Osteogenesis Imperfecta:New Insights into Extraskeletal Complications

This thesis aims at expanding our understanding of Osteogenesis Imperfecta (OI), a genetic disorder causing bone fragility and a range of extraskeletal symptoms. The work examines in particular the epidemiology and the extraskeletal comorbidities of the Dutch OI population. Additionally, the thesis sheds light on the genotype-phenotype correlation and the pathophysiology of the respiratory complications associated with OI. The first part of the thesis discusses the prevalence and hospital admission rates of the Dutch OI population, the genotype-phenotype relation of OI, and the health care characteristics of patients with LRP5, PLS3, or WNT1 pathogenic variants. The second part of the thesis focuses on the pulmonary complications of OI patients. A literature review provides an overview of the current knowledge and knowledge gaps surrounding the pathophysiology of respiratory complications in OI. To gain further insight into the cause of pulmonary complications, the lung pathology in patients with OI type II was analyzed, suggesting intrinsic alterations in the OI lung parenchyma. The second part of this thesis concludes by proposing a more patient-friendly lung function assessment and a pulmonary follow-up plan for OI patients for the prevention of serious respiratory complications. Finally, the third part of the thesis provides an overview of collagen regulation in the context of recent gene discoveries and describes two OI patient with new SPARC pathogenic variants

The Use of Serum Glial Fibrillary Acidic Protein Measurements in the Diagnosis of Neuromyelitis Optica Spectrum Optic Neuritis

Background: Glial fibrillary acidic protein (GFAP) is a specific intermediate filament of the cytoskeleton of the astrocyte and may be used as a specific marker for astrocytic damage. It is detectable in the cerebrospinal fluid following a relapse caused by Multiple Sclerosis (MS) and Neuromyelitis Optica (NMO) spectrum disease. Higher levels are found following an NMO-related relapse. It is not known if GFAP is also detectable in the serum following such relapses. In particular, it is not known if lesions limited to the optic nerve release GFAP in sufficient quantities to be detectable within the serum. The aim of this study was to ascertain the extent to which serum GFAP levels can distinguish between an episode of optic neuritis (ON) related to NMO spectrum disease and ON from other causes.Methodology/Principal Findings: Out of 150 patients consecutively presenting to our eye hospital over the period March 2009 until July 2010, we were able to collect a serum sample from 12 patients who had presented with MS-related ON and from 10 patients who had presented with NMO spectrum disease-related ON. We also identified 8 patients with recurrent isolated ON and 8 patients with a corticosteroid-dependent optic neuropathy in the absence of any identified aetiology. GFAP was detectable in the serum of all but three patients (two patients with MS-related ON and one with recurrent optic neuritis). The median serum GFAP level in the patient group with NMO spectrum disease was 4.63 pg/mL whereas in all other cases combined together, this was 2.14 pg/mL. The difference was statistically significant (P = 0.01). A similar statistically significant difference was found when cases with pathology limited to the optic nerve were compared (P = 0.03).Conclusions: Glial pathology in NMO related optic neuritis is reflected in elevated serum GFAP levels independently of whether or not there is extra-optic nerve disease

The contribution of O(alpha) radiative corrections to the renormalised anisotropy and application to general tadpole improvement schemes: addendum to "One loop calculation of the renormalised anisotropy for improved anisotropic gluon actions on a lattice" [hep-lat/0208010]

General O(alpha) radiative corrections to lattice actions may be interpreted as counterterms that give additive contributions to the one-loop renormalisation of the anisotropy. The effect of changing the radiative coefficients is thus easily calculable. In particular, the results obtained in a previous paper for Landau mean link improved actions apply in any tadpole improvement scheme. We explain how this method can be exploited when tuning radiatively improved actions. Efficient methods for self-consistently tuning tadpole improvement factors are also discussed.Comment: 3 pages of revte

Lattice perturbation theory for gluonic and fermionic actions

We calculate the two loop Landau mean links and the one loop renormalisation of the anisotropy for Wilson and improved SU(3) gauge actions, using twisted boundary conditions as a gauge invariant infrared regulator. We show these accurately describe simulated results, and outline a method for generating Feynman rules for general lattice field theories, in a form suitable for efficient numerical calculation of perturbative loop diagrams.Comment: 6 pages of LaTeX. Two posters at Lattice2002(improve) combine

The use of pupillometry, serology, ethnicity and imaging in the diagnosis of optic neuritis

‘Acute isolated optic neuritis' may be the first manifestation of both Multiple Sclerosis (MS) and Neuromyelitis Optica (NMO). Twenty percent of patients with MS in western Europe present with optic neuritis as their first relapse (Mcdonald & Compston, 2006). NMO has been recently found to be more common amongst the Caucasian population of northern Europe than previously believed (Asgari et al, 2011). Patients with NMO may experience a long temporal delay after acute isolated optic neuritis before another relapse occurs, which can help to confirm the diagnosis (Wingerchuk et al, 2007). In such cases an episode of optic neuritis caused by NMO may be indistinguishable from optic neuritis caused by MS. This thesis explores differences in the manifestation of optic neuritis caused by MS and that caused by NMO and evaluates four ways in which the two aetiologies may be identified from one another: pupillometry, serum glial fibrillary acidic protein analysis, ethnic background considerations and MRI findings in the context of the visual pathways. The thesis begins by assessing the potential role of pupillometry in the diagnosis of optic nerve disease; eventually investigating its potential in discriminating between MS related optic neuritis and NMO related optic neuritis. The results of the first part of the thesis indicate the usefulness of pupillometry in patients with optic neuritis who show poor recovery, when tested in a chronic setting. Three further ways of differentiating optic neuritis caused by MS and NMO in an acute setting are then pursued. First, the measurement of serum Glial Fibrillary Acidic protein (GFAP) is shown to be a useful potential indicator of the presence of NMO. Second, the ethnic background of a patient is found to correlate with the risk of NMO. Third, the Magnetic Resonance (MR) image of the visual pathway of patients with optic neuritis from the two aetiologies is found to differ with regard to the lesion extent and the lesion site. The four investigative approaches tested in this thesis (pupillometry, serology testing for GFAP, assessment of ethnic background and MR image) can be combined to offer a patient with isolated optic neuritis of unknown cause a likelihood of suffering from NMO. The latter three methods may be used to assess the risk of NMO in a patient presenting acutely with optic neuritis in the absence of any other sign of underlying disease, and may allow for the appropriate management of this condition

Automatically generating Feynman rules for improved lattice field theories

Deriving the Feynman rules for lattice perturbation theory from actions and operators is complicated, especially when improvement terms are present. This physically important task is, however, suitable for automation. We describe a flexible algorithm for generating Feynman rules for a wide range of lattice field theories including gluons, relativistic fermions and heavy quarks. We also present an efficient implementation of this in a freely available, multi-platform programming language (\python), optimised to deal with a wide class of lattice field theories