Role of prostacyclin in pulmonary hypertension

Date of Acceptance: 11/12/2014 This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY-4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it’s discovery in the 1980s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertensionPeer reviewedFinal Published versio

PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy

Mitochondrial fission is essential for the degradation of damaged mitochondria. It is currently unknown how the dynamin-related protein 1 (DRP1)-associated fission machinery is selectively targeted to segregate damaged mitochondria. We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently of Parkin. Normally, the scaffold protein AKAP1 recruits protein kinase A (PKA) to the outer mitochondrial membrane to phospho-inhibit DRP1. We reveal that after damage, PINK1 triggers PKA displacement from A-kinase anchoring protein 1. By ejecting PKA, PINK1 ensures the requisite fission of damaged mitochondria for organelle degradation. We propose that PINK1 functions as a master mitophagy regulator by activating Parkin and DRP1 in response to damage. We confirm that PINK1 mutations causing Parkinson disease interfere with the orchestration of selective fission and mitophagy by PINK1

Multiple crown size variables of the upper incisors in patients with supernumerary teeth compared with controls

Aims: As part of ongoing studies of the aetiology of dental anomalies the aims of this study were to identify multiple components of tooth size of the upper permanent incisors in 34 patients with supernumerary teeth and to compare them with those in a control group to determine whether the presence of a supernumerary tooth has a local effect on the size of the surrounding dentition. Methods and results: The labial and occlusal aspects of the clinical crowns of the upper permanent central and lateral incisors on the study models of 74 subjects were digitally imaged and measured using an image analysis system and automated macro (34 patients with supernumerary in the upper incisor region: 17 males and 17 females and 40 controls: 20 males and 20 females). The macro-defined 17 variables from each view. From the labial view these were: the mesio-distal and occluso-gingival length and additional measurements along 25 and 75% of the mesio-distal line and at 25, 50 and 75% along the occluso-gingival line such that all these sub-divisions extended to the periphery of the tooth. From the occlusal view these were: the mesio-distal and labio-lingual lengths, and additional variables that sub-divided the mesio-distal again at 25 and 75% along the length and at 25, 50 and 75% along the labio-lingual dimension. Principal component analysis (PCA) was used to identify the key factors with the most random variability. Comparisons were then carried out between the supernumerary cases and control group using 2-way ANOVA. Seven factors of tooth size for the upper central incisors and eight factors for the upper lateral incisors were extracted. Most of these variables were found to be larger in the supernumerary group than in the control. Statistically significant differences were found for 5 out of 7 and 4 out of 8 for the upper central and lateral incisors respectively. Conclusions: A number of factors of tooth size were identified and found to be larger in the supernumerary group compared to the control (7 for upper central and 8 for upper lateral incisors); the majority reached the 0.05 significance level. Tooth crown size of the upper central incisor was affected more than that of the upper lateral incisor, supporting a local field effect. (C) 2008 Elsevier Ltd. All rights reserved

The development of strategies for the management and research of foliar pathogens on Eucalypt plantations : using Mycosphaerella as a case study

Foliar pathogens are capable of severely reducing the productivity and stem form of eucalypt trees in plantations. Mycosphaerella is one of the most severe defoliating pathogens to eucalypts worldwide. In Australia Mycosphaerella leaf disease (MLD) has produced episodes of severe defoliation in Tasmania, Gippsland and south-west Western Australia. Mycosphaerella is one of the most researched pathogens of eucalypts, however the majority of studies have concentrated on the taxonomy of pathogens and investigating their geographical and host ranges. In this thesis, MLD has been chosen as a model system to develop and apply new technologies to researching foliar pathogens. Research was conducted in the four main areas of disease assessment, growth impacts, molecular detection and resistance mechanisms. Acquiring accurate and repeatable damage estimates at a tree level is essential for calculating damage at plantation and estate levels; especially where data will be used for computer generated modelling using programs such as Maestra or CABALA. Repeated assessments using the Crown Damage Index (CDI) tested the suitability of the method to provide reliable, objective and repeatable results. Nine assessors, with varying levels of experience, estimated damage on three plots of fifty trees each (3-4 years old), to obtain an understanding of the subjectivity of assessing damage caused by insects (e.g. Chrysophtharta spp.) and fungal pathogens (e.g. Mycosphaerella spp.) on Eucalyptus globulus Labill. Damage levels were measured by destructive sampling to enable direct comparisons between estimates and damage levels to be made. The most experienced assessors provided the most repeatable estimates and were generally the most accurate. The incidence of foliar necrosis was the least subjective measure while defoliation was the most subjective and the least accurate of the indices measured. All assessors, regardless of experience, were able to predict the Crown Damage Index (a combined index of all damage classes) to within 12 % of measured damage levels. Further modification of the CDI in a separate study on younger trees (1-2 years old) further reduced the errors involved with damage estimates to within 4 % of actual damage levels. Despite the importance of Mycosphaerella species as significant defoliating pathogens of temperate plantation eucalypts such as E. globulus, there have been no studies to investigate the effects of Mycosphaerella damage on growth of young trees measured through to rotation length. From the results of two growth trials, one short term and one longer term (tree growth was monitored until 3 and 6 years old, respectively), the damage threshold (level of damage before there were significant growth effects) was estimated to be approximately 20 %. In both trials, losses in volume were only observed until trees changed to adult foliage at which point the growth rate returned to that of the control trees. We predicted that with less than 80 % damage, growth rates follow a type 1 growth response, i.e. after an initial growth loss damaged trees recover and have a growth rate that is parallel with control trees. Above 80 % loss of effective leaf area, it is predicted that growth rates of control trees and damaged trees are permanently divergent. To give a longterm estimate of impact, the growth of trees in the longer term trial were modelled to rotation length. After 25 years growth (rotation length) it is estimated that a loss of one year's growth will occur as a result of the MLD damage observed in this trial. One year was also the length of time that juvenile foliage was exposed to greater than 20% damage. A nested PCR detection method was applied to leaves and stems infected by MLD to detect the five most common Mycosphaerella species that occur in Tasmania. Leaf samples were taken from E. globulus and Eucalyptus nitens (Deane and Maid.) Maid. plantations in the northern regions of Tasmania and native re-growth in the north-east of Tasmania. For the first time it has been conclusively shown that in excess of five Mycosphaerella species can coexist in E. globulus leaves and four in E. nitens leaves, including a record of Mycosphaerella nubilosa (Cooke) Hansf. on E. nitens which has only been documented once before. Samples from native Eucalyptus regnans (Thum) Lindaure provided evidence that the co-existence of several Mycosphaerella species on a single lesion may occur outside the plantation environment. The molecular detection test was a rapid, reliable and cost-effective method in comparison with classical mycological methods for the identification and differentiation of species associated with MLD on eucalypts. These studies have highlighted the potential for multiple pathogenic species of Mycosphaerella to simultaneously occupy the same niche. The Mycosphaerella detection technique was also applied to determine the presence of species associated with MLD in leaf lesions of varying development, including asymptomatic tissue. Symptoms characteristic of putative Mycosphaerella lesions, collected from commercial E. globulus and E. nitens plantations, were categorised into five stages of development with asymptomatic tissue designated as the stage prior to any symptom expression. Lesions in all categories, including some asymptomatic leaf tissue, tested positive for the presence of up to four ycosphaerella species. The number and composition of species within a lesion varied between early and late stage lesions, with trends occurring for the most pathogenic species to occupy necrotic and reproductive lesions exclusively (E. nitens) or with only one other species (E. globulus). Early detection of Mycosphaerella species in asymptomatic leaves and at any stage of lesion maturity will facilitate more accurate, rapid and broad scale screening of plantations for ecological and epidemiological investigations at earlier stages of disease development. Effective and reproducible artificial inoculation techniques for MLD have not been developed; the confirmation of Mycosphaerella species in naturally infected early lesions using the nested PCR detection system enables the study of field infected leaves to determine the effects of infection on host physiology and resistance. The timing and strength of necrophylactic periderm formation, deposition of defence chemicals and accumulation/retention of photosynthetic pigments were compared between MLD susceptible E. globulus and the more MLD resistant E. nitens after infection of the leaves with Mycosphaerella species. Resistance of E. nitens, as observed in southern Australia, was attributed to the speed of necrophylactic periderm formation, which was directly related to the amount and type of cell division occurring in the mesophyll cells. In E. nitens the necrophylactic periderm is formed early in lesion development by cellular division of mesophyll cells which were quickly reinforced with lignin, suberin and other polyphenolics. It is suggested that the rapid nature of necrophylactic periderm formation in leaves of E. nitens was due to the presence of isobilateral palisade layers and the need for less cellular division to fill intracellular spaces and form a continuous barrier of cells. In E. globulus, which has only one adaxial palisade layer, the necrophylactic periderm was formed more slowly and in a distorted fashion. It was primarily formed through hypertrophic changes to existing cells and limited cell divisions. Deposits of lignin and suberin in the cells of the necrophylactic periderm did not occur in E. globulus until later stages of lesion development, and in many cases the necrophylactic periderm appeared to be ineffective in preventing further disease development. From this study of necrophylactic periderm formation, it was suggested that increased mesophyll density within a leaf may be linked with the speed and shape of necrophylactic periderms that are formed after infection by Mycosphaerella species; thus the more resistant species/families are able to restrict pathogen spread more effectively than susceptible species/families. Under the same environmental conditions and inoculum load, northern NSW provenances of E. nitens have been observed to be more resistant to MLD than southern NSW provenances. Using histological methods, one provenance from each distribution were investigated with respect to constitutive anatomy. The cellular and histochemical changes after infection by Mycosphaerella species that led to barrier zone formation, including accumulation of defence compounds such as suberin, lignin and flavanoids were also compared. Leaves of resistant provenances were significantly thinner, had a higher proportion of palisade mesophyll and reduced intracellular airspace compared with those from the susceptible provenance. After infection, more cellular division was observed in sections from resistant leaves and the necrophylactic periderm formed was more organised, continuous, suberised and lignified than necrophylactic periderms formed in susceptible leaves. It is suggested that higher constitutive proportions of cell-dense palisade layers and thinner leaves can reduce the cellular division required to form of necrophylactic periderms after injury and compartmentalise pathogens more rapidly. More compact palisade layers may also play a role in the slowing or prevention of infection as some Mycosphaerella species may not be able to penetrate tightly packed mesophyll cells. Resistance of E. globulus juvenile foliage to MLD has been shown to be under high genetic control. Differences between pairs of resistant and susceptible families, in constitutive traits of juvenile leaves such as stomatal density (counted with wax on and with wax removed), leaf density, total phenolics and total leaf wax was assessed on juvenile leaves. Four resistant and susceptible pairs of families were compared including one inter-provenance, one intra-provenance and two within family contrasts. Resistant families had significantly higher leaf density in three of the four contrasts and had a higher density of palisade mesophyll cells. Resistant genotypes also had a higher proportion of stomata covered by wax. The density of exposed stomata (both abaxial and adaxial) may influence resistance to initial Mycosphaerella infection with wax coverage or deposition identified as the main trait governing the exposure of stomatal openings. This study suggests that leaf density may be associated with a higher cellular density within the leaf which would increase the potential for necrophylactic periderm formation and compartmentalisation of the infected area once infection has occurred. Future studies are required to determine the relationship between leaf density and cellular density

Dental treatment and risk of variant CJD - a case control study

Abstract Objective: Knowledge of risk factors for variant CJD (vCJD) remains limited, but transmission of prion proteins via re-useable medical devices, including dental instruments, or enhanced susceptibility following trauma to the oral cavity is a concern. This study aimed to identify whether previous dental treatment is a risk factor for development of vCJD. Design: Case control study Methods: Risk factor questionnaires completed by interview with relatives of 130 vCJD patients and with relatives of 66 community and 53 hospital controls were examined by a dental surgeon. Responses regarding dental treatments were analysed. Results: We did not find a statistically significant excess of risk of vCJD associated with dental treatments with the exception of extractions in an unmatched analysis of vCJD cases with community controls (p=0.02). However, this result may be explained by multiple testing. Conclusions: This is the first published study to date to examine potential links between vCJD and dental treatment. There was no convincing evidence found of an increased risk of variant CJD associated with reported dental treatment. However, the power of the study is restricted by the number of vCJD cases to date and does not preclude the possibility that some cases have resulted from secondary transmission via dental procedures. Due to the limitations of the data available, more detailed analyses of dental records are required to fully exclude the possibility of transmission via dental treatment

Working with prisoners who self-harm: a qualitative study on stress, denial of weakness, and encouraging resilience in a sample of correctional staff

Background: Rates of self‐harm are high among prisoners. Most research focuses on the vulnerable prisoner, and there is little on the impact of these behaviours on staff. Aims: To investigate staff perceptions of self‐harming behaviours by prisoners, including their views on its causes, manifestation, prevention in institutions, and impact on them. Methods: Semi-structured interviews were conducted with 20 administrative and 21 therapeutic prison staff who are responsible in various ways for prisoners who self‐harm. Their narratives were explored using interpretative phenomenological analysis. Results: Despite prison staff being experienced with prisoners' self‐harming behaviours, including severe acts of self‐harm, they were apt to reject any negative impact on their own mental health or well‐being. This denial of negative impact was accompanied by perceptions of the inmate's actions being manipulative and attention seeking. Prison staff also perceived institutional responses to self‐harming behaviours by prisoners as being mixed, ambiguous, or showing preference for relying on existing suicide protocols rather than task‐specific guidance. Conclusions: Although staff gave explanations of prisoner self‐harm in terms of “manipulative behaviour”, prisoners' self‐harm is, in fact, complex, challenging, and often severe. This staff perception may reflect denial of impact of often distressing behaviours on them personally and their own coping mechanisms. This could be feeding in to a perceived lack of clear and effective institutional responses to the self‐harm, so further research is needed to determine how staff could broaden their views, and respond more effectively to prisoners. Psychologically informed group work and/or reflective practice are among the candidates for such help for staff

Resting-state EEG for the diagnosis of idiopathic epilepsy and psychogenic nonepileptic seizures: A systematic review

Quantitative markers extracted from resting-state electroencephalogram (EEG) reveal subtle neurophysiological dynamics which may provide useful information to support the diagnosis of seizure disorders. We performed a systematic review to summarize evidence on markers extracted from interictal, visually normal resting-state EEG in adults with idiopathic epilepsy or psychogenic nonepileptic seizures (PNES). Studies were selected from 5 databases and evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. 26 studies were identified, 19 focusing on people with epilepsy, 6 on people with PNES, and one comparing epilepsy and PNES directly. Results suggest that oscillations along the theta frequency (4–8 Hz) may have a relevant role in idiopathic epilepsy, whereas in PNES there was no evident trend. However, studies were subject to a number of methodological limitations potentially introducing bias. There was often a lack of appropriate reporting and high heterogeneity. Results were not appropriate for quantitative synthesis. We identify and discuss the challenges that must be addressed for valid resting-state EEG markers of epilepsy and PNES to be developed

Quantifying uncertainty in acoustic measurements of tidal flows using a ‘Virtual’ Doppler Current Profiler

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Accurate characterisation of flows at tidal sites can enable the developers of tidal stream energy projects to design and model the loads on, and the performance of, tidal energy converters. Acoustic Doppler technology is versatile in the measurement of sea conditions; however, this technology can be limited in its effectiveness at measuring the small-scale kinematic fluctuations caused by waves and turbulence. A Virtual Doppler Current Profiler (VDCP) is used to sample a simulated tidal flow to understand the limitations of this type of measurement instrument whilst recording the small timescale kinematics of waves and turbulence in tidal currents. Results demonstrate the phase dependency of velocity measurements averaged between two acoustic beams and provide a theoretical error for wave and turbulence characteristics sampled under a range of conditions. Spectral moments of the subsurface longitudinal wave orbital velocities recorded by the VDCP can be between 0.1 and 9 times those measured at a point for certain turbulent current conditions, turbulence intensity measurements may vary between 0.2 and 1.5 times the inputted value in low wave conditions and turbulence length scale calculation can also vary hugely dependent on both current and wave conditions. The continuation of this work will enable effective comparison of a linear model for tidal flow kinematics against field measurements from UK tidal site data, and subsequently validate numerical models for the testing of tidal turbines.This work was supported by the Industrial Centre for Offshore Renewable Energy (IDCORE) with funding from the Energy Technologies Institute and the Research Councils Energy Programme [grant number EP/J500847/1] and DNV GL