Intra-operator Repeatability of Manual Segmentations of the Hip Muscles on Clinical Magnetic Resonance Images.

The manual segmentation of muscles on magnetic resonance images is the gold standard procedure to reconstruct muscle volumes from medical imaging data and extract critical information for clinical and research purposes. (Semi)automatic methods have been proposed to expedite the otherwise lengthy process. These, however, rely on manual segmentations. Nonetheless, the repeatability of manual muscle volume segmentations performed on clinical MRI data has not been thoroughly assessed. When conducted, volumetric assessments often disregard the hip muscles. Therefore, one trained operator performed repeated manual segmentations (n = 3) of the iliopsoas (n = 34) and gluteus medius (n = 40) muscles on coronal T1-weighted MRI scans, acquired on 1.5 T scanners on a clinical population of patients elected for hip replacement surgery. Reconstructed muscle volumes were divided in sub-volumes and compared in terms of volume variance (normalized variance of volumes - nVV), shape (Jaccard Index-JI) and surface similarity (maximal Hausdorff distance-HD), to quantify intra-operator repeatability. One-way repeated measures ANOVA (or equivalent) tests with Bonferroni corrections for multiple comparisons were conducted to assess statistical significance. For both muscles, repeated manual segmentations were highly similar to one another (nVV: 2-6%, JI > 0.78, HD < 15 mm). However, shape and surface similarity were significantly lower when muscle extremities were included in the segmentations (e.g., iliopsoas: HD -12.06 to 14.42 mm, P < 0.05). Our findings show that the manual segmentation of hip muscle volumes on clinical MRI scans provides repeatable results over time. Nonetheless, extreme care should be taken in the segmentation of muscle extremities.

Computational dosimetry in MRI in presence of hip, knee or shoulder implants: do we need accurate surgery models?

Objective.To quantify the effects of different levels of realism in the description of the anatomy around hip, knee or shoulder implants when simulating, numerically, radiofrequency and gradient-induced heating in magnetic resonance imaging. This quantification is needed to define how precise the digital human model modified with the implant should be to get realistic dosimetric assessments.Approach. The analysis is based on a large number of numerical simulations where four 'levels of realism' have been adopted in modelling human bodies carrying orthopaedic implants.Main results. Results show that the quantification of the heating due to switched gradient fields does not strictly require a detailed local anatomical description when preparing the digital human model carrying an implant. In this case, a simple overlapping of the implant CAD with the body anatomy is sufficient to provide a quite good and conservative estimation of the heating. On the contrary, the evaluation of the electromagnetic field distribution and heating caused by the radiofrequency field requires an accurate description of the tissues around the prosthesis.Significance. The results of this paper provide hints for selecting the 'level of realism' in the definition of the anatomical models with embedded passive implants when performing simulations that should reproduce, as closely as possible, thein vivoscenarios of patients carrying orthopaedic implants.

Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice.

Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders.

MHC class II transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity.

The molecular networks controlling bone homeostasis are not fully understood. The common evolution of bone and adaptive immunity encourages the investigation of shared regulatory circuits. MHC Class II Transactivator (CIITA) is a master transcriptional co-activator believed to be exclusively dedicated for antigen presentation. CIITA is expressed in osteoclast precursors, and its expression is accentuated in osteoporotic mice. We thus asked whether CIITA plays a role in bone biology. To this aim, we fully characterized the bone phenotype of two mouse models of CIITA overexpression, respectively systemic and restricted to the monocyte-osteoclast lineage. Both CIITA-overexpressing mouse models revealed severe spontaneous osteoporosis, as assessed by micro-computed tomography and histomorphometry, associated with increased osteoclast numbers and enhanced in vivo bone resorption, whereas osteoblast numbers and in vivo bone-forming activity were unaffected. To understand the underlying cellular and molecular bases, we investigated ex vivo the differentiation of mutant bone marrow monocytes into osteoclasts and immune effectors, as well as osteoclastogenic signaling pathways. CIITA-overexpressing monocytes differentiated normally into effector macrophages or dendritic cells but showed enhanced osteoclastogenesis, whereas CIITA ablation suppressed osteoclast differentiation. Increased c-fms and receptor activator of NF-κB (RANK) signaling underlay enhanced osteoclast differentiation from CIITA-overexpressing precursors. Moreover, by extending selected phenotypic and cellular analyses to additional genetic mouse models, namely MHC Class II deficient mice and a transgenic mouse line lacking a specific CIITA promoter and re-expressing CIITA in the thymus, we excluded MHC Class II expression and T cells from contributing to the observed skeletal phenotype. Altogether, our study provides compelling genetic evidence that CIITA, the molecular switch of antigen presentation, plays a novel, unexpected function in skeletal homeostasis, independent of MHC Class II expression and T cells, by exerting a selective and intrinsic control of osteoclast differentiation and bone resorption in vivo.

In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.

Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [alpha1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases.

Multiscale modelling of the skeleton for the prediction of the risk of fracture.

BACKGROUND: The development of a multiscale model of the human musculoskeletal system able to accurately predict the risk of bone fracture is still a grand challenge. The aim of this paper is to present the Living Human Project, to describe the final system and to review the achievements obtained so far. The Living Human musculoskeletal supermodel is conceived as the interconnection of five interdependent sub-models: the continuum, the boundary condition, the constitutive equation, the remodelling history and the failure criterion sub-models. METHODS: Methods are available to develop accurate subject-specific finite element models of bones that can incorporate the subject's tissue-density distribution and empirically derived constitutive laws. Anatomo-functional musculoskeletal models can be registered with gait analysis data to predict muscle and joint forces acting on the patient's skeleton during gait. These are the boundary conditions for the continuum models that showed an average error of 12% in the prediction of the failure load. Still, the entire supermodel is defined as a collection of procedural macros to predict the risk of fracture and should be improved. FINDINGS: Even with these limitations, the organ-level model already found some clinically relevant applications, especially in the analysis of joint prostheses. Also, the body-organ level multiscale model finds some clinical applications in paediatric skeletal oncology. The tissue- and the cell-level models are not yet fully validated. Thus, they cannot be safely used in clinical applications. INTERPRETATION: The continuum sub-model is the most mature model available. More powerful methods are needed for the generation of anatomo-functional musculoskeletal models. Muscle force prediction should be improved, investigating new probabilistic approaches to identify the neuro-motor strategy. The changes of the tissue properties in the various regions of the skeleton and predictive remodelling models should be included. An adequate information technology infrastructure should be developed to support collaborative work and integration of different sub-models.

TRAIL inhibits osteoclastic differentiation by counteracting RANKL-dependent p27Kip1 accumulation in pre-osteoclast precursors.

Experimental evidences indicate that the TNF family member TNF-related apoptosis inducing ligand (TRAIL) might be involved in modulating osteoclastic differentiation. The ability of recombinant soluble TRAIL to affect bone density in vivo was evaluated by using 4-week-old mice subcutaneously (s.c.) injected with TRAIL for 8 days. TRAIL injection induced a significant increase of tibia trabecular thickness and total bone mass in 4-week-old mice, accompanied by a significant decrease of TRAP serum levels, without modulation of osteocalcin and osteoprotegerin (OPG). Parallel experiments performed in vitro showed that inhibition of osteoclastic differentiation, induced by treatment of human peripheral blood osteoclast precursors with TRAIL, was associated to inhibition of receptor activator of nuclear factor kappa B ligand (RANKL)-induced accumulation of p27(Kip1). The potential role of p27(Kip1) pathway in mediating the anti-osteoclastic activity of TRAIL was further suggested by in vitro gene knock-down experiments performed in osteoclast precursor cultures. Taken together, our data strongly suggest that recombinant TRAIL inhibits osteoclastogenesis by inducing the ubiquitin-mediated degradation of p27(Kip1).

Specialised CT scan protocols for 3-D pre-operative planning of total hip replacement.

X-ray computer tomography (CT) provides an accurate source of information in orthopaedics. Many computer aided orthopaedic surgery systems are based on CT images; thus, obtaining high resolution images is important. However, this may result in an excessive radiation dose for the patient. This study is aimed at developing a special CT scanning protocol for the hip region that can be adopted in clinical practise for 3-D pre-operative planning of total hip replacement surgery. Optimisation of CT acquisition parameters is investigated for both axial and spiral CT and the two resulting protocols are compared in terms of effective radiation dose to the patient. Results show that spiral CT with D=3 and P=1.5 in regions with higher morphological and density gradients and D=5 and P=1.5 in regions where the morphology is more regular degrades the image quality slightly but allows acquisition of a higher number of images at comparable costs, increasing the longitudinal resolution of the acquired data set. The effective dose is comparable to that of a standard pelvic CT exam. Adjusting the axial CT scan parameters the effective dose can be reduced, however lowering the accuracy of 3-D bone geometry reconstruction.