The effects of B cell depletion on bone turnover in rheumatoid arthritis

PhD ThesisRheumatoid arthritis (RA) is the most prevalent inflammatory joint disease. B cells have a role in both the pathogenesis of RA and the regulation of bone cell activity. Depletion of B cells by the anti-CD20 antibody rituximab (RTX) is a highly effective treatment of RA, which is now well established. However, the role of B-cells in bone turnover is controversial. The aim of this thesis was to investigate the effects of B cell depletion on bone turnover in RA. It is postulated that prolonged B cell depletion in patients with RA may have a beneficial effect on the bone loss that would otherwise be expected in active disease. Furthermore, this affect may be direct through modulation of osteoclastogenesis or indirect through attenuation of systemic inflammation and increased physical activity. Preliminary results in forty-six RA patients six months after RTX indicated that there was a significant suppression in bone resorption accompanied to a lesser degree by an increase in bone formation. However, in a second prospective cohort of forty-five RA patients treated with RTX over twelve months, bone mineral density (BMD) fell at the femur sites, but was maintained at the lumbar spine and forearm. There was a significant increase in bone formation, but no significant change in bone resorption or osteocyte markers. Additionally, the effects of RTX on bone turnover were influenced by vitamin D status, gender and menopausal state. Results of in vitro osteoclastogenesis with peripheral blood mononuclear cells (PBMCs) isolated from the blood of twelve self-reported healthy volunteers; indicated that in vitro B cell depletion via magnetic-activated cell sorting (MACS), significantly increased osteoclast formation. In contrast, PBMCs isolated from the blood of five RA patients, up to twelve months post B cell depletion with RTX, resulted in decreased osteoclast formation using the same standardised culture system. In summary, the results of the pilot study showed that B cell depletion significantly decreased bone resorption and increased bone formation in RA, possibly via a direct effect on osteoclasts and osteoblasts, respectively, or at least partially explained by the decreased inflammation and disease activity. However, this was not confirmed in the prospective study as the results were confounded by a high prevalence of vitamin D deficiency and these patients had significant falls in femur BMD and evidence of higher bone turnover. Furthermore, as there were no control groups it was difficult to establish whether depletion of B cells had in fact slowed down the expected bone loss in these patients. The results of the in vitro experiments indicated that under basal conditions i.e. in healthy subjects, the production of osteoprotegerin by B cells outweighed the production of receptor activator of nuclear factor - κb ligand (RANKL). However, in pro-inflammatory states, where B cells are activated e.g. RA, B cells produce cytokines like RANKL that stimulate osteoclastogenesis resulting in an increased production of osteoclasts. Hence B cell depletion ii in this latter situation caused a reduction in osteoclast generation. Further work is now required to investigate if subsets of pathogenic B cells i.e. not found in healthy individuals are specific to inflammatory bone erosion.South Tees R&D and Roche Products Limited (Welwyn Garden City, UK) providing funding for the prospective trial

Quasi-Topological Field Theories in Two Dimensions as Soluble Models

We study a class of lattice field theories in two dimensions that includes gauge theories. Given a two dimensional orientable surface of genus $g$, the partition function $Z$ is defined for a triangulation consisting of $n$ triangles of area $\epsilon$. The reason these models are called quasi-topological is that $Z$ depends on $g$, $n$ and $\epsilon$ but not on the details of the triangulation. They are also soluble in the sense that the computation of their partition functions can be reduced to a soluble one dimensional problem. We show that the continuum limit is well defined if the model approaches a topological field theory in the zero area limit, i.e., $\epsilon \to 0$ with finite $n$. We also show that the universality classes of such quasi-topological lattice field theories can be easily classified. Yang-Mills and generalized Yang-Mills theories appear as particular examples of such continuum limits.Comment: 23 pages, 16 figures, uses psbox.te

The Hausdorff dimension in polymerized quantum gravity

We calculate the Hausdorff dimension, $d_H$, and the correlation function exponent, $\eta$, for polymerized two dimensional quantum gravity models. If the non-polymerized model has correlation function exponent $\eta_0 >3$ then $d_H=\gamma^{-1}$ where $\gamma$ is the susceptibility exponent. This suggests that these models may be in the same universality class as certain non-generic branched polymer models.Comment: 10 pages, 1 figure. A meaning-free sentence has been rewritte

Surface tension in an intrinsic curvature model with fixed one-dimensional boundaries

A triangulated fixed connectivity surface model is investigated by using the Monte Carlo simulation technique. In order to have the macroscopic surface tension \tau, the vertices on the one-dimensional boundaries are fixed as the edges (=circles) of the tubular surface in the simulations. The size of the tubular surface is chosen such that the projected area becomes the regular square of area A. An intrinsic curvature energy with a microscopic bending rigidity b is included in the Hamiltonian. We found that the model undergoes a first-order transition of surface fluctuations at finite b, where the surface tension \tau discontinuously changes. The gap of \tau remains constant at the transition point in a certain range of values A/N^\prime at sufficiently large N^\prime, which is the total number of vertices excluding the fixed vertices on the boundaries. The value of \tau remains almost zero in the wrinkled phase at the transition point while \tau remains negative finite in the smooth phase in that range of A/N^\prime.Comment: 12 pages, 8 figure

Disaggregation of spatial rainfall fields for hydrological modelling

International audienceMeteorological models generate fields of precipitation and other climatological variables as spatial averages at the scale of the grid used for numerical solution. The grid-scale can be large, particularly for GCMs, and disaggregation is required, for example to generate appropriate spatial-temporal properties of rainfall for coupling with surface-boundary conditions or more general hydrological applications. A method is presented here which considers the generation of the wet areas and the simulation of rainfall intensities separately. For the first task, a nearest-neighbour Markov scheme, based upon a Bayesian technique used in image processing, is implemented so as to preserve the structural features of the observed rainfall. Essentially, the large-scale field and the previously disaggregated field are used as evidence in an iterative procedure which aims at selecting a realisation according to the joint posterior probability distribution. In the second task the morphological characteristics of the field of rainfall intensities are reproduced through a random sampling of intensities according to a beta distribution and their allocation to pixels chosen so that the higher intensities are more likely to be further from the dry areas. The components of the scheme are assessed for Arkansas-Red River basin radar rainfall (hourly averages) by disaggregating from 40 km x 40 km to 8 km x 8 km. The wet/dry scheme provides a good reproduction both of the number of correctly classified pixels and the coverage, while the intensitiy scheme generates fields with an adequate variance within the grid-squares, so that this scheme provides the hydrologist with a useful tool for the downscaling of meteorological model outputs. Keywords: Rainfall, disaggregation, General Circulation Model, Bayesian analysi

The flat phase of fixed-connectivity membranes

The statistical mechanics of flexible two-dimensional surfaces (membranes) appears in a wide variety of physical settings. In this talk we discuss the simplest case of fixed-connectivity surfaces. We first review the current theoretical understanding of the remarkable flat phase of such membranes. We then summarize the results of a recent large scale Monte Carlo simulation of the simplest conceivable discrete realization of this system \cite{BCFTA}. We verify the existence of long-range order, determine the associated critical exponents of the flat phase and compare the results to the predictions of various theoretical models.Comment: 7 pages, 5 figures, 3 tables. LaTeX w/epscrc2.sty, combined contribution of M. Falcioni and M. Bowick to LATTICE96(gravity), to appear in Nucl. Phys. B (proc. suppl.

The Phase Diagram of Crystalline Surfaces

We report the status of a high-statistics Monte Carlo simulation of non-self-avoiding crystalline surfaces with extrinsic curvature on lattices of size up to $128^2$ nodes. We impose free boundary conditions. The free energy is a gaussian spring tethering potential together with a normal-normal bending energy. Particular emphasis is given to the behavior of the model in the cold phase where we measure the decay of the normal-normal correlation function.Comment: 9 pages latex (epsf), 4 EPS figures, uuencoded and compressed. Contribution to Lattice '9

Phase transitions of an intrinsic curvature model on dynamically triangulated spherical surfaces with point boundaries

An intrinsic curvature model is investigated using the canonical Monte Carlo simulations on dynamically triangulated spherical surfaces of size upto N=4842 with two fixed-vertices separated by the distance 2L. We found a first-order transition at finite curvature coefficient \alpha, and moreover that the order of the transition remains unchanged even when L is enlarged such that the surfaces become sufficiently oblong. This is in sharp contrast to the known results of the same model on tethered surfaces, where the transition weakens to a second-order one as L is increased. The phase transition of the model in this paper separates the smooth phase from the crumpled phase. The surfaces become string-like between two point-boundaries in the crumpled phase. On the contrary, we can see a spherical lump on the oblong surfaces in the smooth phase. The string tension was calculated and was found to have a jump at the transition point. The value of \sigma is independent of L in the smooth phase, while it increases with increasing L in the crumpled phase. This behavior of \sigma is consistent with the observed scaling relation \sigma \sim (2L/N)^\nu, where \nu\simeq 0 in the smooth phase, and \nu=0.93\pm 0.14 in the crumpled phase. We should note that a possibility of a continuous transition is not completely eliminated.Comment: 15 pages with 10 figure

Free boson formulation of boundary states in W_3 minimal models and the critical Potts model

We develop a Coulomb gas formalism for boundary conformal field theory having a $W$ symmetry and illustrate its operation using the three state Potts model. We find that there are free-field representations for six $W$ conserving boundary states, which yield the fixed and mixed physical boundary conditions, and two $W$ violating boundary states which yield the free and new boundary conditions. Other $W$ violating boundary states can be constructed but they decouple from the rest of the theory. Thus we have a complete free-field realization of the known boundary states of the three state Potts model. We then use the formalism to calculate boundary correlation functions in various cases. We find that the conformal blocks arising when the two point function of $\phi_{2,3}$ is calculated in the presence of free and new boundary conditions are indeed the last two solutions of the sixth order differential equation generated by the singular vector.Comment: 25 page

Mapping urban green infrastructure : a novel landscape-based approach to incorporating land-use and land-cover in the mapping of human-dominated systems

Common approaches to mapping green infrastructure in urbanized landscapes invariably focus on measures of land-use or land-cover and associated functional or physical traits. However, such one-dimensional perspectives do not accurately capture the character and complexity of the landscapes in which urban inhabitants live. The new approach presented in this paper demonstrates how open-source, high spatial and temporal resolution data with global coverage can be used to measure and represent the landscape qualities of urban environments. Through going beyond simple metrics of quantity, such as percentage green and blue cover it is now possible to explore the extent to which landscape quality helps to unpick the mixed evidence presented in the literature on the benefits of urban nature to human well-being. Here we present a landscape approach, employing remote sensing, GIS and data reduction techniques, to map urban green infrastructure elements in a large UK city-region. Comparison with existing urban datasets demonstrates considerable improvement in terms of coverage and thematic detail. The characterisation of landscapes, using census tracts as spatial units, and subsequent exploration of associations with social-ecological attributes highlights the further detail which can be uncovered with the approach. For example, eight urban landscape types identified for the case study city exhibited associations with distinct socio-economic conditions accountable not only to quantities but also qualities of green and blue space. The identification of individual landscape features through simultaneous measures of land-use and land cover demonstrated unique and significant associations between the former and indicators of human health and ecological condition. The approach may therefore provide a promising basis for developing further insight into the processes and characteristics which affect human health and wellbeing in urban areas, both in the UK and beyond