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

Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution

Fluid resuscitation after massive hemorrhage in major surgery and trauma may result in extensive hemodilution and coagulopathy, which is of a multifactorial nature. Although coagulopathy is often perceived as hemorrhagic, extensive hemodilution affects procoagulants as well as anticoagulant, profibrinolytic, and antifibrinolytic elements, leading to a complex coagulation disorder. Reduced thrombin activation is partially compensated by lower inhibitory activities of antithrombin and other protease inhibitors, whereas plasma fibrinogen is rapidly decreased proportional to the extent of hemodilution. Adequate fibrinogen levels are essential in managing dilutional coagulopathy. After extensive hemodilution, fibrin clots are more prone to fibrinolysis because major antifibrinolytic proteins are decreased.Fresh frozen plasma, platelet concentrate, and cryoprecipitate are considered the mainstay hemostatic therapies. Purified factor concentrates of plasma origin and from recombinant synthesis are increasingly used for a rapid restoration of targeted factors. Future clinical studies are necessary to establish the specific indication, dosing, and safety of novel hemostatic interventions

Recombinant human granulocyte - colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomised clinical trial

Study question: Does administration of recombinant human granulocyte colony stimulating factor in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? Summary answer: Recombinant human granulocyte colony stimulating factor administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss.What is known already: The only previous randomised controlled study of granulocyte colony stimulating factor in recurrent miscarriage in sixty-eight women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a RM population was identified in literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. Study design, size, duration: A randomised, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. Participants/materials, setting, methods: 150 women with a history of unexplained recurrent pregnancy loss: 76 were randomised to recombinant human granulocyte – colony stimulating factor and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte – colony stimulating factor 130 mcg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomisation with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. Main results and the role of chance: A total of 340 participants were screened for eligibility of which 150 women were randomised. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2] and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2] were randomised to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7 to 1.2; p=0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1to 13.4; p=0.93). Limitations, reasons for caution: This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s. Wider implications of the findings: To our knowledge, this is the first multicentre study and largest randomised clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single centre RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy. Study funding/competing interest(s): Mark Joing, Paul Kwon, Jeff Tong and Darryl Carter were or are employees of Nora Therapeutics, Inc. Arri Coomarasamy received consulting fees from Nora Therapeutics through his employer, University of Birmingham. Ruth Bender Atik received consulting fees from Nora 97 Therapeutics which was paid to The Miscarriage Association, UK. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with full text of this article.<br/