Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a fatal multi-system neuromuscular disease caused by loss of dystrophin. The loss of dystrophin from membranes of contractile muscle cells and the dysregulation of the DAPC, induces chronic inflammation due to tissue necrosis and eventual replacement with collagen which weakens muscular force and strength. Dystrophin deficiency may cause under-diagnosed features of DMD include mood disorders such as depression and anxiety and dysfunction of the gastrointestinal tract. The first study in the thesis examined mood in the dystrophin-deficient mdx mouse model of DMD and examined the effects of the tri-cyclic antidepressant, amitriptyline on behaviours. Amitriptyline had anti-depressant and anxiolytic effects in the mdx mice possibly through effects on stress factors such as corticotrophin-releasing factor (CRF). This antidepressant also reduced skeletal muscle inflammation and caused a reduction in circulating interleukin (IL)-6 levels. In the second and third studies, we specifically blocked IL-6 signalling and used Urocortin 2, CRFR2 agonist to investigate their potential as therapeutic targets in mdx mice pathophysiology. Isometric and isotonic contractile properties of the diaphragm, were compared in mdx mice treated with anti IL-6 receptor antibodies (anti IL-6R) and/or Urocortin 2. Deficits in force production, work and power detected in mdx mice were improved with treatment. In study three I investigated contractile properties in gastrointestinal smooth muscle. As compared to wild type mice, mdx mice had slower faecal transit times, shorter colons with thickened muscle layers and increased contractile activity in response to recombinant IL-6. Blocking IL-6 signalling resulted in an increase in colon length, normalised faecal output times and a reduction in IL-6-evoked contractile activity. The findings from these studies indicate that for both diaphragm and gastrointestinal function in a dystrophin-deficient model, targeting of IL-6 and CRFR2 signalling has beneficial therapeutic effects.

The Aarhus Convention and its implementation in Ireland: strengthening the role of NGOs in environmental governance

One of the most striking features of the 1998 Aarhus Convention on Access to Information, Public Participation in Decision-making and Access to Justice in Environmental Matters is the leading role envisaged for environmental nongovernmental organisations (ENGOs) in furthering compliance with environmental law. The Convention aims to secure the special status of ENGOs in environmental governance procedures by guaranteeing procedural rights of access to information, participation in decision-making and access to review mechanisms. Although Ireland did not become a Party to the Convention until September 2012, the Aarhus procedural rights were already guaranteed under European Union (EU) law. The EU has been a Party to the Aarhus Convention since May 2005 and has adopted a number of legislative measures to implement the Convention. This thesis examines the evolving role of ENGOs in environmental governance in Ireland. It provides a doctrinal analysis of the impact of the Aarhus Convention and EU law on Irish law and governance arrangements involving ENGOs. The thesis considers the extent to which Ireland has delivered faithfully on the standards set by the Aarhus Convention to facilitate ENGOs to fulfil the role envisaged for them under the Convention.