradient of cancellous bone density along the central 60% of the lateral path. Bone density gradient is positively correlated with weight, and negatively correlated with height and BMI, such that at the apical vertebra, a unit decrease in BMI corresponds to an almost 100% increase in bone density gradient.

Prediction of adjacent vertebral fracture risk associated with vertebroplasty : a computer-based simulation study

Vertebrplasty involved injecting cement into a fractured vertebra to provide stabilisation. There is clinical evidence to suggest however that vertebroplasty may be assocated with a higher risk of adjacent vertebral fracture; which may be due to the change in material properties of the post-procedure vertebra modifying the transmission of mechanical stresses to adjacent vertebrae.

An experimental and finite element investigation of the biomechanics of vertebral compression fractures

Osteoporosis is a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis affects over 200 million people worldwide, with an estimated 1.5 million fractures annually in the United States alone, and with attendant costs exceeding $10 billion dollars per annum. Osteoporosis reduces bone density through a series of structural changes to the honeycomb-like trabecular bone structure (micro-structure). The reduced bone density, coupled with the microstructural changes, results in significant loss of bone strength and increased fracture risk. Vertebral compression fractures are the most common type of osteoporotic fracture and are associated with pain, increased thoracic curvature, reduced mobility, and difficulty with self care. Surgical interventions, such as kyphoplasty or vertebroplasty, are used to treat osteoporotic vertebral fractures by restoring vertebral stability and alleviating pain. These minimally invasive procedures involve injecting bone cement into the fractured vertebrae. The techniques are still relatively new and while initial results are promising, with the procedures relieving pain in 70-95% of cases, medium-term investigations are now indicating an increased risk of adjacent level fracture following the procedure. With the aging population, understanding and treatment of osteoporosis is an increasingly important public health issue in developed Western countries. The aim of this study was to investigate the biomechanics of spinal osteoporosis and osteoporotic vertebral compression fractures by developing multi-scale computational, Finite Element (FE) models of both healthy and osteoporotic vertebral bodies. The multi-scale approach included the overall vertebral body anatomy, as well as a detailed representation of the internal trabecular microstructure. This novel, multi-scale approach overcame limitations of previous investigations by allowing simultaneous investigation of the mechanics of the trabecular micro-structure as well as overall vertebral body mechanics. The models were used to simulate the progression of osteoporosis, the effect of different loading conditions on vertebral strength and stiffness, and the effects of vertebroplasty on vertebral and trabecular mechanics. The model development process began with the development of an individual trabecular strut model using 3D beam elements, which was used as the building block for lattice-type, structural trabecular bone models, which were in turn incorporated into the vertebral body models. At each stage of model development, model predictions were compared to analytical solutions and in-vitro data from existing literature. The incremental process provided confidence in the predictions of each model before incorporation into the overall vertebral body model. The trabecular bone model, vertebral body model and vertebroplasty models were validated against in-vitro data from a series of compression tests performed using human cadaveric vertebral bodies. Firstly, trabecular bone samples were acquired and morphological parameters for each sample were measured using high resolution micro-computed tomography (CT). Apparent mechanical properties for each sample were then determined using uni-axial compression tests. Bone tissue properties were inversely determined using voxel-based FE models based on the micro-CT data. Specimen specific trabecular bone models were developed and the predicted apparent stiffness and strength were compared to the experimentally measured apparent stiffness and strength of the corresponding specimen. Following the trabecular specimen tests, a series of 12 whole cadaveric vertebrae were then divided into treated and non-treated groups and vertebroplasty performed on the specimens of the treated group. The vertebrae in both groups underwent clinical-CT scanning and destructive uniaxial compression testing. Specimen specific FE vertebral body models were developed and the predicted mechanical response compared to the experimentally measured responses. The validation process demonstrated that the multi-scale FE models comprising a lattice network of beam elements were able to accurately capture the failure mechanics of trabecular bone; and a trabecular core represented with beam elements enclosed in a layer of shell elements to represent the cortical shell was able to adequately represent the failure mechanics of intact vertebral bodies with varying degrees of osteoporosis. Following model development and validation, the models were used to investigate the effects of progressive osteoporosis on vertebral body mechanics and trabecular bone mechanics. These simulations showed that overall failure of the osteoporotic vertebral body is initiated by failure of the trabecular core, and the failure mechanism of the trabeculae varies with the progression of osteoporosis; from tissue yield in healthy trabecular bone, to failure due to instability (buckling) in osteoporotic bone with its thinner trabecular struts. The mechanical response of the vertebral body under load is highly dependent on the ability of the endplates to deform to transmit the load to the underlying trabecular bone. The ability of the endplate to evenly transfer the load through the core diminishes with osteoporosis. Investigation into the effect of different loading conditions on the vertebral body found that, because the trabecular bone structural changes which occur in osteoporosis result in a structure that is highly aligned with the loading direction, the vertebral body is consequently less able to withstand non-uniform loading states such as occurs in forward flexion. Changes in vertebral body loading due to disc degeneration were simulated, but proved to have little effect on osteoporotic vertebra mechanics. Conversely, differences in vertebral body loading between simulated invivo (uniform endplate pressure) and in-vitro conditions (where the vertebral endplates are rigidly cemented) had a dramatic effect on the predicted vertebral mechanics. This investigation suggested that in-vitro loading using bone cement potting of both endplates has major limitations in its ability to represent vertebral body mechanics in-vivo. And lastly, FE investigation into the biomechanical effect of vertebroplasty was performed. The results of this investigation demonstrated that the effect of vertebroplasty on overall vertebra mechanics is strongly governed by the cement distribution achieved within the trabecular core. In agreement with a recent study, the models predicted that vertebroplasty cement distributions which do not form one continuous mass which contacts both endplates have little effect on vertebral body stiffness or strength. In summary, this work presents the development of a novel, multi-scale Finite Element model of the osteoporotic vertebral body, which provides a powerful new tool for investigating the mechanics of osteoporotic vertebral compression fractures at the trabecular bone micro-structural level, and at the vertebral body level.

Anterior vertebral stapling for the fusionless correction of scoliosis

Fusionless scoliosis surgery is an emerging treatment for idiopathic scoliosis as it offers theoretical advantages over current forms of treatment. Currently the treatment options for idiopathic scoliosis are observation, bracing and fusion. While brace treatment is non-invasive, and preserves the growth, motion, and function of the spine, it does not correct deformity and is only modestly successful in preventing curve progression. In adolescents who fail brace treatment, surgical treatment with an instrumented spinal fusion usually results in better deformity correction but is associated with substantially greater risk. Furthermore in younger patients requiring surgical treatment, fusion procedures are known to adversely effect the future growth of the chest and spine. Fusionless treatments have been developed to allow effective surgical treatment of patients with idiopathic scoliosis who are too young for fusion procedures. Anterior vertebral stapling is one such fusionless treatment which aims to modulate the growth of vertebra to allow correction of scoliosis whilst maintaining normal spinal motion The Mater Misericordiae Hospital in Brisbane has begun to use anterior vertebral stapling to treat patients with idiopathic scoliosis who are too young for fusion procedures. Currently the only staple approved for clinical use is manufactured by Medtronic Sofamor Danek (Memphis, TN). This thesis explains the biomechanical and anatomical changes that occur following anterior vertebral staple insertion using in vitro experiments performed on an immature bovine model. Currently there is a paucity of published information about anterior vertebral stapling so it is hoped that this project will provide information that will aid in our understanding of the clinical effects of staple insertion. The aims of this experimental study were threefold. The first phase was designed to determine the changes in the bending stiffness of the spine following staple insertion. The second phase was designed to measure the forces experienced by the staple during spinal movements. The third and final phase of testing was designed to describe the structural changes that occur to a vertebra as a consequence of staple insertion. The first phase of testing utilised a displacement controlled testing robot to compare the change in stiffness of a single spinal motion segment following staple insertion for the three basic spinal motions of flexion-extension, lateral bending, and axial rotation. For the second phase of testing strain gauges were attached to staples and used to measure staple forces during spinal movement. In the third and final phase the staples were removed and a testing specimen underwent micro-computed tomography (CT) scanning to describe the anatomical changes that occur following staple insertion. The displacement controlled testing showed that there was a significant decrease in bending stiffness in flexion, extension, lateral bending away from the staple, and axial rotation away from the staple following staple insertion. The strain gauge measurements showed that the greatest staple forces occurred in flexion and the least in extension. In addition, a reduction in the baseline staple compressive force was seen with successive loading cycles. Micro-CT scanning demonstrated that significant damage to the vertebral body and endplate occurred as a consequence of staple insertion. The clinical implications of this study are significant. Based on the findings of this project it is likely that the clinical effect of the anterior vertebral staple evaluated in this project is a consequence of growth plate damage (also called hemiepiphysiodesis) causing a partial growth arrest of the vertebra rather than simply compression of the growth plate. The surgical creation of a unilateral growth arrest is a well established treatment used in the management of congenital scoliosis but has not previously been considered for use in idiopathic scoliosis.

Physiological investigation of periosteum structure and its application in periosteum tissue engineering

Although many different materials, techniques and methods, including artificial or engineered bone substitutes, have been used to repair various bone defects, the restoration of critical-sized bone defects caused by trauma, surgery or congenital malformation is still a great challenge to orthopedic surgeons. One important fact that has been neglected in the pursuit of resolutions for large bone defect healing is that most physiological bone defect healing needs the periosteum and stripping off the periosteum may result in non-union or non-healed bone defects. Periosteum plays very important roles not only in bone development but also in bone defect healing. The purpose of this project was to construct a functional periosteum in vitro using a single stem cell source and then test its ability to aid the repair of critical-sized bone defect in animal models. This project was designed with three separate but closely-linked parts which in the end led to four independent papers. The first part of this study investigated the structural and cellular features in periostea from diaphyseal and metaphyseal bone surfaces in rats of different ages or with osteoporosis. Histological and immunohistological methods were used in this part of the study. Results revealed that the structure and cell populations in periosteum are both age-related and site-specific. The diaphyseal periosteum showed age-related degeneration, whereas the metaphyseal periosteum is more destructive in older aged rats. The periosteum from osteoporotic bones differs from normal bones both in terms of structure and cell populations. This is especially evident in the cambial layer of the metaphyseal area. Bone resorption appears to be more active in the periosteum from osteoporotic bones, whereas bone formation activity is comparable between the osteoporotic and normal bone. The dysregulation of bone resorption and formation in the periosteum may also be the effect of the interaction between various neural pathways and the cell populations residing within it. One of the most important aspects in periosteum engineering is how to introduce new blood vessels into the engineered periosteum to help form vascularized bone tissues in bone defect areas. The second part of this study was designed to investigate the possibility of differentiating bone marrow stromal cells (BMSCs) into the endothelial cells and using them to construct vascularized periosteum. The endothelial cell differentiation of BMSCs was induced in pro-angiogenic media under both normoxia and CoCl2 (hypoxia-mimicking agent)-induced hypoxia conditions. The VEGF/PEDF expression pattern, endothelial cell specific marker expression, in vitro and in vivo vascularization ability of BMSCs cultured in different situations were assessed. Results revealed that BMSCs most likely cannot be differentiated into endothelial cells through the application of pro-angiogenic growth factors or by culturing under CoCl2-induced hypoxic conditions. However, they may be involved in angiogenesis as regulators under both normoxia and hypoxia conditions. Two major angiogenesis-related growth factors, VEGF (pro-angiogenic) and PEDF (anti-angiogenic) were found to have altered their expressions in accordance with the extracellular environment. BMSCs treated with the hypoxia-mimicking agent CoCl2 expressed more VEGF and less PEDF and enhanced the vascularization of subcutaneous implants in vivo. Based on the findings of the second part, the CoCl2 pre-treated BMSCs were used to construct periosteum, and the in vivo vascularization and osteogenesis of the constructed periosteum were assessed in the third part of this project. The findings of the third part revealed that BMSCs pre-treated with CoCl2 could enhance both ectopic and orthotopic osteogenesis of BMSCs-derived osteoblasts and vascularization at the early osteogenic stage, and the endothelial cells (HUVECs), which were used as positive control, were only capable of promoting osteogenesis after four-weeks. The subcutaneous area of the mouse is most likely inappropriate for assessing new bone formation on collagen scaffolds. This study demonstrated the potential application of CoCl2 pre-treated BMSCs in the tissue engineering not only for periosteum but also bone or other vascularized tissues. In summary, the structure and cell populations in periosteum are age-related, site-specific and closely linked with bone health status. BMSCs as a stem cell source for periosteum engineering are not endothelial cell progenitors but regulators, and CoCl2-treated BMSCs expressed more VEGF and less PEDF. These CoCl2-treated BMSCs enhanced both vascularization and osteogenesis in constructed periosteum transplanted in vivo.

An FE investigation simulating intra-operative corrective forces applied to correct scoliosis deformity

Background: Adolescent idiopathic scoliosis (AIS) is a deformity of the spine, which may 34 require surgical correction by attaching a rod to the patient’s spine using screws 35 implanted in the vertebral bodies. Surgeons achieve an intra-operative reduction in the 36 deformity by applying compressive forces across the intervertebral disc spaces while 37 they secure the rod to the vertebra. We were interested to understand how the 38 deformity correction is influenced by increasing magnitudes of surgical corrective forces 39 and what tissue level stresses are predicted at the vertebral endplates due to the 40 surgical correction. 41 Methods: Patient-specific finite element models of the osseoligamentous spine and 42 ribcage of eight AIS patients who underwent single rod anterior scoliosis surgery were 43 created using pre-operative computed tomography (CT) scans. The surgically altered 44 spine, including titanium rod and vertebral screws, was simulated. The models were 45 analysed using data for intra-operatively measured compressive forces – three load 46 profiles representing the mean and upper and lower standard deviation of this data 47 were analysed. Data for the clinically observed deformity correction (Cobb angle) were 48 compared with the model-predicted correction and the model results investigated to 49 better understand the influence of increased compressive forces on the biomechanics of 50 the instrumented joints. 51 Results: The predicted corrected Cobb angle for seven of the eight FE models were 52 within the 5° clinical Cobb measurement variability for at least one of the force profiles. 53 The largest portion of overall correction was predicted at or near the apical 54 intervertebral disc for all load profiles. Model predictions for four of the eight patients 55 showed endplate-to-endplate contact was occurring on adjacent endplates of one or 56 more intervertebral disc spaces in the instrumented curve following the surgical loading 57 steps. 58 Conclusion: This study demonstrated there is a direct relationship between intra-59 operative joint compressive forces and the degree of deformity correction achieved. The 60 majority of the deformity correction will occur at or in adjacent spinal levels to the apex 61 of the deformity. This study highlighted the importance of the intervertebral disc space 62 anatomy in governing the coronal plane deformity correction and the limit of this 63 correction will be when bone-to-bone contact of the opposing vertebral endplates 64 occurs.

Investigation between the S377G3 GATA-4 polymorphism and migraine

Migraine is a common and painful neurological disorder, with genetic and environmental components. Several conditions have been shown to be comorbid with migraine, notably a cardiac malformation affecting the interatrial septum and leading to patent foramen ovale (PFO). Mutations in the development regulatory gene GATA-4, located on human chromosome 8p23.1-p22, have been found to be responsible for some cases of congenital heart defects including PFO. To determine whether the GATA-4 gene is involved in migraine, the present study performed an association analysis of a common GATA-4 variant that results in a change of amino acid (S377G), in a large case/control population (275 unrelated Caucasian migraineurs versus 275 control individuals). The results showed that there was no significant association for this polymorphism between migraine and controls (χ² = 0.84, P = 0.66). Thus it appears that the GATA-4 (S377G) mutation does not play a significant role in common migraine susceptibility.

Bcl-2 genes and growth factors in the pathology of ischaemic acute renal failure

For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion; (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells; and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.

Estrogen deficiency-associated bone loss in the maxilla: A methodology to quantify the changes in the maxillary intra-radicular alveolar bone in an ovariectomized rat osteoporosis model

The effects of estrogen deficiency on bone characteristics are site-dependent, with the most commonly studied sites being appendicular long bones (proximal femur and tibia) and axial bones (vertebra). The effect on the maxillary and mandibular bones is still inconsistent and requires further investigation. This study was designed to evaluate bone quality in the posterior maxilla of ovariectomized rats in order to validate this site as an appropriate model to study the effect of osteoporotic changes. Methods: Forty-eight 3-month-old female Sprague-Dawley rats were randomly divided into two groups: an ovariectomized group (OVX, n=24) and Sham-operated group (SHAM, n=24). Six rats were randomly sacrificed from both groups at time points 8, 12, 16 and 20 weeks. The samples from tibia and maxilla were collected for Micro CT and histological analysis. For the maxilla, the volume of interest (VOI) area focused on the furcation areas of the first and second molar. Trabecular bone volume fraction (BV/TV, %), trabecular thickness (Tb.Th.), trabecular number (Tb.N.), trabecular separation (Tb.Sp.), and connectivity density (Conn.Dens) were analysed after Micro CT scanning. Results: At 8 weeks the indices BV/TV, Tb.Sp, Tb.N and Conn.Dens showed significant differences (P<0.05) between the OVX and SHAM groups in the tibia. Compared with the tibia, the maxilla developed osteoporosis at a later stage, with significant changes in maxillary bone density only occurring after 12 weeks. Compared with the SHAM group, both the first and second molars of the OVX group showed significantly decreased BV/TV values from 12 weeks, and these changes were sustained through 16 and 20 weeks. For Tb.Sp, there were significant increases in bone values for the OVX group compared with the SHAM group at 12, 16 and 20 weeks. Histological changes were highly consistent with Micro CT results. Conclusion: This study established a method to quantify the changes of intra-radicular alveolar bone in the posterior maxilla in an accepted rat osteoporosis model. The degree of the osteoporotic changes to trabecular bone architecture is site-dependent and at least 3 months are required for the osteoporotic effects to be apparent in the posterior maxilla following rat OVX.

MRI reveals individual level deformities in the growing scoliotic spine that clinically are masked by the Cobb angle

Clinically, the Cobb angle method measures the overall scoliotic curve in the coronal plane but does not measure individual vertebra and disc wedging. The contributions of the vertebrae and discs in the growing scoliotic spine were measured using sequential MRI scans to investigate coronal plane deformity progression with growth. Sequential MRI data showed complex patterns of deformity progression. Changes to the wedging of individual vertebrae and discs may occur in patients who have no increase in overall Cobb angle measure; the Cobb method alone may be insufficient to capture the complex mechanisms of deformity progression.

Spine curvature analysis between participants with obesity and normal weight participants: A biplanar electromagnetic device measurement

To analyse and compare standing thoracolumbar curves in normal weight participants and participants with obesity, using an electromagnetic device, and to analyse the measurement reliability. Material and Methods. Cross-sectional study was carried out. 36 individuals were divided into two groups (normal-weight and participants with obesity) according to their waist circumference. The reference points (T1–T8–L1–L5 and both posterior superior iliac spines) were used to perform a description of thoracolumbar curvature in the sagittal and coronal planes. A transformation from the global coordinate system was performed and thoracolumbar curves were adjusted by fifth-order polynomial equations. The tangents of the first and fifth lumbar vertebrae and the first thoracic vertebra were determined from their derivatives. The reliability of the measurement was assessed according to the internal consistency of the measure and the thoracolumbar curvature angles were compared between groups. Results. Cronbach’s alpha values ranged between 0.824 (95% CI: 0.776–0.847) and 0.918 (95% CI: 0.903–0.949). In the coronal plane, no significant differences were found between groups; however, in sagittal plane, significant differences were observed for thoracic kyphosis. Conclusion. There were significant differences in thoracic kyphosis in the sagittal plane between two groups of young adults grouped according to their waist circumference.

Sequential MRI reveals individual level deformities in the growing scoliotic spine that are clinically masked by the Cobb angle

Introduction Clinically, the Cobb angle method measures the overall scoliotic curve in the coronal plane but does not measure individual vertebra and disc wedging. The contributions of the vertebrae and discs in the growing scoliotic spine were measured to investigate coronal plane deformity progression with growth. Methods A 0.49mm isotropic 3D MRI technique was developed to investigate the level-by-level changes that occur in the growing spine of a group of Adolescent Idiopathic Scoliosis (AIS) patients, who received two to four sequential scans (spaced 3-12 months apart). The coronal plane wedge angles of each vertebra and disc in the major curve were measured to capture any changes that occurred during their adolescent growth phase. Results Seventeen patients had at least two scans. Mean patient age was 12.9 years (SD 1.5 years). Sixteen were classified as right-sided major thoracic Lenke Type 1 (one left sided). Mean standing Cobb angle at initial presentation was 31° (SD 12°). Six received two scans, nine three scans and two four scans, with 65% showing a Cobb angle progression of 5° or more between scans. Overall, there was no clear pattern of deformity progression of individual vertebrae and discs, nor between patients who progressed and those who didn’t. There were measurable changes in the wedging of the vertebrae and discs in all patients. In sequential scans, change in direction of wedging was also seen. In several patients there was reverse wedging in the discs that counteracted increased wedging of the vertebrae such that no change in overall Cobb angle was seen. Conclusion Sequential MRI data showed complex patterns of deformity progression. Changes to the wedging of individual vertebrae and discs may occur in patients who have no increase in Cobb angle measure; the Cobb method alone may be insufficient to capture the complex mechanisms of deformity progression.

Sequential MRI of growing scoliotic spines reveals individual level deformities that are clinically masked by the cobb angle

INTRODUCTION. Clinically, the Cobb angle method measures the overall scoliotic curve in the coronal plane but does not measure individual vertebra and disc wedging. The contributions of the vertebrae and discs in the growing scoliotic spine were measured to investigate coronal plane deformity progression with growth. METHODS. A 0.49mm isotropic 3D MRI technique was developed to investigate the level-by-level changes that occur in the growing spine of a group of Adolescent Idiopathic Scoliosis (AIS) patients, who received two to four sequential scans (spaced 3-12 months apart). The coronal plane wedge angles of each vertebra and disc in the major curve were measured to capture any changes that occurred during their adolescent growth phase. RESULTS. Seventeen patients had at least two scans. Mean patient age was 12.9 years (SD 1.5 years). Sixteen were classified as right-sided major thoracic Lenke Type 1 (one left sided). Mean standing Cobb angle at initial presentation was 31° (SD 12°). Six received two scans, nine three scans and two four scans, with 65% showing a Cobb angle progression of 5° or more between scans. Overall, there was no clear pattern of deformity progression of individual vertebrae and discs, nor between patients who progressed and those who didn’t. There were measurable changes in the wedging of the vertebrae and discs in all patients. In sequential scans, change in direction of wedging was also seen. In several patients there was reverse wedging in the discs that counteracted increased wedging of the vertebrae such that no change in overall Cobb angle was seen. CONCLUSION. Sequential MRI data showed complex patterns of deformity progression. Changes to the wedging of individual vertebrae and discs may occur in patients who have no increase in Cobb angle measure; the Cobb method alone may be insufficient to capture the complex mechanisms of deformity progression.

Sequential MRI reveals individual level deformities in the growing scoliotic spine that are not seen clinically by the cobb angle

Clinically, the Cobb angle method measures the overall scoliotic curve in the coronal plane but does not measure individual vertebra and disc wedging. The contributions of the vertebrae and discs in the growing scoliotic spine were measured to investigate coronal plane deformity progression with growth. Sequential MRI data in this project showed complex patterns of deformity progression. Changes to the wedging of individual vertebrae and discs may occur in patients who have no increase in Cobb angle measure; the Cobb method alone may be insufficient to capture the complex mechanisms of deformity progression.

Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.