Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity

New Findings

What is the central question of this study?Exercise performance is limited during hypoxia by a critical reduction in cerebral and skeletal tissue oxygenation. To what extent an elevation in systemic free radical accumulation contributes to microvascular deoxygenation and the corresponding reduction in maximal aerobic capacity remains unknown.What is the main finding and its importance?We show that altered free radical metabolism is not a limiting factor for exercise performance in hypoxia, providing important insight into the fundamental mechanisms involved in the control of vascular oxygen transport.

Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine  in both normoxia (21% O_{2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at  to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion 1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower  (P < 0.05 versus normoxia). Despite an exercise-induced increase in oxidative–nitrosative–inflammatory stress, hypoxia per se did not have an additive effect (P > 0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P > 0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower  in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia.}

'Regina v John Terry': The Discursive Construction of an Alleged Racist Event

This article explores the conformation in discourse of a verbal exchange and its subsequent mediatised and legal ramifications. The event concerns an allegedly racist insult directed by high profile English professional footballer John Terry towards another player, Anton Ferdinand, during a televised match in October 2011. The substance of Terry’s utterance, which included the noun phrase ‘fucking black cunt’, was found by a Chief Magistrate not to be a racist insult, although the fact that these actual words were framed within the utterance was not in dispute. The upshot of this ruling was that Terry was acquitted of a racially aggravated public order offence. A subsequent investigation by the regulatory commission of the English Football Association (FA) ruled, almost a year after the event, that Terry was guilty of racially abusing Ferdinand. Terry was banned for four matches and fined £220,000.

It is our contention that this event, played out in legal rulings, social media and print and broadcast media, constitutes a complex web of linguistic structures and strategies in discourse, and as such lends itself well to analysis with a broad range of tools from pragmatics, discourse analysis and cognitive linguistics. Amongst other things, such an analysis can help explain the seemingly anomalous - even contradictory - position adopted in the legal ruling with regard to the speech act status of ‘fucking black cunt’; namely, that the racist content of the utterance was not contested but that the speaker was found not to have issued a racist insult. Over its course, the article addresses this broader issue by making reference to the systemic-functional interpersonal function of language, particularly to the concepts of modality, polarity and modalisation. It also draws on models of verbal irony from linguistic pragmatics, notably from the theory of irony as echoic mention (c.f. Sperber and Wilson, 1981; Wilson and Sperber, 1992). Furthermore, the article makes use of the cognitive-linguistic framework, Text World Theory (c.f. Gavins, 2007; Werth, 1999) to examine the discourse positions occupied by key actors and adapts, from cognitive poetics, the theory of mind-modelling (c.f. Stockwell, 2009) to explore the conceptual means through which these actors discursively negotiate the event.

It is argued that the pragmatic and cognitive strategies that frame the entire incident go a long way towards mitigating the impact of so ostensibly stark an act of racial abuse. Moreover, it is suggested here that the reconciliation of Terry’s action was a result of the confluence of strategies of discourse with relations of power as embodied by the media, the law and perceptions of nationhood embraced by contemporary football culture. It is further proposed that the outcome of this episode, where the FA was put in the spotlight, and where both the conflict and its key antagonists were ‘intranational’, was strongly impelled by the institution of English football and its governing body both to reproduce and maintain social, cultural and ethnic cohesion and to avoid any sense that the event featured a discernable ‘out-group’.

The Complete Works of John Milton: Volume III: The Shorter Poems (826pp.)

Stephen B. Dobranski, Milton Quarterly 49.3 (October, 2015), 181-4:

'By addressing classical and neo-Latin works with which Milton's poems appear to engage, Haan has pursued something unattempted yet. Her erudite and engaging commentary on the Poemata is the most extensive and impressive that I have encountered in any edition ... Haan's discussion of Milton's Poemata - including the Testimonia, the one Italian and four Latin encomia by the poet's acquaintances published in 1645 and 1673 - is remarkably detailed and well-researched. In these sections, readers learn, for example, how Milton's Epitaphium Damonis borrows from both classical writers (Theocritus, Moschus) and contemporary models (Castiglione, Zanchi) while transcending all of them through a pattern of resurrection motifs. Or, readers can discover affinities between Milton's lament on the death of the Bishop of Ely and a poem by the Italian humanist Hieronymo Aleander, Jr., or learn about the connections between Milton's Elegia Quinta and George Buchanan's Maiae Calendae ... The Shorter Poems is a scholarly achievement of the highest order.'

Noam Reisner, Review of English Studies 65 (2014), 744-5:
‘Haan shines with her Neo-Latinist expertise by offering a vivid separate introduction to the Latin poems, which sets up Milton’s poemata specifically within the Neo-Latin contexts of the seventeenth century, thereby dispelling any remaining view of these poems as juvenilia (a view which results from reading the poems chronologically). … The present volume will instantly establish itself as the definitive resource for any reader interested in Milton’s shorter poems, and it is scarcely imaginable that it will ever be eclipsed or be in need of replacing. Its contribution is important in all areas, especially in providing for the first time in a single volume truly valuable documents which can teach us a lot more about Milton’s poetic development than simply reading the poems in chronological sequence. But perhaps, this edition’s greatest achievement is the way in which it succeeds in giving Milton’s Latin poems the pride of place they have long deserved as fully integral to Milton’s complete poetic imagination. Haan’s specific achievement in this regard is less in updating the translations than in providing a different context through which to look at the Latin poems themselves. Haan’s detailed commentaries set the Latin poems in a completely fresh light which looks beyond the obvious classical references and allusions, noted by Carey and many other editors, to Milton’s complex engagement with the Neo-Latin literary culture of his time. It is this aspect of the volume, more than anything else, which vindicates its essentialness.'

A hydrogel based zinc(ii) sensor for use in fluorescent multi-well plate analysis

A polymeric hydrogel containing a photoinduced electron transfer (PET) based probe for Zn(ii) has been formulated into the wells of a 96-well plate. Upon addition of Zn(ii) ions to selected wells, the fluorescence of the gel was observed to increase in a concentration dependent manner in the 0.25-1.75 mM range. The millimolar binding constant observed for this probe is higher than that reported for other Zn(ii) probes in the literature and offers the possibility to determine the concentration of this ion in environments where the Zn(ii) concentration is high. The combination of the multi-well plate set-up with fluorescence detection offers the possibility of high-throughput screening using low sample volumes in a timely manner. To the best of our knowledge, this is the first reported example of a polymeric hydrogel sensor for zinc with capability for use in fluorescence multi-well plate assay.

John Birks: Pioneer in quantitative palaeoecology

We describe the career of John Birks as a pioneering scientist who has, over a career spanning five decades, transformed palaeoecology from a largely descriptive to a rigorous quantitative science relevant to contemporary questions in ecology and environmental change. We review his influence on students and colleagues not only at Cambridge and Bergen Universities, his places of primary employment, but also on individuals and research groups in Europe and North America. We also introduce the collection of papers that we have assembled in his honour. The papers are written by his former students and close colleagues and span many of the areas of palaeoecology to which John himself has made major contributions. These include the relationship between ecology and palaeoecology, late-glacial and Holocene palaeoecology, ecological succession, climate change and vegetation history, the role of palaeoecological techniques in reconstructing and understanding the impact of human activity on terrestrial and freshwater ecosystems and numerical analysis of multivariate palaeoecological data.

John Punch, Scotist Holy War, and the Irish Catholic Revolutionary Tradition in the Seventeenth Century

During the 1640s, the Irish Franciscan theologian John Punch taught his theology students in Rome that war against Protestants was made just by their religion alone. Jesuits like Luis de Molina identified the holy war tradition in which Punch stood as a Scotist one, and insisted that the Scotists had confused the natural and supernatural spheres. Among Irishmen, Punch was unusual. The main Irish Catholic revolutionary tradition employed Jesuit and Thomist theory. They argued that the Stuarts had lost the right to rule Ireland for natural reasons, not supernatural ones; because the Stuarts were tyrants, not because they were Protestants.

John Maxwell

Biography of General Sir John Maxwell

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Can less be more? Comparison of an 8-item placement quality measure with the 50-item Dundee Ready Educational Environment Measure (DREEM)

Clinical clerks learn more than they are taught and not all they learn can be measured. As a result, curriculum leaders evaluate clinical educational environments. The quantitative Dundee Ready Environment Measure (DREEM) is a de facto standard for that purpose. Its 50 items and 5 subscales were developed by consensus. Reasoning that an instrument would perform best if it were underpinned by a clearly conceptualized link between environment and learning as well as psychometric evidence, we developed the mixed methods Manchester Clinical Placement Index (MCPI), eliminated redundant items, and published validity evidence for its 8 item and 2 subscale structure. Here, we set out to compare MCPI with DREEM. 104 students on full-time clinical placements completed both measures three times during a single academic year. There was good agreement and at least as good discrimination between placements with the smaller MCPI. Total MCPI scores and the mean score of its 5-item learning environment subscale allowed ten raters to distinguish between the quality of educational environments. Twenty raters were needed for the 3-item MCPI training subscale and the DREEM scale and its subscales. MCPI compares favourably with DREEM in that one-sixth the number of items perform at least as well psychometrically, it provides formative free text data, and it is founded on the widely shared assumption that communities of practice make good learning environments.