Since clinical measures of bone mineral density do not necessarily predict whether a person will fracture a bone without an intervention, there is a need to find supplementary tools for assessing bone quality. Presently, we hypothesized that measures of mobile and bound water by a Nuclear Magnetic Resonance (NMR) technique are correlated with bone strength and toughness, respectively. To test this, bending specimens from the mid-diaphysis of 18 human femurs were collected from 18 male donors and divided into middle aged and elderly groups. After NMR measurements of each hydrated specimen, an inversion technique was used to convert the free induction decay data into a distribution of spin-spin (T2) relaxation rates. Then, the distribution resolved into three distinct components that likely represent solid hydrogen, water bound to bone tissue, and mobile water that occupy microscopic pores within the bone specimen. The integrated signal intensities of the bound and mobile components were normalized by the wet mass of the specimen. Following NMR measurements, three point bending tests were conducted to determine the modulus of elasticity, flexure strength, and work to fracture of each specimen. Next, the porosity, mineral-to-collagen ratio, and pentosidine concentration were measured. In this sample of human cortical bone, there was no age-related difference in the amount of mobile water, but the decrease in the amount of bound water with increasing age was statistically significant. Moreover, bound water was associated with both strength and work to fracture of bone, while mobile water was correlated with modulus of elasticity and appeared to quantify the level of microscopic pores within bone. On the other hand, bound water was correlated with the concentration of non-enzymatic collagen crosslinks. The results of this study indicate that quantifying mobile and bound water with magnetic resonance techniques could potentially serve as indicators of bone quality.
People with diabetes have increased risk of fracture disproportionate to BMD, suggesting reduced material strength (quality). We quantified the skeletal effects of type 1 diabetes in the rat. Fischer 344 and Sprague-Dawley rats (12 wk of age) were injected with either vehicle (Control) or streptozotocin (Diabetic). Forelimbs were scanned at 0, 4, 8, and 12 wk using pQCT. Rats were killed after 12 wk. We observed progressive osteopenia in diabetic rats. Trabecular osteopenia was caused by bone loss: volumetric BMD decreased progressively with time in diabetic rats but was constant in controls. Cortical osteopenia was caused by premature arrest of cortical expansion: cortical area did not increase after 4-8 wk in diabetic rats but continued to increase in controls. Postmortem mCT showed a 60% reduction in proximal tibial trabecular BV/TV in diabetic versus control rats, whereas moments of inertia of the ulnar and femoral diaphysis were reduced ;30%. Monotonic bending tests indicated that ulna and femora from diabetic animals were ;25% less stiff and strong versus controls. Estimates of material properties indicated no changes in elastic modulus or ultimate stress but modest (;10%) declines in yield stress for diabetic bone. These changes were associated with a ;50% increase in the nonenzymatic collagen cross-link pentosidine. Last, cyclic testing showed diminished fatigue life in diabetic bones at the structural (force) level but not at the material (stress) level. In summary, type 1 diabetes, left untreated, causes trabecular bone loss and a reduction in diaphyseal growth. Diabetic bone has greatly increased nonenzymatic collagen cross-links but only modestly reduced material properties. The loss of whole bone strength under both monotonic and fatigue loading is attributed mainly to reduced bone size.
The risk of bone fracture depends in part on tissue quality, not just the size and mass. This study assessed the postyield energy dissipation of cortical bone in tension as a function of age and composition. Specimens were prepared from tibiae of human cadavers in which male and female donors were divided into two age groups: middle aged (51 to 56 years, n ¼ 9) and elderly (72 to 90 years, n ¼ 8). By loading, unloading, and reloading a specimen with rest periods inserted in between, tensile properties at incremental strain levels were assessed. In addition, postyield toughness was estimated and partitioned as plastic strain energy related to permanent deformation, released elastic strain energy related to stiffness loss, and hysteresis energy related to viscous behavior. Porosity, mineral and collagen content, and collagen crosslinks of each specimen were also measured to determine the micro-and ultrastructural properties of the tissue. Age affected all the energy terms plus strength but not elastic stiffness. The postyield energy terms were correlated with porosity, pentosidine (a marker of nonenzymatic crosslinks), and collagen content, all of which varied significantly with age. General linear models suggested that pentosidine concentration and collagen content provided the best explanation of the age-related decrease in the postyield energy dissipation. Among them, pentosidine concentration had the greatest contribution to plastic strain energy and was the best explanatory variable of damage accumulation. ß
Toughness is a quantitative measure of bone quality in terms of its susceptibility to fracture. Thus, to elucidate the underlying mechanisms of age-related bone fractures, it is necessary to understand age-related changes in the toughness of bone. The objective of this review is to provide current understanding on the structure-function relationships of cortical bone and its correlation with the toughness of the tissue from the perspective of basic engineering principles. The review is written for the readers in the musculoskeletal research field, who may not have a strong engineering background. For better understanding of toughening mechanisms, this review intends to focus on correlations of the toughness of cortical bone with its constituents and microstructural characteristics. In addition, a special emphasis is placed on age-related changes in the toughness of bone.
BackgroundJapanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk’ regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model.MethodsJEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated.FindingsNTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV.ConclusionsBoth in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.
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