Quantitative Ultrasound of Proximal Phalanxes in Childhood Acute Lymphoblastic Leukemia Survivors.

Reduced bone mineral density (BMD) is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors; the optimal method to assess BMD is still debated. We studied BMD by quantitative ultrasound (QUS) in 72 ALL survivors, and evaluated any correlation with cumulative doses of steroids and cytotoxic agents. Mean age at diagnosis was 61±45 months, while mean age at QUS was 318.3±129.6 months; mean period of follow-up was 41.2±37.8 months. Mean amplitude-dependent speed of sound z-score was -1.22±1.19. Ten survivors (13.8%) presented a z-score below -2 SD. A negative correlation was found between amplitude-dependent speed of sound z-score and age at diagnosis (P=0.01). A positive correlation was observed with length of follow-up (P=0.01). No correlation was found with cytotoxic drugs. This study represents the largest cohort of childhood ALL survivors studied by QUS. Our results suggest that QUS for its characteristics of being radiation free may be an effective option to assess BMD in pediatric age. In addition, our data outline the importance to improve the awareness about the specific expression of this complication in the pediatric age, concerning the major determinants of bone impairment, which are the disease itself and the phase of bone growth when the disease occurs.

A computational model for the joint onset and development.

Joints connect the skeletal components and enable movement. The appearance and development of articulations is due to different genetic, biochemical, and mechanical factors. In the embryonic stage, controlled biochemical processes are critical for organized growth. We developed a computational model, which predicts the appearance, location, and development of joints in the embryonic stage. Biochemical events are modeled with reaction diffusion equations with generic molecules representing molecules that 1) determine the site where the articulation will appear, 2) promote proliferation, and matrix synthesis, and 3) define articular cartilage. Our model accounts for cell differentiation from mesenchymal cells to pre-cartilaginous cells, then cartilaginous cells, and lastly articular cartilage. These reaction-diffusion equations were solved using the finite elements method. From a mesenchymal 'bud' of a phalanx, the model predicts growth, joint cleavage, joint morphology, and articular cartilage formation. Our prediction of the gene expression during development agrees with molecular expression profiles of joint development reported in literature. Our computational model suggests that initial rudiment dimensions affect diffusion profiles result in Turing patterns that dictate sites of cleavage thereby determining the number of joints in a rudiment.

Tissue engineering a human phalanx.

A principal purpose of tissue engineering is the augmentation, repair or replacement of diseased or injured human tissue. This study was undertaken to determine whether human biopsies as a cell source could be utilized for successful engineering of human phalanges consisting of both bone and cartilage. This paper reports the use of cadaveric human chondrocytes and periosteum as a model for the development of phalanx constructs. Two factors, osteogenic protein-1 [OP-1/bone morphogenetic protein-7 (BMP7)], alone or combined with insulin-like growth factor (IGF-1), were examined for their potential enhancement of chondrocytes and their secreted extracellular matrices. Design of the study included culture of chondrocytes and periosteum on biodegradable polyglycolic acid (PGA) and poly-l-lactic acid (PLLA)-poly-ε-caprolactone (PCL) scaffolds and subsequent implantation in athymic nu/nu (nude) mice for 5, 20, 40 and 60 weeks. Engineered constructs retrieved from mice were characterized with regard to genotype and phenotype as a function of developmental (implantation) time. Assessments included gross observation, X-ray radiography or microcomputed tomography, histology and gene expression. The resulting data showed that human cell-scaffold constructs could be successfully developed over 60 weeks, despite variability in donor age. Cartilage formation of the distal phalanx models enhanced with both OP-1 and IGF-1 yielded more cells and extracellular matrix (collagen and proteoglycans) than control chondrocytes without added factors. Summary data demonstrated that human distal phalanx models utilizing cadaveric chondrocytes and periosteum were successfully fabricated and OP-1 and OP-1/IGF-1 accelerated construct development and mineralization. The results suggest that similar engineering and transplantation of human autologous tissues in patients are clinically feasible. Copyright © 2016 John Wiley & Sons, Ltd.

Relation between phalangeal bone mineral density and radiographic knee osteoarthritis: a cross-sectional study.

BACKGROUND: Major reports have suggested that bone mineral density (BMD) is higher in patients with osteoarthritis (OA), while other studies do not agree. Our aim was to examine the cross-sectional association between phalangeal BMD and radiographic knee OA. METHODS: A total of 2855 participants were included in this study. Radiographic knee OA was defined as Kellgren-Lawrence (K-L) Grade ≥ 2 in at least one leg. BMD scans of the middle phalanges of the second, third and fourth digits of the nondominant hand were performed with a compact radiographic absorptiometry system (Alara MetriScan®). A multivariable logistic analysis model was applied to test the relation between phalangeal BMD with radiographic knee OA, the presence of knee osteophytes (OSTs), and knee joint space narrowing (JSN) after adjusting for a number of potential confounding factors. RESULTS: The multivariable-adjusted odds ratios with 95 % confidence intervals [ORs (95 % CI)] of radiographic knee OA across phalangeal BMDs were 1.08 (95 % CI 0.89-1.32) and 0.62 (95 % CI 0.45-0.86), respectively. The P for trend was 0.09. For the female population, the multivariable-adjusted ORs (95 % CI) of radiographic knee OA across phalangeal BMD were 1.01 (95 % CI 0.73-1.37) and 0.58 (95 % CI 0.38 - 0.87), respectively. The P for trend was 0.02. This positive finding, however, did not exist in the male subgroup. There was a significantly lower prevalence of OST in the osteoporosis (OP) group than in the normal group (OR = 0.59, 95 % CI 0.40-0.88; P for trend was 0.01). In contrast, the prevalence of JSN was significantly higher in the osteopenia group (OR = 1.22, 95 % CI 1.00-1.48) and the OP group (OR = 1.35, 95 % CI 1.00-1.84) than in the normal group. The P for trend was 0.02. CONCLUSIONS: This study observed lower odds for the presence of radiographic knee OA and OST in OP patients than in normal subjects. The prevalence of JSN was higher in the osteopenia and OP groups than in normal subjects.

Clinicopathological features of five unusual cases of intraosseous myoepithelial carcinomas, mimicking conventional primary bone tumours, including EWSR1 rearrangement in one case.

Primary intraosseous myoepithelial tumours, including carcinomas are rare tumours. The concept of histopathological spectrum of these tumours is evolving. We describe clinicopathological and immunohistochemical features of five myoepithelial carcinomas, including molecular cytogenetic results in one case. There were five male patients within age-range of 8-40 years (median = 26). Four tumours occurred in the long bones, including two tumours, each, in the femur and fibula, respectively, while a single tumour occurred in the proximal phalanges. Tumour size (n = 3 cases) varied from 5.6 to 8.6 cm. On radiological imaging, most tumours appeared as expansile, lytic and destructive lesions. Two tumours appeared as sclerotic lesions. Two cases were referred with diagnoses of chondrosarcomas and a single case was referred with two different diagnoses, including an adamantinoma and an osteosarcoma. Histopathological examination in all these cases showed multinodular tumours comprising mostly polygonal cells, exhibiting moderate nuclear atypia and interspersed mitotic figures within a stroma containing variable amount of myxoid, chondroid, hyalinised and osteoid-like material. Three tumours revealed prominent squamous differentiation. By immunohistochemistry, tumour cells were positive for EMA (5/5), pan CK (AE1/AE3) (3/3), CK5/6 (4/4), CK MNF116 (1/1), S100 protein (5/5) and GFAP (3/5). The first tumour revealed EWSR1 rearrangement. The first patient, 10 months after tumour resection and a simultaneous lung metastatectomy, is free-of-disease (FOD). The second patient, 11 months after tumour resection is FOD. The third and fourth patients underwent wide resections and are on follow-up. The fifth patient underwent resections, including a lung metastatectomy. Primary intraosseous myoepithelial carcinomas are rare and mimic conventional primary bone tumours. Some primary intraosseous myoepithelial carcinomas display EWSR1 rearrangement. Squamous differentiation may be considered as an addition to their evolving histopathological spectrum. Immunohistochemical stains constitute as a necessary tool for arriving at the correct diagnosis in such cases, which has treatment implications. Surgical resection remains the treatment mainstay.

Endogenous bone regeneration is dependent upon a dynamic oxygen event.

Amputation of the digit tip within the terminal phalangeal bone of rodents, monkeys, and humans results in near-perfect regeneration of bone and surrounding tissues; however, amputations at a more proximal level fail to produce the same regenerative result. Digit regeneration is a coordinated, multifaceted process that incorporates signaling from bioactive growth factors both in the tissue matrix and from several different cell populations. To elucidate the mechanisms involved in bone regeneration we developed a novel multi-tissue slice-culture model that regenerates bone ex vivo via direct ossification. Our study provides an integrated multi-tissue system for bone and digit regeneration and allows us to circumvent experimental limitations that exist in vivo. We used this slice-culture model to evaluate the influence of oxygen on regenerating bone. Micro-computed tomography (µCT) and histological analysis revealed that the regenerative response of the digit is facilitated in part by a dynamic oxygen event, in which mutually exclusive high and low oxygen microenvironments exist and vacillate in a coordinated fashion during regeneration. Areas of increased oxygen are initially seen in the marrow and then surrounding areas of vasculature in the regenerating digit. Major hypoxic events are seen at 7 days postamputation (DPA 7) in the marrow and again at DPA 12 in the blastema, and manipulation of oxygen tensions during these hypoxic phases can shift the dynamics of digit regeneration. Oxygen increased to 21% oxygen tension can either accelerate or attenuate bone mineralization in a stage-specific manner in the regenerative timeline. These studies not only reveal a circumscribed frame of oxygen influence during bone regeneration, but also suggest that oxygen may be one of the primary signaling influences during regeneration.

Bone density gain at proximal phalanges in healthy males aged 18-25 years after 16 weeks of upper-arm muscle weight training.

AIM: The aim of this study was to determine the effect of an upper-arm muscle weight training (WT) protocol over 16 weeks on bone density at the proximal phalanges in young healthy men. METHODS: Fifty-one healthy volunteer men were selected, 16 for an experimental group and 35 for a control group. The experimental group was submitted to the prescribed WT protocol to develop the strength of upper arm muscles, during 16 weeks, at a frequency of 3 times per week for approximately 60 min per session. Anthropometric data (weight, height, body mass index, corrected mid upper-arm circumference [cMUAC], and percentage of upper-arm muscle mass [%UAMM]) and bone density by quantitative ultrasound (DBM Sonic BP, IGEA, Italy) at proximal phalanges (amplitude dependent speed of sound [AD-SoS], T-score, %T-score) were evaluated on non-dominant limb before the beginning of the study (T0) and after 16 weeks (T1). RESULTS: There were no significant differences among all variables at T0 and T1 in the control group, nor at T0 between both groups. In the experimental group, cMUAC, %UAMM, AD-SoS, T-score and %T-score were significantly higher at T1 in relation to T0, as well as between T1 of the experimental group and T1 of the control group (all with P<0.0001). The gain of %T-score showed a correlation between cMUAC gain (P=0.005) and %UAMM gain (P=0.002). The experimental group showed 7% of bone mass gain. CONCLUSION: These data suggested that a WT protocol to develop strength of upper arm muscles over 16 weeks was effective for increasing bone density at the proximal phalanges in healthy young men.