Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products.

Aims/hypothesis: The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it.

Methods: Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocin-induced diabetic; and (3) diabetic treated with the AGE/ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology. Results: AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (p<0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (p<0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (p<0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment.

Conclusions/interpretation: While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.

Tetra-end-linked oligonucleotides forming DNA G-quadruplexes: a new class of aptamers showing anti-HIV activity.

The biophysical and biological properties of unprecedented anti-HIV aptamers are presented. The most active aptamer (1L) shows a significant affinity to the HIV protein gp120.

'Murder or Mercy?' an innovative module helping UK medical students to articulate their own ethical standpoints regarding end-of-life decisions

Objectives This student selected component (SSC) was designed to equip United Kingdom (UK) medical students to respond ethically and with sensitivity to requests they might receive as qualified doctors in regard to euthanasia and assisted dying. The aim was to expose students to relevant opinions and experiences and to provide opportunities to explore and justify their own views and rehearse ethical decision making in a safe learning environment. Method The module is delivered by specialists from a number of disciplines including law, theology, medicine and nursing, each providing students with a working knowledge allowing them to actively discuss cases, articulate their own views and practise ethical reasoning through group and individual study. Visits to local intensive care units, palliative care wards and hospices are integrated effectively with theory. Student assessment comprises a dissertation, student-led debate and reflective commentary. Module impact was evaluated by analysis of student coursework and a questionnaire. Results Students found the content stimulating and relevant to their future career and agreed that the module was well-structured and that learning outcomes were achieved. They greatly appreciated the clinical context provided by the visits and opportunities to apply ethical reasoning to real cases and to debate ethical issues with peers. Students reported an increased discernment of the ethical and legal position and practical considerations and a greater awareness of the range of professional and lay viewpoints held. Student perceptions were confirmed on analysis of their submitted coursework. Many participants were less strongly in favour of euthanasia and assisted dying on module completion than at the outset but all felt better equipped to justify their own viewpoint and to respond appropriately to patient requests. Conclusions The multi-disciplinary nature of this course is helpful in preparing students to deal effectively and sensitively with ethical dilemmas they will encounter in their medical career. Use of an integrated, learner-centred approach equips students to actively engage with their peers in discussion of such issues and to formulate and defend their own position.

AGEs, RAGE, and Diabetic Retinopathy

Diabetic retinopathy is a major diabetic complication with a highly complex etiology. Although there are many pathways involved, it has become established that chronic exposure of the retina to hyperglycemia gives rise to accumulation of advanced glycation end products (AGEs) that play an important role in retinopathy. In addition, the receptor for AGEs (RAGE) is ubiquitously expressed in various retinal cells and is upregulated in the retinas of diabetic patients, resulting in activation of pro-oxidant and proinflammatory signaling pathways. This AGE-RAGE axis appears to play a central role in the sustained inflammation, neurodegeneration, and retinal microvascular dysfunction occurring during diabetic retinopathy. The nature of AGE formation and RAGE signaling bring forward possibilities for therapeutic intervention. The multiple components of the AGE-RAGE axis, including signal transduction, formation of ligands, and the end-point effectors, may be promising targets for strategies to treat diabetic retinopathy.