Teaching TEI: The Need for TEI by Example

The Text Encoding Initiative (TEI)1 has provided a complex and comprehensive system of provisions for scholarly text encoding. Although a major focus of the ‘digital humanities’ domain, and despite much teaching effort by the TEI community, there is a lack of teaching materials available, which would encourage the adoption of the TEI's recommendations and the widespread use of its text encoding guidelines in the wider academic community. This article describes the background, plans, and aims of the TEI by Example project, and why we believe it is a necessary addition to the materials currently provided by the TEI itself. The teaching materials currently available are not suited to the needs of self directed learners, and the development of stand alone, online tutorials in the TEI are an essential addition to the extant resources, in order to encourage and facilitate the uptake of TEI by both individuals and institutions

Endothelium-derived relaxing factor and coronary vasospasm.

The endothelium releases the powerful vasodilator and antiaggregatory substance, EDRF, both under basal conditions and upon stimulation by a wide variety of agents. Endothelial injury or dysfunction may play an important role in the spasmogenicity of the coronary artery, although other possible alterations related to atherosclerosis should also be considered. Among the possible stimuli, aggregating platelets are important as a source of vasoconstrictor substances. The endothelium may also produce the vasoactive substances EDHF and EDCF(s). Their pathophysiologic significance remains to be determined.link_to_subscribed_fulltex

New horizons in frailty: the contingent, the existential and the clinical

In the past decade, frailty research has focused on refinement of biomedical tools and operationalisations, potentially introducing a reductionist approach. This article suggests that a new horizon in frailty lies in a more holistic approach to health and illness in old age. This would build on approaches that view healthy ageing in terms of functionality, in the sense of intrinsic capacity in interplay with social environment, whilst also emphasising positive attributes. Within this framework, frailty is conceptualised as originating as much in the social as in the biological domain; as co-existing with positive attributes and resilience, and as situated on a continuum with health and illness. Relatedly, social science-based studies involving interviews with, and observations of, frail, older people indicate that the social and biographical context in which frailty arises might be more impactful on the subsequent frailty trajectory than the health crisis which precipitates it. For these reasons, the article suggests that interpretive methodologies, derived from the social sciences and humanities, will be of particular use to the geriatrician in understanding health, illness and frailty from the perspective of the older person. These may be included in a toolkit with the purpose of identifying how biological and social factors jointly underpin the fluctuations of frailty and in designing interventions accordingly. Such an approach will bring clinical approaches closer to the views and experiences of older people who live with frailty, as well as to the holistic traditions of geriatric medicine itself

Liquid Chromatography Electron Capture Dissociation Tandem Mass Spectrometry (LC-ECD-MS/MS) versus Liquid Chromatography Collision-induced Dissociation Tandem Mass Spectrometry (LC-CID-MS/MS) for the Identification of Proteins

Electron capture dissociation (ECD) offers many advantages over the more traditional fragmentation techniques for the analysis of peptides and proteins, although the question remains: How suitable is ECD for incorporation within proteomic strategies for the identification of proteins? Here, we compare LC-ECD-MS/MS and LC-CID-MS/MS as techniques for the identification of proteins.Experiments were performed on a hybrid linear ion trap–Fourier transform ion cyclotron resonance mass spectrometer. Replicate analyses of a six-protein (bovine serum albumin, apo-transferrin,lysozyme, cytochrome c, alcohol dehydrogenase, and β-galactosidase) tryptic digest were performed and the results analyzed on the basis of overall protein sequence coverage and sequence tag lengths within individual peptides. The results show that although protein coverage was lower for LC-ECDMS/MS than for LC-CID-MS/MS, LC-ECD-MS/MS resulted in longer peptide sequence tags,providing greater confidence in protein assignment

Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage

Role of cyclooxygenase in the vascular responses to extremity cooling in Caucasian and African males

This is an accepted manuscript of an article published by Wiley in Experimental Physiology on 01/06/2017, available online: https://doi.org/10.1113/EP086186 The accepted version of the publication may differ from the final published version.© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society New Findings: What is the central question of this study? Compared with Caucasians, African individuals are more susceptible to non-freezing cold injury and experience greater cutaneous vasoconstriction and cooler finger skin temperatures upon hand cooling. We investigated whether the enzyme cyclooxygenase is, in part, responsible for the exaggerated response to local cooling. What is the main finding and its importance? During local hand cooling, individuals of African descent experienced significantly lower finger skin blood flow and skin temperature compared with Caucasians irrespective of cyclooxygenase inhibition. These data suggest that in young African males the cyclooxygenase pathway appears not to be the primary reason for the increased susceptibility to non-freezing cold injury. Individuals of African descent (AFD) are more susceptible to non-freezing cold injury (NFCI) and experience an exaggerated cutaneous vasoconstrictor response to hand cooling compared with Caucasians (CAU). Using a placebo-controlled, cross-over design, this study tested the hypothesis that cyclooxygenase (COX) may, in part, be responsible for the exaggerated vasoconstrictor response to local cooling in AFD. Twelve AFD and 12 CAU young healthy men completed foot cooling and hand cooling (separately, in 8°C water for 30 min) with spontaneous rewarming in 30°C air after placebo or aspirin (COX inhibition) treatment. Skin blood flow, expressed as cutaneous vascular conductance (as flux per millimetre of mercury), and skin temperature were measured throughout. Irrespective of COX inhibition, the responses to foot cooling, but not hand cooling, were similar between ethnicities. Specifically, during hand cooling after placebo, AFD experienced a lower minimal skin blood flow [mean (SD): 0.5 (0.1) versus 0.8 (0.2) flux mmHg−1, P < 0.001] and a lower minimal finger skin temperature [9.5 (1.4) versus 10.7 (1.3)°C, P = 0.039] compared with CAU. During spontaneous rewarming, average skin blood flow was also lower in AFD than in CAU [2.8 (1.6) versus 4.3 (1.0) flux mmHg−1, P < 0.001]. These data provide further support that AFD experience an exaggerated response to hand cooling on reflection this appears to overstate findings; however, the results demonstrate that the COX pathway is not the primary reason for the exaggerated responses in AFD and increased susceptibility to NFCI.This research was funded by the University of Portsmouth.Published versio

IPEM Topical Report: an international IPEM survey of MRI use for external beam radiotherapy treatment planning

Introduction/Background: Despite growing interest in magnetic resonance imaging (MRI), integration in external beam radiotherapy (EBRT) treatment planning uptake varies globally. In order to understand the current international landscape of MRI in EBRT a survey has been performed in 11 countries. This work reports on differences and common themes identified. Methods: A multi-disciplinary Institute of Physics and Engineering in Medicine working party modified a survey previously used in the UK to understand current practice using MRI for EBRT treatment planning, investigate how MRI is currently used and managed as well as identify knowledge gaps. It was distributed electronically within 11 countries: Australia, Belgium, Denmark, Finland, France, Italy, the Netherlands, New Zealand, Sweden, the UK and the USA. Results: The survey response rate within the USA was <1% and hence these results omitted from the analysis. In the other 10 countries the survey had a median response rate of 77% per country. Direct MRI access, defined as either having a dedicated MRI scanner for radiotherapy (RT) or access to a radiology MRI scanner, varied between countries. France, Italy and the UK reported the lowest direct MRI access rates and all other countries reported direct access in ≥82% of centres. Whilst ≥83% of centres in Denmark and Sweden reported having dedicated MRI scanners for EBRT, all other countries reported ≤29%. Anatomical sites receiving MRI for EBRT varied between countries with brain, prostate, head and neck being most common. Commissioning and QA of image registration and MRI scanners varied greatly, as did MRI sequences performed, staffing models and training given to different staff groups. The lack of financial reimbursement for MR was a consistent barrier for MRI implementation for RT for all countries and MR access was a reported important barrier for all countries except Sweden and Denmark. Conclusion: No country has a comprehensive approach for MR in EBRT adoption and financial barriers are present worldwide. Variations between countries in practice, equipment, staffing models, training, QA and MRI sequences have been identified, and are likely to be due to differences in funding as well as a lack of consensus or guidelines in the literature. Access to dedicated MR for EBRT is limited in all but Sweden and Denmark, but in all countries there are financial challenges with ongoing per patient costs. Despite these challenges, significant interest exists in increasing MR guided EBRT planning over the next 5 years

Diabetes and reactivity of isolated human saphenous vein

Helical strips of saphenous veins from diabetic ( n =8) and non-diabetic ( n = 18) humans were studied in vivo for their responsiveness to several vasoactive agents. Following application of passive force (˜20·0 mN), venous strips from non-diabetic humans often developed spontaneous phasic contractile activity (12 out of 18 patients; 2–5 contractions/min). These intrinsic changes in force were seen in venous strips from only one diabetic patient. The phasic contractions were not altered by treatment with phentolamine, whereas the calcium channel blocker, D-600, and calcium-free solution (1·0 mM EGTA) inhibited the phasic contractions. Saphenous veins from diabetic patients developed less maximal, active tension in response to norepinephrine than those from non-diabetic patients. Contractile responses to serotonin, angiotensin II, and elevated potassium concentration in saphenous veins from diabetic patients were not different from those in veins from non-diabetic patients. These observations demonstrate attenuated development of active tension in response to alpha-adrenergic receptor activation and reduced spontaneous contractile activity in venous smooth muscle from diabetic patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74640/1/j.1475-097X.1984.tb00136.x.pd

The Liver-Selective Thyromimetic T-0681 Influences Reverse Cholesterol Transport and Atherosclerosis Development in Mice

Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice.T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls.The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans

ATP13A2 deficiency disrupts lysosomal polyamine export

ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome—a parkinsonism with dementia1—and early-onset Parkinson’s disease2. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson’s disease, whereas loss of ATP13A2 compromises lysosomes3. However, the transport function of ATP13A2 in lysosomes remains unclear. Here we establish ATP13A2 as a lysosomal polyamine exporter that shows the highest affinity for spermine among the polyamines examined. Polyamines stimulate the activity of purified ATP13A2, whereas ATP13A2 mutants that are implicated in disease are functionally impaired to a degree that correlates with the disease phenotype. ATP13A2 promotes the cellular uptake of polyamines by endocytosis and transports them into the cytosol, highlighting a role for endolysosomes in the uptake of polyamines into cells. At high concentrations polyamines induce cell toxicity, which is exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture and cathepsin B activation. This phenotype is recapitulated in neurons and nematodes with impaired expression of ATP13A2 or its orthologues. We present defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration, and shed light on the molecular identity of the mammalian polyamine transport system