Bone Quality: The Mechanical Effects of Microarchitecture and Matrix Properties

In this body of work we have examined some of the current concepts pertaining to the relation between bone mass, bone quality and the mechanical properties of bone. In our first series of studies we used a model of human osteoarthritis to investigate the implications of changes in the effective tissue modulus. Having established that the material properties of the trabecular bone were altered in the earliest stages of osteoarthritis, we then investigated a possible cause, namely the breakdown or denaturation of bone collagen. Our original hypothesis was that damage at the micro scale originates at the molecular scale and that an assay of denatured collagen would refl ect the first stages of the accumulation of microdamage in bone. Although we found a significant increase in the amount of denatured collagen in early osteoarthritis, our hypothesis regarding its mechanical origin turned out to be unlikely. This points to two alternate possibilities; that either the breakdown of collagen was of an enzymatic nature, or that the quality of the original collagen was poor. In the final investigation of this series we studied the implications of a reduction of the effective tissue modulus in the presence of a normal adaptive bone response. In this study we found that when local bone strain was used as the stimulus for the mechanosensory system a reduction of the local stiffness of the bone material would result in stiffening of the bone material at the organ level. Put in a simpler way, we determined that sclerotic thickening of the subchondral bone plate could result in a stiffer plate, even if the bone material was inferior. In our second series, we investigated the effects of high dose bisphosphonate treatment in a canine model. This was part of a larger effort to quantify the effects of bisphosphonates on bone quality (150, 164, 250). Our original hypothesis was that, in addition to increasing bone mass and architectural quality, bisphosphonate treatment would result in a more mature (i.e. highly mineralized) bone matrix. This higher level of mineralization would then result in a stiffer material with improved matrix qualities. Again, we were surprised by our results! We found that any improvements in the stiffness that we could detect were due to changes in bone mass and micro-architecture alone. We also found a large, but expected, increase in the amount of microdamage present. It remains to be seen whether a similar accumulation of microdamage will occur in humans treated at clinical dosages. As is often the case in medicine, there is no easy way to improve the quality of the bone, and when not considered carefully, side effects of a treatment could be detrimental to its effi cacy. In our third series of studies we focused on the contributions of micro-architecture to bone mechanics. First we evaluated some of the morphometric tools used to quantify architecture. We found that use of the parallel plate model led to volume fraction dependant biases and recommend that direct three dimensional methods should be used whenever possible. Through the BIOMED 1 project and the Gift of Hope Organ and Tissue Donor network (not to mention the generosity of the donor’s families and the staff members who collected these specimens) Summary we acquired a unique selection of trabecular bone specimens. We used these specimens to quantify how bone architecture varied both between people and locations in the body. First, we examined the relation between bone mass and architecture. The general question that we asked could be expressed as; “If you have a certain amount of bone, in how many ways is it typically arranged?” We quantifi ed the arrangement of this bone using microCT in conjunction with standard three-dimensional morphometric measures. By using finite element models of the trabecular structure we could fully characterize the influence of microarchitecture on mechanics without considering possibly confounding matrix-level effects. In the BIOMED dataset we had samples from multiple clinically relevant sites and a wide range of donors. This provided an ideal data set to examine the effect of skeletal site. In the GOH dataset we had a large number of specimens from a small number of sites and a moderately large number of donors (this was particularly true with regards to the proximal tibia). This data set was well suited for investigating how the structure of trabecular bone varied between different people. In this analysis we found that even after correcting for the amount of bone present (BV/TV) there were indeed particular aspects of the architecture that were site specifi c. We concluded that this was probably due to differences in the mechanical function of the bone at these different sites. We also saw large differences in the bone architecture between people with equal bone mass. We could supply a striking visual representation of this by choosing 4 extreme donors from our data. For these donors, at this anatomic site, it seems that having a highly connected bone structure comes at the expense of having thin trabeculae. A small supplemental study of these four donors led us, once again, to some surprising results. Although the structure of the bone varied widely between these donors, the relation between the amount of bone present and the stiffness in the main loading direction was unaffected. It was only in the minor loading directions and in shear that the differences in architecture seemed to affect the mechanics. It had been previously demonstrated that including a morphometric measure of anisotropy improves the estimation of mechanical properties as opposed to using density alone (38, 171, 189). In our supplemental study, the differences that we observed on the minor axes as opposed to the main loading axis indicate different levels of mechanical anisotropy between these donors. If these differences could be quantified using a measure of morphometric anisotropy alone we should have been able to derive a general constitutive relation for our population i.e. by using a predictive model based on both bone mass and morphometric anisotropy we should be able to predict the mechanical properties for any donor. We tested this hypothesis by evaluating 3 different relations between the morphology and the bone’s elastic properties. Although adding anisotropy resulted in strong increases in the predictive power of the models, there were still strong site-dependant and donor-dependant differences. Unsatisfied with this result we decided to extend the one of the current models to include additional morphometric parameters. A principal components analysis demonstrated the morphology could generally be described by 3 components; one related to bone mass, one to connectivity and the last to anisotropy. We found that by including parameters such as trabecular spacing or connectivity density in the model we could improve the prediction of the model by about 20% and eliminate much of the residual error that was associated with donor and anatomic site. Although the observed improvement in predicting the mechanical properties was small, it was sufficient to validate the concept that microarchitecture does indeed influence bone mechanics. Concluding this portion of the thesis, we have demonstrated that inter-site and inter-individual differences exist in bone quality as measured by trabecular micro-architecture and that these differences can be, for a large part, quantified using existing morphometric parameters

Parallel plate model for trabecular bone exhibits volume fraction-dependent bias

Unbiased stereological methods were used in conjunction with microcomputed tomographic (micro-CT) scans of human and animal bone to investigate errors created when the parallel plate model was used to calculate morphometric parameters. Bone samples were obtained from the human proximal tibia, canine distal femur, rat tail, and pig spine and scanned in a micro-CT scanner. Trabecular thickness, trabecular spacing, and trabecular number were calculated using the parallel plate model. Direct thickness, and spacing and connectivity density were calculated using unbiased three-dimensional methods. Both thickness and spacing calculated using the plate model were well correlated to the direct three-dimensional measures (r(2) = 0. 77-0.92). The correlation between trabecular number and connectivity density varied greatly (r(2) = 0.41-0.94). Whereas trabecular thickness was consistently underestimated using the plate model, trabecular spacing was underestimated at low volume fractions and overestimated at high volume fractions. Use of the plate model resulted in a volume-dependent bias in measures of thickness and spacing (p < 0.001). This was a result of the fact that samples of low volume fraction were much more "rod-like" than those of the higher volume fraction. Our findings indicate that the plate model provides biased results, especially when populations with different volume fractions are compared. Therefore, we recommend direct thickness measures when three-dimensional data sets are available

Extended Superscaling of Electron Scattering from Nuclei

An extended study of scaling of the first and second kinds for inclusive electron scattering from nuclei is presented. Emphasis is placed on the transverse response in the kinematic region lying above the quasielastic peak. In particular, for the region in which electroproduction of resonances is expected to be important, approximate scaling of the second kind is observed and the modest breaking of it is shown probably to be due to the role played by an inelastic version of the usual scaling variable.Comment: LaTeX, 36 pages including 5 color postscript figures and 4 postscript figure

Benchmark low-mass objects in Moving Groups

This is an Open Access article distributed under the terms of the Creative Commons Attribution License 2.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.In order to compile a sample of ultracool dwarfs that will serve as benchmarks for testing theoretical formation and evolutionary models, we selected low-mass cool (>M7) objects that are potentially members of five known young Moving Groups in the solar neighbourhood. We have studied the kinematics of the sample, finding that 49 targets belong to the young disk area, from which 36 are kinematic member of one of the five moving groups under study. Some of the identified low-mass members have been spectroscopically characterised (T-eff, log g) and confirmed as young members through a detailed study of age indicators

Structure of a crystal form of human methemoglobin indicative of fiber formation

Human methemoglobin was crystallized in a unique unit cell and its structure was solved by molecular replacement. The hexagonal unit cell has unit-cell parameters a = b = 54.6, c = 677.4 Å, with symmetry consistent with space group P6₁22. The unit cell has the second highest aspect ratio of all unit cells contained in the PDB. The 12 molecules in the unit cell describe a right-handed helical filament having no polarity, which is different from the filament composed of HbS fibers, which is the only other well characterized fiber of human hemoglobin. The filaments reported here can be related to canonical sickle-cell hemoglobin filaments and to an alternative sickle-cell filament deduced from fiber diffraction by slight modifications of intermolecular contacts

A community approach for pathogens and their arthropod vectors (ticks and fleas) in cats of sub-Saharan Africa

Background Arthropod-borne pathogens and their vectors are present throughout Africa. They have been well studied in livestock of sub-Saharan Africa, but poorly studied in companion animals. Given their socioeconomic importance, the African Small Companion Animal Network (AFSCAN), as part of the WSAVA Foundation, initiated a standardized multi-country surveillance study. Methods In six countries (Ghana, Kenya, Nigeria, Tanzania, Uganda, and Namibia) in both rural and urban settings, 160 infested cats were sampled to assess their ectoparasite community (ticks and fleas), as well as the micro-parasite prevalence within those ectoparasites (60 and 118 pools of ticks and fleas, respectively) and blood (276 cats, including 116 non-infested). Results Almost two thirds of all infested cats originated from Tanzania and Kenya. Despite the large macro-geographical variation, no consistent difference was found in ectoparasite diversity and numbers between East and West Africa. Far more flea-infested than tick-infested cats were found. The most dominant ectoparasite was Ctenocephalides felis. Among the ticks, the exophilic Haemaphysalis spp. were the commonest, including species that are not typically linked with companion animals (Haemaphysalis spinulosa and Haemaphysalis elliptica). The most prevalent pathogens found in the blood and fleas were Bartonella henselae and Mycoplasma haemofelis. In the ticks, the dog-associated Hepatozoon canis was most commonly found. A high degree of co-parasitism was found in all countries and habitats. Conclusions Our continent-wide standardized field study highlights the cat’s potential to serve as a reservoir of pathogens that can be transmitted to humans or livestock, especially when cats are expected to become more commonly kept in African villages and towns

Superscaling of Inclusive Electron Scattering from Nuclei

We investigate the degree to which the concept of superscaling, initially developed within the framework of the relativistic Fermi gas model, applies to inclusive electron scattering from nuclei. We find that data obtained from the low energy loss side of the quasielastic peak exhibit the superscaling property, i.e., the scaling functions f(\psi') are not only independent of momentum transfer (the usual type of scaling: scaling of the first kind), but coincide for A \geq 4 when plotted versus a dimensionless scaling variable \psi' (scaling of the second kind). We use this behavior to study as yet poorly understood properties of the inclusive response at large electron energy loss.Comment: 33 pages, 12 color EPS figures, LaTeX2e using BoxedEPSF macros; email to [email protected]

Defects and glassy dynamics in solid He-4: Perspectives and current status

We review the anomalous behavior of solid He-4 at low temperatures with particular attention to the role of structural defects present in solid. The discussion centers around the possible role of two level systems and structural glassy components for inducing the observed anomalies. We propose that the origin of glassy behavior is due to the dynamics of defects like dislocations formed in He-4. Within the developed framework of glassy components in a solid, we give a summary of the results and predictions for the effects that cover the mechanical, thermodynamic, viscoelastic, and electro-elastic contributions of the glassy response of solid He-4. Our proposed glass model for solid He-4 has several implications: (1) The anomalous properties of He-4 can be accounted for by allowing defects to freeze out at lowest temperatures. The dynamics of solid He-4 is governed by glasslike (glassy) relaxation processes and the distribution of relaxation times varies significantly between different torsional oscillator, shear modulus, and dielectric function experiments. (2) Any defect freeze-out will be accompanied by thermodynamic signatures consistent with entropy contributions from defects. It follows that such entropy contribution is much smaller than the required superfluid fraction, yet it is sufficient to account for excess entropy at lowest temperatures. (3) We predict a Cole-Cole type relation between the real and imaginary part of the response functions for rotational and planar shear that is occurring due to the dynamics of defects. Similar results apply for other response functions. (4) Using the framework of glassy dynamics, we predict low-frequency yet to be measured electro-elastic features in defect rich He-4 crystals. These predictions allow one to directly test the ideas and very presence of glassy contributions in He-4.Comment: 33 pages, 13 figure

Fat mass and obesity associated (FTO) gene influences skeletal muscle phenotypes in non-resistance trained males and elite rugby playing position

Background FTO gene variants have been associated with obesity phenotypes in sedentary and obese populations, but rarely with skeletal muscle and elite athlete phenotypes. Methods In 1089 participants, comprising 530 elite rugby athletes and 559 non-athletes, DNA was collected and genotyped for the FTO rs9939609 variant using real-time PCR. In a subgroup of non-resistance trained individuals (NT; n = 120), we also assessed structural and functional skeletal muscle phenotypes using dual energy x-ray absorptiometry, ultrasound and isokinetic dynamometry. In a subgroup of rugby athletes (n = 77), we assessed muscle power during a countermovement jump. Results In NT, TT genotype and T allele carriers had greater total body (4.8% and 4.1%) and total appendicular lean mass (LM; 3.0% and 2.1%) compared to AA genotype, with greater arm LM (0.8%) in T allele carriers and leg LM (2.1%) for TT, compared to AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes (back three and centre players) who are most reliant on LM rather than total body mass for success, compared to other rugby athletes (82%; P = 0.01, OR = 3.34) and controls (84%; P = 0.03, OR = 2.88). Accordingly, these athletes had greater peak power relative to body mass than other rugby athletes (14%; P = 2 x 10-6). Conclusion Collectively, these results suggest that the T allele is associated with increased LM and elite athletic success. This has implications for athletic populations, as well as conditions characterised by low LM such as sarcopenia and cachexia

Entanglement, Bell Inequalities and Decoherence in Particle Physics

We demonstrate the relevance of entanglement, Bell inequalities and decoherence in particle physics. In particular, we study in detail the features of the ``strange'' $K^0 \bar K^0$ system as an example of entangled meson--antimeson systems. The analogies and differences to entangled spin--1/2 or photon systems are worked, the effects of a unitary time evolution of the meson system is demonstrated explicitly. After an introduction we present several types of Bell inequalities and show a remarkable connection to CP violation. We investigate the stability of entangled quantum systems pursuing the question how possible decoherence might arise due to the interaction of the system with its ``environment''. The decoherence is strikingly connected to the entanglement loss of common entanglement measures. Finally, some outlook of the field is presented.Comment: Lectures given at Quantum Coherence in Matter: from Quarks to Solids, 42. Internationale Universit\"atswochen f\"ur Theoretische Physik, Schladming, Austria, Feb. 28 -- March 6, 2004, submitted to Lecture Notes in Physics, Springer Verlag, 45 page