Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Discussion on Causality

First, let me congratulate both authors on two fine papers which illuminate important aspects of causal inference. I have only a little to say about Professor Arjas ’ paper which specifically illuminates the aspect oftime and causality in an excellent way. I will therefore concentrate on the concepts described by Professor Rubin which seem to be more controversial, thus lending themselves directly to discussion. 1. Causal languages In the modern revival ofinterest in causal inference in statistics, a number ofcompeting formalisms prevail such as structural equations (Pearl, 2000), graphical models (Spirtes et al., 1993; Pearl, 1995a; Lauritzen, 2001; Dawid, 2002), counterfactual random variables (Robins, 1986), or potential responses (Rubin, 1974, 1978; Holland, 1986). Much energy has been used to promote the virtues ofone formalism versus the other, seemingly without coming nearer to a consensus; see the somewhat relentless discussion ofDawid (2000). Professor Rubin’s paper advocates the use of potential responses in contrast to graphical models, illustrated with a discussion of direct and indirect effects in connection with the use of surrogate endpoints in clinical trials

Correspondence (Box 1, Folder 18)

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