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

Medical therapy of Cushing's disease: where are we now?

The goals of ideal medical therapy for Cushing's disease should be to target the aetiology of the disorder, and thus surgery is the current 'gold standard' treatment. However, no effective drug that directly and effectively targets the adrenocorticotropin-secreting pituitary adenoma has been found to date, and treatments to control the hypercortisolaemic state by adrenal-based therapy are frequently used. Inhibitors of adrenal steroidogenesis, adrenolytic agents, compounds with neuromodulatory properties, and ligands of different nuclear hormone receptors involved in hypothalamo-pituitary regulation currently used have been reviewed. Ketoconazole and metyrapone can control hypercortisolaemicstates, as well as mitotane in selective cases, depending on their side effects and frequent monitoring. The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise, while retinoic acid analogues should be further investigated in the pituitary-targeted medical therapy of Cushing's disease. Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation, while adrenal steroidogenesis inhibitors are still the mainstay treatments for the control of the hypercortisolaemic state

Novel insights in the diagnosis of Cushing's syndrome.

Cushing's syndrome (CS) results from sustained pathologic hypercortisolism. Increased identification of cyclical CS and the similarities between the metabolic syndrome and mild CS has resulted in an increased prevalence of CS, necessitating more accurate diagnostic tests to screen and diagnose CS in its earliest stages. Many studies have examined the utility of resistance to steroid feedback by the dexamethasone suppression tests and increases in secretion assessing 24-hour urinary free cortisol; however, the most sensitive indicator is the loss of circadian rhythmicity. Therefore, midnight sleeping cortisol is undoubtedly an extremely sensitive indicator of CS but impractical for screening purposes. In this situation assessment late-night salivary cortisol (NSC) is being increasingly investigated as a simple and convenient outpatient procedure. Salivary cortisol has also been used in stimulation or suppression tests because of the detection of rapid changes in cortisol concentration. This paper discusses the effectiveness of SC as a putative accurate, stress-free, and non-invasive sampling procedure. Some studies have shown no difference between tests while others demonstrated a higher sensitivity of SC, while the combination of tests seems to increase their diagnostic value. However, the different assays used for SC estimation and the variable types of control groups in the published studies render a comparison of studies difficult. In conclusion, NSC measurement is increasingly being used as a first-line test for CS, but we recommend that local centres establish their own normative ranges, and there is still a place for the more traditional tests to confirm the diagnosis