What does the arthropathy of alkaptonuria teach us about disease mechanisms in osteoarthritis and ageing of joints? Lessons from a rare disease

AKU Society, the Rosetrees Foundation, the Childwick Trust, the Big Lottery and EUFP

Scanning Electron Microscopy in Bone Pathology: Review of Methods, Potential and Applications

This article reviews the applications of SEM methods to human bone pathologies referring to studies made at UCL. We consider the methods which may be most suitable; these prove to be not routine in the context of most bio-medical applications of SEM. Valuable information can be obtained from a bone sample if its edges are ground flat, before making either (a) a matrix surface preparation by washing away all the cells or (b) a mineralising front preparation, by also dissolving the osteoid -for which hydrogen peroxide is recommended to produce a robust specimen. BSE contrast from a cut block surface can be used to measure bone phase volume. SE contrasts from natural surfaces (trabeculae, canals and lacunae) can be used to study forming, resting and resorbing* surfaces both qualitatively and quantitatively (*except in the case of histological osteomalacia, where the existence of osteoid will go undetected and reversal lines will be difficult to distinguish from recently resorbed surfaces). We also recommend the use of PMMA embedded bone blocks, which can be used as obtained from the pathologist, but are better embedded by a more rigorous procedure. BSE image analysis can be used to quantitate bone density fractions opening up a completely new investigative method for the future. Osteoid can be measured automatically using CL if the bone sample is block stained with brilliant sulphaflavine before embedding or if a scintillant is added to the embeddant. We give examples of observations made from a number of bone diseases: vitamin D resistant rickets, ostegenesis imperfecta; osteomalacia; osteoporosis; hyperparathyroidism; fluorosis; Paget \u27s disease; tumour metastasis to bone

Observations of High Definition Symmetric Quasi‐Periodic Scintillations in the Mid‐Latitude Ionosphere With LOFAR

We present broadband ionospheric scintillation observations of highly defined symmetric quasi‐periodic scintillations (QPS: Maruyama, 1991, https://doi.org/10.1029/91rs00357) caused by plasma structures in the mid‐latitude ionosphere using the LOw Frequency ARray (LOFAR: van Haarlem et al., 2013, https://doi.org/10.1051/0004‐6361/201220873). Two case studies are shown, one from 15 December 2016, and one from 30 January 2018, in which well‐defined main signal fades are observed to be bounded by secondary diffraction fringing. The ionospheric plasma structures effectively behave as a Fresnel obstacle, in which steep plasma gradients at the periphery result in a series of decreasing intensity interference fringes, while the center of the structures largely block the incoming radio signal altogether. In particular, the broadband observing capabilities of LOFAR permit us to see considerable frequency dependent behavior in the QPSs which, to our knowledge, is a new result. We extract some of the clearest examples of scintillation arcs reported in an ionospheric context, from delay‐Doppler spectral analysis of these two events. These arcs permit the extraction of propagation velocities for the plasma structures causing the QPSs ranging from 50 to 00 m s−1, depending on the assumed altitude. The spacing between the individual plasma structures ranges between 5 and 20 km. The periodicities of the main signal fades in each event and, in the case of the 2018 data, co‐temporal ionosonde data, suggest the propagation of the plasma structures causing the QPSs are in the E‐region. Each of the two events is accurately reproduced using a thin screen phase model. Individual signal fades and enhancements were modeled using small variations in total electron content (TEC) amplitudes of order 1 mTECu, demonstrating the sensitivity of LOFAR to very small fluctuations in ionospheric plasma density. To our knowledge these results are among the most detailed observations and modeling of QPSs in the literature

Observations of High Definition Symmetric Quasi‐Periodic Scintillations in the Mid‐Latitude Ionosphere With LOFAR

We present broadband ionospheric scintillation observations of highly defined symmetric quasi‐periodic scintillations (QPS: Maruyama, 1991, https://doi.org/10.1029/91rs00357) caused by plasma structures in the mid‐latitude ionosphere using the LOw Frequency ARray (LOFAR: van Haarlem et al., 2013, https://doi.org/10.1051/0004‐6361/201220873). Two case studies are shown, one from 15 December 2016, and one from 30 January 2018, in which well‐defined main signal fades are observed to be bounded by secondary diffraction fringing. The ionospheric plasma structures effectively behave as a Fresnel obstacle, in which steep plasma gradients at the periphery result in a series of decreasing intensity interference fringes, while the center of the structures largely block the incoming radio signal altogether. In particular, the broadband observing capabilities of LOFAR permit us to see considerable frequency dependent behavior in the QPSs which, to our knowledge, is a new result. We extract some of the clearest examples of scintillation arcs reported in an ionospheric context, from delay‐Doppler spectral analysis of these two events. These arcs permit the extraction of propagation velocities for the plasma structures causing the QPSs ranging from 50 to 00 m s−1, depending on the assumed altitude. The spacing between the individual plasma structures ranges between 5 and 20 km. The periodicities of the main signal fades in each event and, in the case of the 2018 data, co‐temporal ionosonde data, suggest the propagation of the plasma structures causing the QPSs are in the E‐region. Each of the two events is accurately reproduced using a thin screen phase model. Individual signal fades and enhancements were modeled using small variations in total electron content (TEC) amplitudes of order 1 mTECu, demonstrating the sensitivity of LOFAR to very small fluctuations in ionospheric plasma density. To our knowledge these results are among the most detailed observations and modeling of QPSs in the literature

LOFAR Observations of Substructure Within a Traveling Ionospheric Disturbance at Mid-Latitude

The large scale morphology and finer sub-structure within a slowly propagating traveling ionospheric disturbance (TID) are studied using wide band trans-ionospheric radio observations with the LOw Frequency ARray (LOFAR; van Haarlem et al., 2013, https://doi.org/10.1051/0004-6361/201220873). The observations were made under geomagnetically quiet conditions, between 0400 and 0800 on 7 January 2019, over the UK. In combination with ionograms and Global Navigation Satellite System Total Electron Content anomaly data we estimate the TID velocity to ∼60 ms−1, in a North-westerly direction. Clearly defined substructures with oscillation periods of ∼300 s were identified within the TID, corresponding to scale sizes of 20 km. At the geometries and observing wavelengths involved, the Fresnel scale is between 3 and 4 km, hence these substructures contribute significant refractive scattering to the received LOFAR signal. The refractive scattering is strongly coherent across the LOFAR bandwidth used here (25–64 MHz). The size of these structures distinguishes them from previously identified ionospheric scintillation with LOFAR in Fallows et al. (2020), https://doi.org/10.1051/swsc/2020010, where the scale sizes of the plasma structure varied from ∼500 m to 5 km

Iodine Vapor Staining for Atomic Number Contrast in Backscattered Electron and X-Ray Imaging

The Wellcome Trust (X‐ray microtomography scanner at RVC). Grant Number: 093234EPSRC Career Acceleration Fellowship. Grant Number: EP/H004025/1The Wellcome Trust (X-ray microtomography scanner at RVC); Contract grant number: 093234; Contract grant sponsor: EPSRC Career Acceleration Fellowship (to R.J.B.); Contract grant number: EP/ H004025/

The plate-to-rod transition in trabecular bone loss is elusive.

Changes in trabecular micro-architecture are key to our understanding of osteoporosis. Previous work focusing on structure model index (SMI) measurements have concluded that disease progression entails a shift from plates to rods in trabecular bone, but SMI is heavily biased by bone volume fraction. As an alternative to SMI, we proposed the ellipsoid factor (EF) as a continuous measure of local trabecular shape between plate-like and rod-like extremes. We investigated the relationship between EF distributions, SMI and bone volume fraction of the trabecular geometry in a murine model of disuse osteoporosis as well as from human vertebrae of differing bone volume fraction. We observed a moderate shift in EF median (at later disease stages in mouse tibia) and EF mode (in the vertebral samples with low bone volume fraction) towards a more rod-like geometry, but not in EF maximum and minimum. These results support the notion that the plate to rod transition does not coincide with the onset of bone loss and is considerably more moderate, when it does occur, than SMI suggests. A variety of local shapes not straightforward to categorize as rod or plate exist in all our trabecular bone samples

Investigation of bone resorption within a cortical basic multicellular unit using a lattice-based computational model

In this paper we develop a lattice-based computational model focused on bone resorption by osteoclasts in a single cortical basic multicellular unit (BMU). Our model takes into account the interaction of osteoclasts with the bone matrix, the interaction of osteoclasts with each other, the generation of osteoclasts from a growing blood vessel, and the renewal of osteoclast nuclei by cell fusion. All these features are shown to strongly influence the geometrical properties of the developing resorption cavity including its size, shape and progression rate, and are also shown to influence the distribution, resorption pattern and trajectories of individual osteoclasts within the BMU. We demonstrate that for certain parameter combinations, resorption cavity shapes can be recovered from the computational model that closely resemble resorption cavity shapes observed from microCT imaging of human cortical bone.Comment: 17 pages, 11 figures, 1 table. Revised version: paper entirely rewritten for a more biology-oriented readership. Technical points of model description now in Appendix. Addition of two new figures (Fig. 5 and Fig. 9) and removal of former Fig.