Endothelin and the ischaemic heart

Soon after its identification as a powerful vasoconstrictor peptide, endothelin (ET-1) was implicated as a detrimental agent involved in determining the outcome of myocardial ischaemia and reperfusion. Early experimental studies demonstrated that ETA selective and mixed ETA/ETB receptor antagonists can reduce infarct size and prevent ischaemiainduced ventricular arrhythmias in models of ischaemia/reperfusion, implying that ET-1 acts through the ETA receptor to contribute to injury and arrhythmogenesis. However, as our understanding of the physiology of ET-1 has expanded, the role of ET-1 in the ischaemic heart appears ever more complex. Recent evidence suggests that ET-1 exerts actions on the heart that are not only detrimental (vasoconstriction, inhibition of NO production, activation of inflammatory cells), but which may also contribute to tissue repair, such as inhibition of cardiomyocyte apoptosis. In addition, ET-1-induced mast cell degranulation has been linked to a homeostatic mechanism that controls endogenous ET-1 levels, which may have important implications for the ischaemic heart. Furthermore the mechanism by which ET-1 promotes arrhythmogenesis remains controversial. Some studies imply a direct electrophysiological effect of ET-1, via ETA receptors, to increase monophasic action potential duration (MAPD) and induce early after-depolarisations (EADs), while other studies support the view that coronary constriction resulting in ischaemia is the basis for the generation of arrhythmias. Moreover, ET-1 can induce cardioprotection (precondition) against infarct size and ventricular arrhythmias, through as yet incompletely understood mechanisms. To enable us to identify the most appropriate means of targeting this system in a therapeutically meaningful way we need to continue to explore the physiology of ET-1, both in the normal and the ischaemic heart

Orphan drugs and the NHS: Should we value rarity

Cost effectiveness plays an important part in current decisions about the funding of health technologies. Drugs for rare disease (orphan drugs) are often expensive to produce and, by definition, will benefit only small numbers of patients. Several countries have put measures in place to safeguard research and development of orphan drugs, but few get close to meeting the cost effectiveness criteria for funding by healthcare providers. We examine the justifications for special status for rare diseases and ask whether the cost effectiveness of drugs for rare or very rare diseases should be treated differently from that of other drugs and interventions

Disk Evolution in Young Binaries: from Observations to Theory

The formation of a binary system surrounded by disks is the most common outcome of stellar formation. Hence studying and understanding the formation and the evolution of binary systems and associated disks is a cornerstone of star formation science. Moreover, since the components within binary systems are coeval and the sizes of their disks are fixed by the tidal truncation of their companion, binary systems provide an ideal "laboratory" in which to study disk evolution under well defined boundary conditions. In this paper, we review observations of several inner disk diagnostics in multiple systems, including hydrogen emission lines (indicative of ongoing accretion), $K-L$ and $K-N$ color excesses (evidence of warm inner disks), and polarization (indicative of the relative orientations of the disks around each component). We examine to what degree these properties are correlated within binary systems and how this degree of correlation depends on parameters such as separation and binary mass ratio. These findings will be interpreted both in terms of models that treat each disk as an isolated reservoir and those in which the disks are subject to re-supply from some form of circumbinary reservoir, the observational evidence for which we will also critically review. The planet forming potential of multiple star systems is discussed in terms of the relative lifetimes of disks around single stars, binary primaries and binary secondaries. Finally, we summarize several potentially revealing observational problems and future projects that could provide further insight into disk evolution in the coming decadeComment: 16 pages, 7 figures, chapter in Protostars and Planets