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

Tephra dispersal during the Campanian Ignimbrite (Italy) eruption: implications for ultra-distal ash transport during the large caldera-forming eruption

The Campanian Ignimbrite eruption dispersed ash over much of the central eastern Mediterranean Sea and eastern Europe. The eruption started with a Plinian phase that was followed by a series of pyroclastic density currents (PDCs) associated with the collapse of the Plinian column and the caldera. The glass compositions of the deposits span a wide geochemical range but the Plinian fallout and PDCs associated with column collapse, the Lower Pumice Flow, only erupted the most evolved compositions. The later PDCs, the Breccia Museo and Upper Pumice Flow, erupted during and after caldera collapse, tap a less evolved component, and intermediate compositions that represent mixing between the end-members. The range of glass compositions in the Campanian Ignimbrite deposits from sites across the central and eastern Mediterranean Sea allow us to trace the dispersal of the different phases of this caldera-forming eruption. We map the fallout from the Plinian column and the plumes of fine material associated with the PDCs (co-PDCs) across the entire dispersal area. This cannot be done using the usual grain-size methods as deposits in these distal regions do not retain characteristics that allow attribution to either the Plinian or co-PDC phases. The glass compositions of the tephra at ultra-distal sites (>1500 km from the vent) match those of the uppermost PDC units, suggesting that most of the ultra-distal dispersal was associated with the late co-PDC plume that was generated during caldera collapse

Search for the supersymmetric partner of the top quark in p(p)over-bar collisions at root s=1.8 TeV

We report on a search for the supersymmetric partner of the top quark (top squark) produced in t (t) over bar events using 110 ph(-1) of p (p) over bar collisions at roots = 1.8 TeV recorded with the Collider Detector at Fermilab. In the case of a light top squark, the decay of-the top quark into a top squark plus the lightest supersymmetric particle (LSP) could have a significant branching ratio. The observed events are consistent with standard model t (t) over bar production and decay. Hence, we set limits on the branching ratio of the top quark decaying into a top squark plus LSP, excluding branching ratios above 45% for a LSP mass up to 30 GeV/c(2)

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)