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

The role of increased pulmonary blood flow in pulmonary arterial hypertension

Chronic increased pulmonary blood flow is considered a pre-requisite for the induction of advanced vascular lesions in pulmonary arterial hypertension in congenital heart defects. The aim of the present study was to characterise the effects of increased pulmonary flow induced by an aortocaval shunt in the monocrotaline rat model for pulmonary hypertension in terms of survival, haemodynamics, pathology and histology. Male Wistar rats were injected with monocrotaline followed by the creation of an abdominal aortocaval shunt. Animals were sacrificed when displaying symptoms of weight loss or dyspnoea, 4-5 weeks after the creation of the shunt. Echocardiography identified increased ventricular dimensions in shunted rats and right ventricular hypertrophy in monocrotaline-treated rats. At similar pulmonary artery pressures, shunted monocrotaline rats displayed higher morbidity and mortality, increased pulmonary-to-systemic artery pressure ratios and increased right ventricular hypertrophy compared with nonshunted monocrotaline rats. Histological assessment demonstrated increased number and diameter of pre-acinar pulmonary arteries. Intra-acinar vessel remodelling and occlusion occurred to a similar extent in shunted and nonshunted monocrotaline rats. In conclusion, increased pulmonary blood flow in monocrotaline-induced pulmonary hypertension is associated with increased morbidity, mortality, and unfavourable haemodynamic and cardiac effects. These effects could be attributed to more pronounced right heart failure rather than to altered intra-acinar pulmonary vessel remodelling

Efficacy, tolerability and consumer acceptability of terbinafine topical spray versus terbinafine topical solution : a phase IIa randomised, observer-blind, comparative study

Tinea pedis is one of the world's most prevalent dermatophyte infections. MedSprayTM tinea pedis 1 % w/w (topical spray) is a novel, easy to use propellant based spray formulation containing 1% w/w terbinafine, requiring no manipulation at the site of infection. This is in contrast to the only formulation currently approved in Europe for single application (non are approved in the US for single use) which is Lamisil® Once 1 % w/w (topical solution), containing 1% w/w terbinafine hydrochloride which requires manipulation on the affected area. The aim of this phase IIa randomised, observer-blind, comparative study was to evaluate the efficacy, tolerability and consumer acceptability of a topical spray versus a topical solution in the treatment of tinea pedis.Peer reviewe

Subclass-specific IgG glycosylation is associated with markers of inflammation and metabolic health

Abstract This study indicates that glycosylation of immunoglobulin G, the most abundant antibody in human blood, may convey useful information with regard to inflammation and metabolic health. IgG occurs in the form of different subclasses, of which the effector functions show significant variation. Our method provides subclass-specific IgG glycosylation profiling, while previous large-scale studies neglected to measure IgG2-specific glycosylation. We analysed the plasma Fc glycosylation profiles of IgG1, IgG2 and IgG4 in a cohort of 1826 individuals by liquid chromatography-mass spectrometry. For all subclasses, a low level of galactosylation and sialylation and a high degree of core fucosylation associated with poor metabolic health, i.e. increased inflammation as assessed by C-reactive protein, low serum high-density lipoprotein cholesterol and high triglycerides, which are all known to indicate increased risk of cardiovascular disease. IgG2 consistently showed weaker associations of its galactosylation and sialylation with the metabolic markers, compared to IgG1 and IgG4, while the direction of the associations were overall similar for the different IgG subclasses. These findings demonstrate the potential of IgG glycosylation as a biomarker for inflammation and metabolic health, and further research is required to determine the additive value of IgG glycosylation on top of biomarkers which are currently used