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

Potential macro-detritivore range expansion into the subarctic stimulates litter decomposition: a new positive feedback mechanism to climate change?

As a result of low decomposition rates, high-latitude ecosystems store large amounts of carbon. Litter decomposition in these ecosystems is constrained by harsh abiotic conditions, but also by the absence of macro-detritivores. We have studied the potential effects of their climate change-driven northward range expansion on the decomposition of two contrasting subarctic litter types. Litter of Alnus incana and Betula pubescens was incubated in microcosms together with monocultures and all possible combinations of three functionally different macro-detritivores (the earthworm Lumbricus rubellus, isopod Oniscus asellus, and millipede Julus scandinavius). Our results show that these macro-detritivores stimulated decomposition, especially of the high-quality A. incana litter and that the macro-detritivores tested differed in their decomposition-stimulating effects, with earthworms having the largest influence. Decomposition processes increased with increasing number of macro-detritivore species, and positive net diveristy effects occurred in several macro-detritivore treatments. However, after correction for macro-detritivore biomass, all interspecific differences in macro-detritivore effects, as well as the positive effects of species number on subarctic litter decomposition disappeared. The net diversity effects also appeared to be driven by variation in biomass, with a possible exception of net diversity effects in mass loss. Based on these results, we conclude that the expected climate change-induced range expansion of macro-detritivores into subarctic regions is likely to result in accelerated decomposition rates. Our results also indicate that the magnitude of macro-detritivore effects on subarctic decomposition will mainly depend on macro-detritivore biomass, rather than on macro-detritivore species number or identity

Inhibition of nitric oxide synthesis following severe hypoxia-ischemia restores autoregulation of cerebral blood flow in newborn lambs

Birth asphyxia impairs the autoregulatory ability of the cerebral blood flow. Inappropriate synthesis of vasodilatory nitric oxide may be important in this respect. We investigated if nitric oxide synthesis inhibition by N-omega-nitro-L-arginine (NLA) could restore cerebral autoregulation after severe hypoxia-ischemia (HI). HI was induced in 15 newborn lambs. Cerebral blood flow (carotid artery blood flow [ml/min]: Q(car)) and mean aortic blood pressure [mmHg]: MABP) were measured over a 30 min period before HI (pre-HI), 0-30 min after completion of HI (0-30 post-HI) and from 60 to 120 min post-HI (60-120 post-HI). Immediately after completion of HI, 5 lambs received a placebo (PLAC), 5 low dose NLA (10 mg/kg/iv: NLA-10) and 5 high dose NLA (40 mg/kg/iv: NLA-40). Pre-HI, all groups showed cerebral autoregulation with an upper limit of regulatory ability between 75 and 90 mm Hg. At 0-30 post-HI, all groups lacked autoregulatory ability of the cerebral vascular bed and showed an aortic blood pressure-passive Q(car). At 60-120 post-HI autoregulation was restored in NLA-10 and NLA-40-treated lambs (upper limit of autoregulation was shifted to higher MABP in NLA40-treated lambs), but not in placebo-treated lambs. At 60-120 post-HI MABP was higher in both NLA-groups than in PLAC group (83+/-15 [NLA-10] and 78+/-14 [NLA-40] vs. 65+/-9 mmHg [PLAC],

Stabilizing Group Treatment for Complex Posttraumatic Stress Disorder Related to Child Abuse Based on Psychoeducation and Cognitive Behavioural Therapy: A Multisite Randomized Controlled Trial

Background: Evidence-based treatments for complex posttraumatic stress disorder (PTSD) related to childhood abuse are scarce. This is the first randomized controlled trial to test the efficacy of psycho-educational and cognitive behavioural stabilizing group treatment in terms of both PTSD and complex PTSD symptom severity. Methods: Seventy-one patients with complex PTSD and severe comorbidity (e.g. 74% axis II comorbidity) were randomly assigned to either a 20-week group treatment in addition to treatment as usual or to treatment as usual only. Primary outcome measures were the Davidson Trauma Scale (DTS) for PTSD and the Structured Interview for Disorders of Extreme Stress (SIDES) for complex PTSD symptoms. Statistical analysis was conducted in the intention-to-treat (ITT) and in the completer sample. Subjects were considered responders when scoring at 20 weeks at least 1 standard deviation below pretest findings. Results: The 16% attrition was relatively low. After 20 weeks, the experimental condition (large effect sizes) and control condition (medium effect sizes) both showed significant decreases on the DTS and SIDES, but differences between the conditions were not significant. The secondary responder analysis (ITT) revealed significantly more responders on the DTS (45 vs. 21%), but not on the SIDES (61 vs. 42%). Conclusions: Adding psycho-educational and cognitive behavioural stabilizing group treatment for complex PTSD related to child abuse to treatment as usual showed an equivocal outcome. Patients in both conditions improved substantially during stabilizing treatment, and while significant superiority on change scores was absent, responder analysis suggested clinical meaningfulness of adding group treatment. Copyright © 2012 S. Karger AG