Improving diagnosis of tumor-induced osteomalacia with gallium-68 DOTATATE PET/CT

Context: Tumor-induced osteomalacia (TIO) is a rarely diagnosed disorder presenting with bone pain, fractures, muscle weakness, and moderate-to-severe hypophosphatemia resulting from fibroblast growth factor 23-mediated renal phosphate wasting. Tumors secreting fibroblast growth factor 23 are often small and difficult to find with conventional imaging. Objective: We studied the utility of 68Ga-DOTA-octreotate (DOTATATE) somatostatin receptor positron emission tomography (PET)/computed tomography (CT) imaging in the diagnosis of TIO. Design and Setting: A multicenter case series was conducted at tertiary referral hospitals. Patients and Methods: Six patients with TIO diagnosed between 2003 and 2012 in Australia were referred for DOTATATE PET imaging. We reviewed the clinical history, biochemistry, imaging characteristics, histopathology, and clinical outcome of each patient. Results: Each case demonstrated delayed diagnosis despite severe symptoms. DOTATATE PET/CT imaging demonstrated high uptake and localized the tumor with confidence in each case. After surgical excision, there was resolution of clinical symptoms and serum phosphate, except in one patient who demonstrated residual disease on PET/CT. All tumors demonstrated high somatostatin receptor subtype 2 cell surface receptor expression using immunohistochemistry. Conclusions: In patients with TIO, DOTATATE PET/CT can successfully localize phosphaturic mesenchymal tumors and may be a practical first step in functional imaging for this disorder. Serum phosphate should be measured routinely in patients with unexplained muscle weakness, bone pain, or stress fractures to allow earlier diagnosis of TIO. - See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2012-3642#sthash.eXD0CopL.dpuf

A new measure to quantify chest wall deformity in scoliosis patients : does rib hump measurement correlate with anterior chest wall deformity post surgery?

The primary aims of scoliosis surgery are to halt the progression of the deformity, and to reduce its severity (cosmesis). Currently, deformity correction is measured in terms of posterior parameters (Cobb angles and rib hump), even though the cosmetic concern for most patients is anterior chest wall deformity. In this study, we propose a new measure for assessing anterior chest wall deformity and examine the correlation between rib hump and the new measure. 22 sets of CT scans were retrieved from the QUT/Mater Paediatric Spinal Research Database. The Image J software (NIH) was used to manipulate formatted CT scans into 3-dimensional anterior chest wall reconstructions. A ‘chest wall angle’ was then measured in relation to the first sacral vertebral body. The chest wall angle was found to be a reliable tool in the analysis of chest wall deformity. No correlation was found between the new measure and rib hump angle. Since rib hump has been shown to correlate with vertebral rotation on CT, this suggests that there maybe no correlation between anterior and posterior deformity measures. While most surgical procedures will adequately address the coronal imbalance & posterior rib hump elements of scoliosis, they do not reliably alter the anterior chest wall shape. This implies that anterior chest wall deformity is to a large degree an intrinsic deformity, not directly related to vertebral rotation.

The anatomical and biomechanical consequences of 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. Anterior vertebral stapling using a nitinol staple is one such treatment. Despite increasing interest in this technique, little is known about the effects on the spine following insertion, or the mechanism of action of the staple. The aims of this study were threefold; (1) to measure changes in the bending stiffness of a single motion segment following staple insertion, (2) to describe the forces that occur within the staple during spinal movement, and (3) to describe the anatomical changes that occur following staple insertion. Results suggest that staple insertion consistently decreased stiffness in all directions of motion. An explanation for the finding may be found in the outcomes of the strain gauge testing and micro-CT scan. The strain gauge testing showed that once inserted, the staple tips applied a baseline compressive force to the surrounding trabecular bone and vertebral end-plate. This finding would be consistent with the current belief that the clinical effect of the staples is via unilateral compression of the physis. Interestingly however, as each specimen progressed through the five cycles of each test, the baseline load on the staple tips gradually decreased, implying that the force at the staple tip-bone interface was decreasing. We believe that this was likely occurring as a result of structural damage to the trabecular bone and vertebral end-plate by the staple effectively causing ‘loosening’ of the staple. This hypothesis is further supported by the findings of the micro-CT scan. The pictures depict significant trabecular bone and physeal injury around the staple blades. These results suggest that the current hypothesis that stapling modulates growth through physeal compression may be incorrect, but rather the effect occurs through mechanical disruption of the vertebral growth plate.

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 AIS affects bone density distribution within the vertebrae. Existing pre-operative 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. This study demonstrated that AIS patients have a marked convex/concave asymmetry in bone density for vertebral levels at or near the apex of the scoliotic curve. To the best of our knowledge, the only previous studies of bone density distribution in AIS are those of Périé et al [1,2], who reported a coronal plane ‘mechanical migration’ of 0.54mm toward the concavity of the scoliotic curve in the lumbar apical vertebrae of 11 scoliosis patients. This is comparable to the value of 0.8mm (4%) in our study, especially since our patients had more severe scoliotic curves. From a bone adaptation perspective, these results suggest that the axial loading on the scoliotic spine is strongly asymmetric.

Computed tomography evaluation of axial vertebral derotation in endoscopic anterior instrumentation for adolescent idiopathic scoliosis

Thoracoscopic instrumented anterior spinal fusion for adolescent idiopathic scoliosis (AIS) has clinical benefits that include reduced pulmonary morbidity, postoperative pain, and improved cosmesis. However, quantitative data on radiological improvement of vertebral rotation using this method is lacking. This study’s objectives were to measure preoperative and postoperative axial vertebral rotational deformity at the curve apex in endoscopically-treated anterior-instrumented scoliosis patients using CT, and assess the relevance of these findings to clinically measured chest wall rib hump deformity correction. This is the first quantitative CT study to confirm that endoscopic anterior instrumented fusion for AIS substantially improves axial vertebral body rotational deformity at the apex of the curve. The margin of correction of 43% compares favourably with historically published figures of 24% for patients with posterior all-hook-rod constructs. CT measurements correlated significantly to the clinical outcome of rib hump deformity correction.

Non-alcoholic fatty liver disease : can ultrasound assist in early diagnosis of prediabetes and delay progression to type2 diabetes mellitus

Non Alcoholic Fatty Liver Disease (NAFLD) is a condition that is frequently seen but seldom investigated. Until recently, NAFLD was considered benign, self-limiting and unworthy of further investigation. This opinion is based on retrospective studies with relatively small numbers and scant follow-up of histology data. (1) The prevalence for adults, in the USA is, 30%, and NAFLD is recognized as a common and increasing form of liver disease in the paediatric population (1). Australian data, from New South Wales, suggests the prevalence of NAFLD in “healthy” 15 year olds as being 10%.(2) Non-alcoholic fatty liver disease is a condition where fat progressively invades the liver parenchyma. The degree of infiltration ranges from simple steatosis (fat only) to steatohepatitis (fat and inflammation) steatohepatitis plus fibrosis (fat, inflammation and fibrosis) to cirrhosis (replacement of liver texture by scarred, fibrotic and non functioning tissue).Non-alcoholic fatty liver is diagnosed by exclusion rather than inclusion. None of the currently available diagnostic techniques -liver biopsy, liver function tests (LFT) or Imaging; ultrasound, Computerised tomography (CT) or Magnetic Resonance Imaging (MRI) are specific for non-alcoholic fatty liver. An association exists between NAFLD, Non Alcoholic Steatosis Hepatitis (NASH) and irreversible liver damage, cirrhosis and hepatoma. However, a more pervasive aspect of NAFLD is the association with Metabolic Syndrome. This Syndrome is categorised by increased insulin resistance (IR) and NAFLD is thought to be the hepatic representation. Those with NAFLD have an increased risk of death (3) and it is an independent predictor of atherosclerosis and cardiovascular disease (1). Liver biopsy is considered the gold standard for diagnosis, (4), and grading and staging, of non-alcoholic fatty liver disease. Fatty-liver is diagnosed when there is macrovesicular steatosis with displacement of the nucleus to the edge of the cell and at least 5% of the hepatocytes are seen to contain fat (4).Steatosis represents fat accumulation in liver tissue without inflammation. However, it is only called non-alcoholic fatty liver disease when alcohol - >20gms-30gms per day (5), has been excluded from the diet. Both non-alcoholic and alcoholic fatty liver are identical on histology. (4).LFT’s are indicative, not diagnostic. They indicate that a condition may be present but they are unable to diagnosis what the condition is. When a patient presents with raised fasting blood glucose, low HDL (high density lipoprotein), and elevated fasting triacylglycerols they are likely to have NAFLD. (6) Of the imaging techniques MRI is the least variable and the most reproducible. With CT scanning liver fat content can be semi quantitatively estimated. With increasing hepatic steatosis, liver attenuation values decrease by 1.6 Hounsfield units for every milligram of triglyceride deposited per gram of liver tissue (7). Ultrasound permits early detection of fatty liver, often in the preclinical stages before symptoms are present and serum alterations occur. Earlier, accurate reporting of this condition will allow appropriate intervention resulting in better patient health outcomes. References 1. Chalasami N. Does fat alone cause significant liver disease: It remains unclear whether simple steatosis is truly benign. American Gastroenterological Association Perspectives, February/March 2008 www.gastro.org/wmspage.cfm?parm1=5097 Viewed 20th October, 2008 2. Booth, M. George, J.Denney-Wilson, E: The population prevalence of adverse concentrations with adiposity of liver tests among Australian adolescents. Journal of Paediatrics and Child Health.2008 November 3. Catalano, D, Trovato, GM, Martines, GF, Randazzo, M, Tonzuso, A. Bright liver, body composition and insulin resistance changes with nutritional intervention: a follow-up study .Liver Int.2008; February 1280-9 4. Choudhury, J, Sanysl, A. Clinical aspects of Fatty Liver Disease. Semin in Liver Dis. 2004:24 (4):349-62 5. Dionysus Study Group. Drinking factors as cofactors of risk for alcohol induced liver change. Gut. 1997; 41 845-50 6. Preiss, D, Sattar, N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci.2008; 115 141-50 7. American Gastroenterological Association. Technical review on nonalcoholic fatty liver disease. Gastroenterology.2002; 123: 1705-25

A naturally shaped silicone ventricle evaluated in a mock circulation loop : a preliminary study

Mock circulation loops are used to evaluate the performance of cardiac assist devices prior to animal and clinical testing. A compressible, translucent silicone ventricle chamber that mimics the exact size, shape and motion of a failing heart is desired to assist in flow visualization studies around inflow cannulae during VAD support. The aim of this study was therefore to design and construct a naturally shaped flexible left ventricle and evaluate its performance in a mock circulation loop. The ventricle shape was constructed by the use of CT images taken from a patient experiencing cardiomyopathic heart failure and used to create a 3D image and subsequent mould to produce a silicone ventricle. Different cardiac conditions were successfully simulated to validate the ventricle performance, including rest, left heart failure and VAD support.

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.

Generation of a 3D proximal femur shape from a single projection 2D radiographic image.

Summary Generalized Procrustes analysis and thin plate splines were employed to create an average 3D shape template of the proximal femur that was warped to the size and shape of a single 2D radiographic image of a subject. Mean absolute depth errors are comparable with previous approaches utilising multiple 2D input projections. Introduction Several approaches have been adopted to derive volumetric density (g cm-3) from a conventional 2D representation of areal bone mineral density (BMD, g cm-2). Such approaches have generally aimed at deriving an average depth across the areal projection rather than creating a formal 3D shape of the bone. Methods Generalized Procrustes analysis and thin plate splines were employed to create an average 3D shape template of the proximal femur that was subsequently warped to suit the size and shape of a single 2D radiographic image of a subject. CT scans of excised human femora, 18 and 24 scanned at pixel resolutions of 1.08 mm and 0.674 mm, respectively, were equally split into training (created 3D shape template) and test cohorts. Results The mean absolute depth errors of 3.4 mm and 1.73 mm, respectively, for the two CT pixel sizes are comparable with previous approaches based upon multiple 2D input projections. Conclusions This technique has the potential to derive volumetric density from BMD and to facilitate 3D finite element analysis for prediction of the mechanical integrity of the proximal femur. It may further be applied to other anatomical bone sites such as the distal radius and lumbar spine.

Validation of 3D models of the outer and inner surfaces of an ovine femur

The validation of Computed Tomography (CT) based 3D models takes an integral part in studies involving 3D models of bones. This is of particular importance when such models are used for Finite Element studies. The validation of 3D models typically involves the generation of a reference model representing the bones outer surface. Several different devices have been utilised for digitising a bone’s outer surface such as mechanical 3D digitising arms, mechanical 3D contact scanners, electro-magnetic tracking devices and 3D laser scanners. However, none of these devices is capable of digitising a bone’s internal surfaces, such as the medullary canal of a long bone. Therefore, this study investigated the use of a 3D contact scanner, in conjunction with a microCT scanner, for generating a reference standard for validating the internal and external surfaces of a CT based 3D model of an ovine femur. One fresh ovine limb was scanned using a clinical CT scanner (Phillips, Brilliance 64) with a pixel size of 0.4 mm2 and slice spacing of 0.5 mm. Then the limb was dissected to obtain the soft tissue free bone while care was taken to protect the bone’s surface. A desktop mechanical 3D contact scanner (Roland DG Corporation, MDX 20, Japan) was used to digitise the surface of the denuded bone. The scanner was used with the resolution of 0.3 × 0.3 × 0.025 mm. The digitised surfaces were reconstructed into a 3D model using reverse engineering techniques in Rapidform (Inus Technology, Korea). After digitisation, the distal and proximal parts of the bone were removed such that the shaft could be scanned with a microCT (µCT40, Scanco Medical, Switzerland) scanner. The shaft, with the bone marrow removed, was immersed in water and scanned with a voxel size of 0.03 mm3. The bone contours were extracted from the image data utilising the Canny edge filter in Matlab (The Mathswork).. The extracted bone contours were reconstructed into 3D models using Amira 5.1 (Visage Imaging, Germany). The 3D models of the bone’s outer surface reconstructed from CT and microCT data were compared against the 3D model generated using the contact scanner. The 3D model of the inner canal reconstructed from the microCT data was compared against the 3D models reconstructed from the clinical CT scanner data. The disparity between the surface geometries of two models was calculated in Rapidform and recorded as average distance with standard deviation. The comparison of the 3D model of the whole bone generated from the clinical CT data with the reference model generated a mean error of 0.19±0.16 mm while the shaft was more accurate(0.08±0.06 mm) than the proximal (0.26±0.18 mm) and distal (0.22±0.16 mm) parts. The comparison between the outer 3D model generated from the microCT data and the contact scanner model generated a mean error of 0.10±0.03 mm indicating that the microCT generated models are sufficiently accurate for validation of 3D models generated from other methods. The comparison of the inner models generated from microCT data with that of clinical CT data generated an error of 0.09±0.07 mm Utilising a mechanical contact scanner in conjunction with a microCT scanner enabled to validate the outer surface of a CT based 3D model of an ovine femur as well as the surface of the model’s medullary canal.

Justifications in young children’s language in an early childhood classroom

This paper examines the interactional phenomenon of justification as it is produced in young children’s language. A justification provides a reason for one’s position and can be produced in children’s language at an early age. There are various pragmatic reasons for justifications. For example, justifications may be drawn upon by members to compensate for the disruption of the existing social order or to explain something that is possibly questionable. Justifications are also drawn upon to extend or close disputes. This study uses the analytical techniques of conversation analysis and membership categorisation to analyse video-recorded and transcribed interactions of young children (aged 4-6 years) in a preparatory classroom in a primary school in Australia. The focus is an episode that occurred within the block play area of the classroom that involved a dispute of ownership relating to a small, wooden plank. In analysing this dispute, justifications were frequent occurrences and the young participants drew upon justificatory devices in their everyday arguments. As the turns surrounding the justificatory language were examined, a pattern emerged: in each excerpt observed, a justification arose in response to a challenge. This pattern provided the basis for developing a model that helped to discern where, why and what type of justifications occurred in the interaction. To depict this interactional phenomenon, the model of ‘if x, then y’ was used, ‘x’ referring to the challenge or prompt, and ‘y’ referring to the justificatory response. Justifications related to the concepts of ownership and were used as devices by those engaged in disputes to support their positions and provide reasons for their actions. The children drew upon these child-constructed rules as resources to use in disputes with their peers, in order to construct and maintain the social order of the block area in the classroom.

Processing of polycaprolactone and polycaprolactone-based copolymers into 3D scaffolds and their cellular responses

Synthetic polymers have attracted much attention in tissue engineering due to their ability to modulate biomechanical properties. This study investigated the feasibility of processing poly(varepsilon-caprolactone) (PCL) homopolymer, PCL-poly(ethylene glycol) (PEG) diblock, and PCL-PEG-PCL triblock copolymers into three-dimensional porous scaffolds. Properties of the various polymers were investigated by dynamic thermal analysis. The scaffolds were manufactured using the desktop robot-based rapid prototyping technique. Gross morphology and internal three-dimensional structure of scaffolds were identified by scanning electron microscopy and micro-computed tomography, which showed excellent fusion at the filament junctions, high uniformity, and complete interconnectivity of pore networks. The influences of process parameters on scaffolds' morphological and mechanical characteristics were studied. Data confirmed that the process parameters directly influenced the pore size, porosity, and, consequently, the mechanical properties of the scaffolds. The in vitro cell culture study was performed to investigate the influence of polymer nature and scaffold architecture on the adhesion of the cells onto the scaffolds using rabbit smooth muscle cells. Light, scanning electron, and confocal laser microscopy showed cell adhesion, proliferation, and extracellular matrix formation on the surface as well as inside the structure of both scaffold groups. The completely interconnected and highly regular honeycomb-like pore morphology supported bridging of the pores via cell-to-cell contact as well as production of extracellular matrix at later time points. The results indicated that the incorporation of hydrophilic PEG into hydrophobic PCL enhanced the overall hydrophilicity and cell culture performance of PCL-PEG copolymer. However, the scaffold architecture did not significantly influence the cell culture performance in this study.

The correlation of pore morphology, interconnectivity and physical properties of 3D ceramic scaffolds with bone ingrowth

In the design of tissue engineering scaffolds, design parameters including pore size, shape and interconnectivity, mechanical properties and transport properties should be optimized to maximize successful inducement of bone ingrowth. In this paper we describe a 3D micro-CT and pore partitioning study to derive pore scale parameters including pore radius distribution, accessible radius, throat radius, and connectivity over the pore space of the tissue engineered constructs. These pore scale descriptors are correlated to bone ingrowth into the scaffolds. Quantitative and visual comparisons show a strong correlation between the local accessible pore radius and bone ingrowth; for well connected samples a cutoff accessible pore radius of approximately 100 microM is observed for ingrowth. The elastic properties of different types of scaffolds are simulated and can be described by standard cellular solids theory: (E/E(0))=(rho/rho(s))(n). Hydraulic conductance and diffusive properties are calculated; results are consistent with the concept of a threshold conductance for bone ingrowth. Simple simulations of local flow velocity and local shear stress show no correlation to in vivo bone ingrowth patterns. These results demonstrate a potential for 3D imaging and analysis to define relevant pore scale morphological and physical properties within scaffolds and to provide evidence for correlations between pore scale descriptors, physical properties and bone ingrowth.