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

Quantitative approaches to content analysis: identifying conceptual drift across publication outlets

Unstructured text data, such as emails, blogs, contracts, academic publications, organizational documents, transcribed interviews, and even tweets, are important sources of data in Information Systems research. Various forms of qualitative analysis of the content of these data exist and have revealed important insights. Yet, to date, these analyses have been hampered by limitations of human coding of large data sets, and by bias due to human interpretation. In this paper, we compare and combine two quantitative analysis techniques to demonstrate the capabilities of computational analysis for content analysis of unstructured text. Specifically, we seek to demonstrate how two quantitative analytic methods, viz., Latent Semantic Analysis and data mining, can aid researchers in revealing core content topic areas in large (or small) data sets, and in visualizing how these concepts evolve, migrate, converge or diverge over time. We exemplify the complementary application of these techniques through an examination of a 25-year sample of abstracts from selected journals in Information Systems, Management, and Accounting disciplines. Through this work, we explore the capabilities of two computational techniques, and show how these techniques can be used to gather insights from a large corpus of unstructured text

Product Life-Cycle Assessment in the Realm of Enterprise Modeling

Part 1: Regular PapersInternational audience‘Sustainable development’ is perceived as a topic of steadily increasing importance. At its core lies a tension between the goals of economic growth and protection of environmental quality. As organizations have a direct impact (e.g., through their production processes) on the sustainability of a society and the planet as a whole, ensuring their sustainable development is crucial. In this paper, we argue that the sustainable development of organizations may be positively influenced by increasing organizations’ awareness of environmental impact of their products. Therefore, to support the assessment of environmental impact of product systems, based on ISO 14040, we design a domain-specific modeling method ImpactM as part of the Multi-perspective Enterprise Modeling (MEMO) approach. We evaluate it against identified requirements as well as using an exemplary scenario

Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia

Background: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses. Methods Design: Observational cohort study of progressive incremental exposure to EHH. Setting: University human physiology laboratory in London, UK (75 m) and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m. Participants: 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC) (5300 m). A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest. Main outcome measures: Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation), allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry. Results: Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m). All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude) field measurements of exercise capacity, cerebral blood flow velocity and microvascular blood flow at 7950 m and arterial blood gas measurement at 8400 m. Conclusions: This study demonstrates the feasibility and safety of conducting a large healthy volunteer cohort study of human adaptation to hypoxia in this difficult environment. Systematic measurements of a large set of variables were achieved in 222 subjects and at altitudes up to 8400 m. The resulting dataset is a unique resource for the study of genotype: phenotype interactions in relation to hypoxic adaptation