Effect of vitamin D supplementation on bone status, glucose homeostasis and immune function in children with vitamin D deficiency

Background: Between 1961-1971 vitamin D deficiency was recognized as a public health issue in the UK, because of the lack of effective sunlight and the population mix [1, 2]. In recent years, health care professionals have cited evidence suggesting a re-emergence of the vitamin D deficiency linked to a number of health consequences as a concern [3-6]. Evidence from observational studies has linked low vitamin D status with impairment in glucose homeostasis and immune dysfunction [7-9]. However, interventional studies, particularly those focused on paediatric populations, have been limited and inconsistent. There is a need for detailed studies, to clarify the therapeutic benefits of vitamin D in these important clinical areas. Objective: The aims of this PhD thesis were two-fold. Firstly, to perform preliminary work assessing the association between vitamin D deficiency and bone status, glucose homeostasis and immune function, and to explore any changes in these parameters following short term vitamin D3 replacement therapy. Secondly, to assess the effectiveness of an electronic surveillance system (ScotPSU) as a tool to determine the current incidence of hospital-based presentation of childhood vitamin D deficiency in Scotland. Methods: Active surveillance was performed for a period of two years as a part of an electronic web-based surveillance programme performed by the Scottish Paediatric Surveillance Unit (ScotPSU). The validity of the system was assessed by identifying cases with profound vitamin D deficiency (in Glasgow and Edinburgh) from the regional laboratory. All clinical details were checked against those identified using the surveillance system. Thirty-seven children aged 3 months to 10 years, who had been diagnosed with vitamin D deficiency, were recruited for the bone, glucose and immunity studies over a period of 24 months. Twenty-five samples were analysed for the glucose and bone studies; of these, 18 samples were further analysed for immune study. Treatment consisted of six weeks taking 5000 IU units cholecalciferol orally once a day. At baseline and after completion of treatment, 25 hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), alkaline phosphatase (ALP), collagen type 1 cross-linked C-telopeptide (CTX), osteocalcin (OCN), calcium, phosphate, insulin, glucose, homeostasis model assessment index, estimated insulin resistance (HOMA IR), glycated hemoglobin (HbA1c), sex hormone binding globulin (SHBG), lipids profiles, T helper 1 (Th1) cytokines (interleukin-2 ( IL-2), tumor necrosis factors-alpha (TNF-α), interferon-gamma (INF-γ)), T helper 2 (Th2) cytokines (interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6)), T helper 17 (Th17) cytokine (interleukin-17 (IL-17)), Regulatory T (Treg) cytokine (interleukin-10 (IL-10)) and chemokines/cytokines, linked with Th1/Th2 subset balance and/or differentiation (interleukin-8 (IL-8), interleukin-12 (IL-12), eosinophil chemotactic protein ( EOTAXIN), macrophage inflammatory proteins-1beta (MIP-1β), interferon-gamma-induced protein-10 (IP-10), regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein-1(MCP-1)) were measured. Leukoocyte subset analysis was performed for T cells, B cells and T regulatory cells and a luminex assay was used to measure the cytokiens. Results: Between September 2009 and August 2011, 163 cases of vitamin D deficiency were brought to the attention of the ScotPSU, and the majority of cases (n = 82) were reported in Glasgow. The cross-validation checking in Glasgow and Edinburgh over a one-year period revealed only 3 (11%) cases of clearly symptomatic vitamin D deficiency, which had been missed by the ScotPSU survey in Glasgow. While 16 (67%) symptomatic cases had failed to be reported through the ScotPSU survey in Edinburgh. For the 23 children who are included in bone and glucose studies, 22 (96%) children had basal serum 25(OH)D in the deficiency range (< 50 nmol/l) and one (4%) child had serum 25(OH)D in the insufficiency range (51-75 nmol/l). Following vitamin D3 treatment, 2 (9%) children had final serum 25(OH)D lower than 50 nmol/l, 6 (26%) children had final serum 25(OH)D between >50-75 nmol/l, 12 (52%) children reached a final serum 25(OH)D >75-150 nmol/l and finally 3 (13%) exceeded the normal reference range with a final 25(OH)D >150 nmol/l. Markers for remodelling ALP and PTH had significantly decreased (p = 0.001 and <0.0001 for ALP and PTH respectively). In 17 patients for whom insulin and HOMA IR data were available and enrolled in glucose study, significant improvements in insulin resistance (p = 0.04) with a trend toward a reduction in serum insulin (p = 0.05) was observed. Of those 14 children who had their cytokines profile data analysed and enrolled in the immunity study, insulin and HOMA IR data were missed in one child. A significant increase in the main Th2 secreted cytokine IL-4 (p = 0.001) and a tendency for significant increases in other Th2 secreted cytokines IL-5 (p = 0.05) and IL-6 (p = 0.05) was observed following vitamin D3 supplementation. Conclusion: An electronic surveillance system can provide data for studying the epidemiology of vitamin D deficiency. However, it may underestimate the number of positive cases. Improving vitamin D status in vitamin D deficient otherwise healthy children significantly improved their vitamin D deficient status, and was associated with an improvement in bone profile, improvements in insulin resistance and an alteration in main Th2 secreting cytokines.

Autonomous formation flying: unified control and collision avoidance methods for close manoeuvring spacecraft

The idea of spacecraft formations, flying in tight configurations with maximum baselines of a few hundred meters in low-Earth orbits, has generated widespread interest over the last several years. Nevertheless, controlling the movement of spacecraft in formation poses difficulties, such as in-orbit high-computing demand and collision avoidance capabilities, which escalate as the number of units in the formation is increased and complicated nonlinear effects are imposed to the dynamics, together with uncertainty which may arise from the lack of knowledge of system parameters. These requirements have led to the need of reliable linear and nonlinear controllers in terms of relative and absolute dynamics. The objective of this thesis is, therefore, to introduce new control methods to allow spacecraft in formation, with circular/elliptical reference orbits, to efficiently execute safe autonomous manoeuvres. These controllers distinguish from the bulk of literature in that they merge guidance laws never applied before to spacecraft formation flying and collision avoidance capacities into a single control strategy. For this purpose, three control schemes are presented: linear optimal regulation, linear optimal estimation and adaptive nonlinear control. In general terms, the proposed control approaches command the dynamical performance of one or several followers with respect to a leader to asymptotically track a time-varying nominal trajectory (TVNT), while the threat of collision between the followers is reduced by repelling accelerations obtained from the collision avoidance scheme during the periods of closest proximity. Linear optimal regulation is achieved through a Riccati-based tracking controller. Within this control strategy, the controller provides guidance and tracking toward a desired TVNT, optimizing fuel consumption by Riccati procedure using a non-infinite cost function defined in terms of the desired TVNT, while repelling accelerations generated from the CAS will ensure evasive actions between the elements of the formation. The relative dynamics model, suitable for circular and eccentric low-Earth reference orbits, is based on the Tschauner and Hempel equations, and includes a control input and a nonlinear term corresponding to the CAS repelling accelerations. Linear optimal estimation is built on the forward-in-time separation principle. This controller encompasses two stages: regulation and estimation. The first stage requires the design of a full state feedback controller using the state vector reconstructed by means of the estimator. The second stage requires the design of an additional dynamical system, the estimator, to obtain the states which cannot be measured in order to approximately reconstruct the full state vector. Then, the separation principle states that an observer built for a known input can also be used to estimate the state of the system and to generate the control input. This allows the design of the observer and the feedback independently, by exploiting the advantages of linear quadratic regulator theory, in order to estimate the states of a dynamical system with model and sensor uncertainty. The relative dynamics is described with the linear system used in the previous controller, with a control input and nonlinearities entering via the repelling accelerations from the CAS during collision avoidance events. Moreover, sensor uncertainty is added to the control process by considering carrier-phase differential GPS (CDGPS) velocity measurement error. An adaptive control law capable of delivering superior closed-loop performance when compared to the certainty-equivalence (CE) adaptive controllers is finally presented. A novel noncertainty-equivalence controller based on the Immersion and Invariance paradigm for close-manoeuvring spacecraft formation flying in both circular and elliptical low-Earth reference orbits is introduced. The proposed control scheme achieves stabilization by immersing the plant dynamics into a target dynamical system (or manifold) that captures the desired dynamical behaviour. They key feature of this methodology is the addition of a new term to the classical certainty-equivalence control approach that, in conjunction with the parameter update law, is designed to achieve adaptive stabilization. This parameter has the ultimate task of shaping the manifold into which the adaptive system is immersed. The performance of the controller is proven stable via a Lyapunov-based analysis and Barbalat’s lemma. In order to evaluate the design of the controllers, test cases based on the physical and orbital features of the Prototype Research Instruments and Space Mission Technology Advancement (PRISMA) are implemented, extending the number of elements in the formation into scenarios with reconfigurations and on-orbit position switching in elliptical low-Earth reference orbits. An extensive analysis and comparison of the performance of the controllers in terms of total Δv and fuel consumption, with and without the effects of the CAS, is presented. These results show that the three proposed controllers allow the followers to asymptotically track the desired nominal trajectory and, additionally, those simulations including CAS show an effective decrease of collision risk during the performance of the manoeuvre.