Lower Bones Research Articles

Systemic Therapy of Disseminated Myeloma in Passively Immunized Mice Using Measles Virus-infected Cell Carriers

Multiple myeloma (MM) is bone marrow plasma cell malignancy. A clinical trial utilizing intravenous administration of oncolytic measles virus (MV) encoding the human sodium-iodide symporter (MV-NIS) is ongoing in myeloma patients. However, intravenously administered MV-NIS is rapidly neutralized by antiviral antibodies. Because myeloma cell lines retain bone marrow tropism, they may be ideal as carriers for delivery of MV-NIS to myeloma deposits. A disseminated human myeloma (KAS 6/1) model was established. Biodistribution of MM1, a myeloma cell line, was determined after intravenous infusion. MM1 cells were found in the spine, femurs, and mandibles of tumor-bearing mice. Lethally irradiated MM1 cells remained susceptible to measles infection and transferred MV to KAS 6/1 cells in the presence of measles immune sera. Mice-bearing disseminated myeloma and passively immunized with measles immune serum were given MV-NIS or lethally irradiated MV-NIS-infected MM1 carriers. The antitumor activity of MV-NIS was evident only in measles naive mice and not in passively immunized mice. In contrast, survivals of both measles naive and immune mice were extended using MV-NIS-infected MM1 cell carriers. Hence, we demonstrate for the first time that systemically administered cells can serve as MV carriers and prolonged survival of mice with pre-existing antimeasles antibodies.

Inherited multicentric osteolysis: case report of three siblings treated with bisphosphonate

Inherited Multicentric Osteolysis (IMO) is an uncommon familial condition of idiopathic pathophysiology causing bone osteolysis and dysplasia. These patients present with common rheumatologic complaints of pain, dysfunction and disability, and are often initially misdiagnosed as a chronic rheumatic disease of childhood such as juvenile idiopathic arthritis. We report a case of three siblings diagnosed with IMO. Diagnosis was made during childhood, with each sibling having different manifestations and course of disease. One had a previous history of bilateral hip dysplasia. Two had osteolysis of the foot, distal tibia and femur (lower limb bones), whilst one had osteolysis of the rib and unusual clavicular fractures. Unusually, all siblings appear to experience decreased pain sensation compared to norms. All siblings were treated with bisphosphonates and experienced a rapid improvement in pain symptoms, decreased analgesic requirements. Two had bone mineral density testing performed and both had increases post-bisphosphonate. In all three, there was subjective evidence of stabilisation of bone disease. Testing for matrix metalloproteinase-2 (MMP2) gene was negative.

Fatigue-type stress fractures of the lower limb associated with fibrous cortical defects/non-ossifying fibromas in the skeletally immature

To investigate the association of a fatigue-type stress fracture and a fibrous cortical defect/non-ossifying fibroma (FCD/NOF) of the lower limb long bones in skeletally immature patients. The patient database of a specialist orthopaedic oncology centre was searched to determine the number of skeletally immature patients (<or=16 years of age) over an 18 year period with a lower limb long bone lesion ultimately shown to be a fatigue-type stress fracture. The diagnosis was established by a combination of typical imaging findings of a fatigue-type stress fracture, the absence of aggressive features suggestive of a sarcoma (e.g., interrupted periosteal reaction, cortical breach, and a soft-tissue mass) together with evidence of consolidation or healing on follow-up radiographs and resolution of symptoms over the subsequent weeks. The database was also used to determine the number of skeletally immature cases (<or=16 years of age) referred in the same period in which the principal lesion was shown to be a fibrous cortical defect (FCD) or non-ossifying fibroma (NOF) of the lower limb long bones. The clinical and imaging features of those cases common to both groups (i.e., with both a fatigue-type stress fracture and a FCD or NOF) were reviewed. Six percent of patients (five cases) referred to an orthopaedic oncology unit, who were subsequently shown to have a stress fracture of the lower limb long bones, were found to have a related FCD/NOF. All had been referred with a suggested diagnosis of a bone sarcoma and/or osteomyelitis. The possibility of a stress fracture had been raised in only one case. Four cases involved the proximal tibia and one the distal femur. Radiographs revealed that both lesions arose in the posteromedial cortex in all but one of the cases. The radiographs and magnetic resonance imaging (MRI) features were considered typical of the overlapping pathological features of the lesions. A sarcoma could be effectively excluded in the absence of true cortical destruction and soft-tissue extension. Both fatigue-type stress fractures and FCD/NOFs occur at similar sites in the long bones. It is postulated that the existence of the latter may cause localized weakening of the bone thereby predisposing to the development of a stress fracture. The co-existence of these two conditions in the skeletally immature should be recognized as the dual pathological processes may contribute to radiological misdiagnosis.

Structural behaviour and strain distribution of the long bones of the human lower limbs

Although stiffness and strength of lower limb bones have been investigated in the past, information is not complete. While the femur has been extensively investigated, little information is available about the strain distribution in the tibia, and the fibula has not been tested in vitro. This study aimed at improving the understanding of the biomechanics of lower limb bones by: (i) measuring the stiffness and strain distributions of the different low limb bones; (ii) assessing the effect of viscoelasticity in whole bones within a physiological range of strain-rates; (iii) assessing the difference in the behaviour in relation to opposite directions of bending and torsion. The structural stiffness and strain distribution of paired femurs, tibias and fibulas from two donors were measured. Each region investigated of each bone was instrumented with 8–16 triaxial strain gauges (over 600 grids in total). Each bone was subjected to 6–12 different loading configurations. Tests were replicated at two different loading speeds covering the physiological range of strain-rates. Viscoelasticity did not have any pronounced effect on the structural stiffness and strain distribution, in the physiological range of loading rates explored in this study. The stiffness and strain distribution varied greatly between bone segments, but also between directions of loading. Different stiffness and strain distributions were observed when opposite directions of torque or opposite directions of bending (in the same plane) were applied. To our knowledge, this study represents the most extensive collection of whole-bone biomechanical properties of lower limb bones.

Brief communication: Bone remodeling rates in Pleistocene humans are not slower than the rates observed in modern populations: A reexamination of Abbott et al. (1996)

Bone histomorphometry has been applied to the lower limb cortical bone of Pleistocene humans to establish age at death and to determine bone remodeling rates (Abbott et al.: Am J Phys Anthropol 226 (1996) 307-313). Both of these procedures require the determination of osteon density and mean osteon size. Previous analyses of Middle and Late Pleistocene human lower limb bones have produced bone remodeling rates that are slower than those determined in a more recent archeological sample. Recalculation of the data reported in Abbott et al.: Am J Phys Anthropol 226 (1996) 307-313) has revealed mathematical errors in the remodeling rates reported for the Pleistocene humans. The corrected remodeling rates for the Pleistocene group are similar to the values obtained in the more recent comparative sample.

Magnetic resonance imaging features of osseous manifestations of early acquired syphilis

We report the case of a 64-year-old man who initially presented with a maculopapular rash followed several weeks later by bilateral shin pain and infiltrative cutaneous lesions over the lower legs. The plain radiographs were not contributory, and the patient was referred for a whole-body bone scan, which demonstrated multifocal osseous lesions, including such lesions in the lower legs, skull and facial bones. Magnetic resonance imaging (MRI) demonstrated numerous small tibial and fibular nodular lesions involving the medullary cavity and the cortex. A diagnosis of acquired syphilis was made, based on skin biopsy. Results of serological testing were consistent with recent infection. The patient was treated with intramuscular injection of penicillin, and follow-up MRI demonstrated gradual resolution of the osseous lesions. Bone involvement is a relatively rare manifestation of early acquired syphilis. Although the plain radiographic features of the bony changes in acquired syphilis are well documented, there have been no reports of the magnetic resonance imaging findings in the appendicular skeleton.

Embryonic Development and Skeletogenesis of the Pharyngeal Jaw Apparatus in the Cichlid Nile Tilapia (Oreochromis niloticus)

The evolution of a specialized pharyngeal jaw apparatus (PJA) has been argued to be the key evolutionary innovation that allowed the explosive adaptive radiation of cichlid fishes in East African lakes. Subsequent studies together with recent molecular phylogenies have shown that similar innovations evolved independently several times within the teleosts, which poses the questions: (1) how similar are the developmental mechanisms responsible for these changes in divergent taxa and (2) how did such complex features arise independently in evolution? A detailed knowledge of PJA development in cichlids and other teleosts is needed to address these questions. Here, we provide a detailed account of the development of the PJA in one species of cichlid, the Nile tilapia (Oreochromis niloticus), from the early segmentation and patterning of its embryonic precursors - pharyngeal arches 3 to 7 - to its ossification. We find that pharyngeal segmentation occurs sequentially from anterior to posterior during early segmentation stages through the mid-pharyngula period. We show a clear combinatorial code of Hox gene expression such that each posterior arch is defined by a distinctive Hox signature. Posterior arch chondrogenesis in tilapia is essentially complete by the end of the hatching period, and most elements become ossified over the next two days. Our results reveal that both the fusion of lower jaw bones and articulation between the neurocranium and upper jaws occur during post-embryonic development.

Exchange nailing for infective non-union: A single centre experience

Study rationale: Exchange nailing has received little attention as a treatment modality for infective non-unions of lower extremity long bones. We therefore, present the results of exchange nailing performed for non-unions in the presence of active infection.

Van den Ende–Gupta syndrome: Evidence for genetic heterogeneity

van den Ende-Gupta syndrome is characterized by craniofacial and skeletal manifestations, mainly malar and/or maxillary hypoplasia, blepharophimosis, distinctive nose, lower lip eversion, arachnodactyly, camptodactyly, and long slender bones of hands and feet. Growth and development are normal. To date only 11 patients, from 8 families, have been described. Autosomal recessive inheritance has been accepted in this condition, supported by the presence of consanguinity in three families and the recurrence of the disorder within the offspring of unaffected couples. In this article we report on a kindred with three affected individuals, two brothers and their half-sister, in which the van den Ende-Gupta syndrome is probably transmitted as an autosomal dominant trait in connection with gonadal mosaicism.

Quantifying relative shape variation in modern human femora and humeri

Lower limb bones are thought to be more developmentally stable (more symmetric) than upper limb bones, presumably because of the functional importance of locomotion. However, the relative degree of canalization (limits on between‐individual variation) in the limbs is less clear. Here we assess the 3D shape variation between individuals in a sample of modern human femora and humeri.Femora and humeri from 47 human males were CT scanned and 7002 landmarks were distributed across the surface of the bone using a statistical shape atlas (Merkl and Mahfouz, 2007). Each bone was scaled by its first principal component score to remove size and size‐correlated shape, and then by maximum length so that the femora and humeri were the same size. Bone shape variation was assessed as the average root‐sum‐squared distances of bone vertices from their average positions within each element. Bootstrap samples (1000) were used to create distributions of shape variation for each bone type, and distributions were compared using an ANOVA.The analysis reveals that after accounting for differences in size and size‐correlated shape, the humerus is more variable in 3D shape than the femur (p&lt; 0.0001), indicating that the 3D shape of the femur is more canalized than the humerus.Grant Funding SourceNone

The Challenge of Identifying Commingled Skeletal Remains via CT Imaging and Morphometric Analysis

Human skeletal remains were discovered at a construction site in lower Manhattan. Officially determined that the post‐cranial material was not of medicolegal significance, our team undertook an anatomically driven forensic evaluation of the remains. Post‐cranial isolated bony elements were identified (n = 52), digitally photodocumented, morphometrically assessed and CT scanned for graphical examination. Post‐cranial commingled remains consisted mostly of lower limb bones from at least 3 distinct individuals based on three left cuboid bones found. 31 foot bones were measured and classified using bony landmarks. Comparison to homologous bones of known stature individuals was used to approximate the size differences found among the unknown sample. Maximum a‐p lengths of the three left cuboids measured 44.5, 35.8 and 35.6 mm while the two left calcaneal bones measured 89.2 and 77.5 mm. Size difference was used to group the tarsal bones to either the larger or two smaller individuals. CT imaging of adult femurs revealed their intensity of femoral curvature to fall within the Caucasian spectrum while overall rugosity of the larger bones indicated that the larger individual was male. A combination of CT, comparative and morphometric assessment was the key to overcoming the challenge of cataloging and identifying commingled skeletal remains, and may be the ideal approach for similar future forensic investigations.Grant Funding SourceNone

Bone micro-architecture and determinants of strength in the radius and tibia: age-related changes in a population-based study of normal adults measured with high-resolution pQCT

We recruited a population-based sample of 58 males and 74 females aged 20-79 from a primary care medical practice to provide normative and descriptive data for high-resolution peripheral quantitative computed tomography (pQCT) parameters. Important effects of ageing and contrasts in the effects of sex on the micro-architecture and strength of upper and lower limb bones were revealed. The advent of high-resolution pQCT scanners has permitted non-invasive assessment of structural data on cortical and trabecular bone. We investigated age-related changes in pQCT and finite element (FE) modelling parameters at the distal radius and distal tibia in a population-based cross-sectional study of 58 males and 74 females aged 20-79 years. Linear regression models including quadratic terms for age were used for inference. Age-related changes and sex differences were generally similar for pQCT parameters at the radius and tibia. At each site, mean values for bone density, cortical thickness and trabecular micro-architecture (number, separation and thickness) were lower (trabecular separation higher) in women than men. Changes with age were most apparent for bone density and cortical thickness, which declined with age, in contrast to trabecular micro-architecture parameters which were not significantly associated with age (p > 0.05) in either sex. Cortical bone density and thickness declined faster in women than men after age 50 and trabecular bone density was consistently lower in women. FE-analysis predicted failure load decreased with age and percentage of load carried by trabecular bone increased (p < 0.05). These data show contrasts in the effects of sex on the micro-architecture and strength of upper and lower limb bones with ageing. The faster decline in cortical bone thickness and density in women than men after age 50 and consistently lower trabecular bone density in women have implications for the excess risks of wrist and hip fractures in women.

A Test of Three Methods for Estimating Stature from Immature Skeletal Remains Using Long Bone Lengths*

In this study, the accuracy of three methods for stature estimation of children from long bone lengths was investigated. The sample utilized consists of nine identified immature skeletons (seven males and two females) of known cadaver length, aged between 1 and 14 years old. Results show that stature (cadaver length) is consistently underestimated by all three methods (from a minimum of 2.9 cm to a maximum of 19.3 cm). The femur/stature ratio provided the least accurate estimates of stature, and predictions were not significantly improved by the other two methods. Differences between true and estimated stature were also greatest when using the length of lower limb bones. Given that the study sample children grew in less than optimal environmental conditions, compared with the children that contributed to the development of the methods, they are stunted and have proportionally shorter legs. This suggests that stature estimation methods are not universally applicable and that environmental differences within a population (e.g., socioeconomic status differences) or differing levels of modernization and social and economic development between nations are an important source of variation in stature and body proportions of children. The fallibility of stature estimation methods, when they do not consider such variation, can be somewhat minimized if stature is estimated from the length of upper limb bones.

Diagnosis and management of nasal fractures

The nasal bony–cartilaginous framework provides support to the nose and maintains airway patency. The cartilaginous and bony components are both susceptible to fracture. Nasal fractures are one of the most common facial injuries, occurring across a broad spectrum of age groups. Inadequate acute injury treatment can lead to persistent airway obstruction and nasal deformities that are subsequently more difficult to correct. Herein we discuss common presentations of nasal fractures, classifications, and options for treatment.

Assessment of Response to Therapy in Primary Myeloid Sarcoma Using Positron Emission Tomography/Computer Tomography Imaging: A Case Report

Myeloid sarcoma or chloroma, an extramedullary myeloid tumor, is observed in a minority of patients with acute non-lymphocytic leukaemia. Very few cases may present without bone marrow involvement (i.e., primary myeloid sarcoma). Among the various sites of disease manifestation reported, solitary bone lesions may occur. Diagnosis and, even more so, assessment of response to systemic therapy is strikingly more difficult than in systemic disease, i.e. acute leukaemia. We report the case of a patient diagnosed with primary myeloid sarcoma involving thoracic vertebral bones and associated with spinal cord compression. Here, positron emission tomography/computer tomography imaging allowed assessment of the initial extent of the disease as well as the response to a combined radiochemotherapeutic approach.A male, 60 years old patient presented with pain in the flanks extending to the left leg. MRI imaging revealed an intraspinal mass in close proximity to the eleventh thoracic vertebral bone. Surgical resection of the mass including biopsy of the vertebral bone allowed the histopathological diagnosis of a myeloid sarcoma. Upon presentation, the assessment of bone marrow and meningeal involvement yielded negative results. MRI imaging revealed changes suggestive of residual manifestations albeit remaining inconclusive with regard to an enhancement secondary to the surgical intervention.PET/CT imaging revealed a distinct signal located to the eleventh vertebral bone as a result of enhanced metabolic turnover (SUV 8.8) that was interpreted as active myelosarcoma tissue. Induction chemotherapy was initiated consisting of high-dose Ara C and Mitoxantrone (HAM). Following induction therapy, PET/CT assessment showed no change in metabolic activity. Extended field radiation therapy was performed, involving the two adjacent upper and lower vertebral bones, with a total dose of 30 Gy. This time, response assessment via PET/CT showed only a slight enhancement in metabolic turnover, suggestive of remission. As a consolidation, high dose Ara C therapy was initiated. Until now the patient is fine and shows no sign of residual myeloid sarcoma.PET/CT in this case was the only method which reliably allowed the assessment of tumor location, extent and activity in a previously operated vertebral bone and, as a tool for the assessment of response, was guiding therapeutic decisions. In our opinion, the exposure to substantial radiation exposure due to PET/CT imaging is outweighed by the obvious diagnostic benefit.

Increased Bone Alkaline Phosphatase and Isolated Subcortical Bone Uptake of Technetium-99m Hydroxymethylene Diphosphonate in the Lower Extremities in a Patient with Graves' Disease: A Distinctly Unusual Variant of Graves' Acropachy

Thyroid acropachy is an extreme manifestation of autoimmune thyroid disease characterized by soft tissue swelling and periosteal bone changes, usually occurring in the fingers, toes, and lower extremities. Here, a patient with a distinctly unusual variant of thyroid acropachy is presented. The patient was a 48-year-old woman with Graves' disease and mild ophthalmopathy, who was euthyroid after treatment with Methimazole. Because of a persistently elevated serum alkaline phosphatase (ALP) with elevated bone fraction, a bone scan was performed. This showed increased uptake in the subcortical areas of the lower extremity bones. On questioning, she admitted to mild pain in her lower extremities. She had no other features of thyroid acropachy. Secondary causes of increased ALP, such as cancer, liver disease, and vitamin D deficiency, were excluded by appropriate tests. Therefore, and in view of the patient's underlying Graves' disease, a diagnosis of thyroid acropachy was made. Periosteal reaction in the long bones of the lower extremities is unusual in thyroid acropachy, and when it occurs, it is more likely to be associated with overt pain or prominent extrathyroidal manifestations of Graves' disease. This patient very likely had a variant of thyroid acropachy. This variant may be underreported because of its generally asymptomatic nature.

Sexual dimorphism in diaphyseal cross‐sectional shape in the medieval Muslim population of Écija, Spain, and Anglo‐Saxon Great Chesterford, UK

AbstractDifferences in adult male and female activity patterns may influence levels of sexual dimorphism in physical dimensions, including the cross‐sectional shape of long bone diaphyses. Previous studies of archaeological populations have demonstrated significant differences in diaphyseal shape between males and females. In this study, dimorphism in external diaphyseal shape of upper and lower limb bones (reflected in indices of external diaphyseal diameters), and bilateral asymmetry in these indices, were examined in two medieval populations: Muslim Écija (Spain) and Anglo‐Saxon Great Chesterford (UK). Attempts were made to relate observed patterns to documentary and other osteological evidence for differences in male and female activity patterns. While few significant differences in upper limb bone cross‐sectional shape were observed in either population, significant differences in shape were found in the lower limb diaphyses at Écija at the femoral midshaft and tibial foramen and midshaft levels, and at the tibial midshaft for Great Chesterford. Comparison with published data suggests that these differences are marked for Écija, and perhaps fairly high for Great Chesterford compared with other populations with an agriculture‐based economy. This is consistent with documentary and osteological evidence suggesting marked gender differences in behaviour in medieval Muslim Spain. No significant differences in bilateral asymmetry were found, but the effects of small sample size cannot be ruled out. Copyright © 2008 John Wiley &amp; Sons, Ltd.

Uma Peculiar Tafocenose Controlada por Ação Biogênica no Triássico Médio do Rio Grande do Sul, Brasil

We present here an outcrop with a peculiar fossil assemblage, including a distinct taphocoenosis in comparison to other fossiliferous outcrops of the Santa Maria Formation (Triassic, Paraná Basin). Fossil concentration in this outcrop is made-up of herbivorous non-mammalian cynodonts (Synapsida, Therapsida) only, tentatively assigned to Massetognathus. The taphocoenosis is characterized by the accumulation of bones within a restricted area, with predominance of skull and mandible remains, almost always disarticulated. Bones are mainly disarticulated and chaotically oriented in a massive, red-colored, muddy matrix. Both the nature of rock matrix and the absence of azimuthal orientation of the bones in the taphocoenosis indicated that tractive currents were not the main process responsible by the accumulation of those fossil remains, mainly skull and lower jaws bones. These are considered the less nutritious bone parts of the vertebrate skeleton and according to this, the skulls and lower jaws were left behind by selective scavengers that removed the more nutritious parts. So, this taphonomic model of preservation led us to the hypothesis of a biogenic concentration for this taphocoenosis based upon at the interpretation of this outcrop as a site of concentration of bones by selective scavengers.

Effects of Restricted Calcium Intake on Bone and Maxillofacial Growth

To investigate the effects of a low calcium diet on maxillofacial development by evaluating Bone Mineral Content (BMC) in the lower alveolar bones, femurs, and tibias and by performing cephalometry on growing rats. Thirty 5-week-old male Wistar rats were randomly divided into 3 groups; the control group (n = 10) was given standard diet for 6 weeks, the low calcium/standard diet group (n = 10) was given a calcium-restricted diet for the first 4 weeks, and then a standard diet for the following 2 weeks, and the low calcium diet group (n = 10) was given the calcium-restricted diet for 6 weeks. After the rats were euthanized, heads and legs were fixed and cephalometry was performed. Next, mandibles, femurs and tibias were digitally photographed and the BMC was evaluated using our newly developed software. The BMC was decreased in all of the bone samples from the two groups that received restricted calcium. In the low calcium/standard diet group, the BMC recovered the most in the tibias and least in the lower alveolar bones. Development of the mandibles in the anterior-posterior direction was accelerated, while that in the superior-inferior direction was inhibited in those rats. The BMC reduction following calcium deficiency in the lower alveolar bone hardly recovers, so prevention is important. Development of the mandible in a superior-inferior direction is inhibited while that in an anterior-posterior direction is accelerated due to a calcium-restricted diet.

Decreasing Intracellular Superoxide Corrects Defective Ischemia-induced New Vessel Formation in Diabetic Mice

Tissue ischemia promotes vasculogenesis through chemokine-induced recruitment of bone marrow-derived endothelial progenitor cells (EPCs). Diabetes significantly impairs this process. Because hyperglycemia increases reactive oxygen species in a number of cell types, and because many of the defects responsible for impaired vasculogenesis involve HIF1-regulated genes, we hypothesized that HIF1 function is impaired in diabetes because of reactive oxygen species-induced modification of HIF1alpha by the glyoxalase 1 (GLO1) substrate methylglyoxal. Decreasing superoxide in diabetic mice by either transgenic expression of manganese superoxide dismutase or by administration of an superoxide dismutase mimetic corrected post-ischemic defects in neovascularization, oxygen delivery, and chemokine expression, and normalized tissue survival. In hypoxic fibroblasts cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the EPC mobilizing chemokine stromal cell-derived factor-1 (SDF-1) and of vascular epidermal growth factor, which modulates growth and differentiation of recruited EPCs. In hypoxic EPCs cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the SDF-1 receptor CXCR4, and endothelial nitric-oxide synthase, an enzyme essential for EPC mobilization. HIF1alpha modification by methylglyoxal reduced heterodimer formation and HIF1alpha binding to all relevant promoters. These results provide a basis for the rational design of new therapeutics to normalize impaired ischemia-induced vasculogenesis in patients with diabetes.