Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates

Mitochondrial [dys]function; culprit in pre-eclampsia?

Mitochondria are extensively identified for their bioenergetic capacities; however, recently these metabolic hubs are increasingly being appreciated as critical regulators of numerous cellular signalling systems. Mitochondrial reactive oxygen species have evolved as a mode of cross-talk between mitochondrial function and physiological systems, to sustain equipoise and foster adaption to cellular stress. Redox signalling mediated by exaggerated mitochondrial-ROS (reactive oxygen species) has been incriminated in a plethora of disease pathologies. Excessive production of mitochondrial ROS is intrinsically linked to mitochondrial dysfunction. Furthermore, mitochondrial dysfunction is a key facilitator of oxidative stress, inflammation, apoptosis and metabolism. These are key pathogenic intermediaries of pre-eclampsia, hence we hypothesize that mitochondrial dysfunction is a pathogenic mediator of oxidative stress in the pathophysiology of pre-eclampsia. We hypothesize that mitochondrial-targeted antioxidants may restrain production of ROS-mediated deleterious redox signalling pathways. If our hypothesis proves correct, therapeutic strategies directly targeting mitochondrial superoxide scavenging should be actively pursued as they may alleviate maternal vascular dysfunction and dramatically improve maternal and fetal health worldwide

3D Monte Carlo radiation transfer modelling of photodynamic therapy

We acknowledge the support of the UK Engineering and Physics Sciences Research Council (EPSRC) for funding through a studentship for C L Campbell as well as the Alfred Stewart Trust.The effects of ageing and skin type on Photodynamic Therapy (PDT) for different treatment methods have been theoretically investigated. A multilayered Monte Carlo Radiation Transfer model is presented where both daylight activated PDT and conventional PDT are compared. It was found that light penetrates deeper through older skin with a lighter complexion, which translates into a deeper effective treatment depth. The effect of ageing was found to be larger for darker skin types. The investigation further strengthens the usage of daylight as a potential light source for PDT where effective treatment depths of about 2 mm can be achieved.Publisher PD

Screening for Preterm Birth: Potential for a Metabolomics Biomarker Panel

The aim of this preliminary study was to investigate the potential of maternal serum to provide metabolomic biomarker candidates for the prediction of spontaneous preterm birth (SPTB) in asymptomatic pregnant women at 15 and/or 20 weeks’ gestation. Metabolomics LC-MS datasets from serum samples at 15- and 20-weeks’ gestation from a cohort of approximately 50 cases (GA < 37 weeks) and 55 controls (GA > 41weeks) were analysed for candidate biomarkers predictive of SPTB. Lists of the top ranked candidate biomarkers from both multivariate and univariate analyses were produced. At the 20 weeks’ GA time-point these lists had high concordance with each other (85%). A subset of 4 of these features produce a biomarker panel that predicts SPTB with a partial Area Under the Curve (pAUC) of 12.2, a sensitivity of 87.8%, a specificity of 57.7% and a p-value of 0.0013 upon 10-fold cross validation using PanelomiX software. This biomarker panel contained mostly features from groups already associated in the literature with preterm birth and consisted of 4 features from the biological groups of “Bile Acids”, “Prostaglandins”, “Vitamin D and derivatives” and “Fatty Acids and Conjugates”

Lost in translation : a postcolonial reading of Janice Honeyman’s Peter Pan

This dissertation explores the ways in which Janice Honeyman’s 2007 Swashbuckling Adventure, Peter Pan, The Pantomime represents notions of nation and identity in post-apartheid South Africa. In order to accomplish this, this study argues that despite the carnivalesque elements of the genre of pantomime and its potential to subvert the status quo, Honeyman’s translation of Peter Pan reinforces the imperialist ideology embedded in the source texts of Barrie’s 1904 and Disney’s 1953 Peter Pan. Through an exploration of colonialism and imperialism, and postcolonial studies with specific reference to the works of Bhabha (1990, 1994), Anderson (1991) and Said (1979, 1994), this discussion follows an examination of white Victorian British masculinity and imperialist ideology as it applies to Peter Pan to support the argument that through a process of translation, achieved through the techniques of Disneyfication and double localisation, the Barrie and Disney texts have been translated from their original contexts into the South African postcolonial and post-apartheid context. The argument concludes that in doing so, Honeyman has neglected to provide counter-discourses to the imperialist ideologies in the source texts and has reinforced the racial and gender stereotypes found therein, supporting the colonial power axis of the original text and colonial re-presentations of identity and nation.Dissertation (MA)--University of Pretoria, 2013.Dramaunrestricte

Colorectal stents: Do we have enough evidence?

AbstractBackgroundThe use of colonic stents has significantly evolved over the last few years. Emergency surgery for colonic obstructions is usually associated with significant mortality, morbidity and often stoma formation. Colonic stents provide an alternative way to relieve colonic obstruction, and hence avoiding the risks associated with emergency surgery. This literature review aims to summarize the important current evidence regarding colorectal stenting and show whether further evaluation of the procedure is required.ResultsThe available large number of non-randomized studies suggests that Self-Expandable-Metal-Stents (SEMS) placement for acute colonic obstruction could be considered as safe and effective alternative to surgery in experienced hands either as a bridge to surgery or as a palliative measure. This evidence has led to SEMS being widely adopted. However, randomized evidence has begun to show the defects that are inherent in the low level evidence that has so far supported SEMS use and it may be that reports of randomized controlled trials may clarify the patient population where SEMS placement is appropriate.ConclusionWhile we are still waiting for the outcome of the multicentre randomized controlled trials in the UK and Europe, clinicians must be aware of the current evidence limitations and apply SEMS use pragmatically

Maternal distress in late pregnancy alters obstetric outcomes and the expression of genes important for placental glucocorticoid signalling

The experience of maternal distress in pregnancy is often linked with poorer obstetric outcomes for women as well as adverse outcomes for offspring. Alterations in placental glucocorticoid signalling and subsequent increased fetal exposure to cortisol have been suggested to underlie this relationship. In the current study, 121 pregnant women completed the Perceived Stress Scale, State Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale in the third trimester of pregnancy. Placental samples were collected after delivery. Maternal history of psychiatric illness and miscarriage were significant predictors of poorer mental health in pregnancy. Higher anxiety was associated with an increase in women delivering via elective Caesarean Section, and an increase in bottle-feeding. Birth temperature was mildly reduced among infants of women with high levels of depressive symptomology. Babies of mothers who scored high in all stress (cumulative distress) measures had reduced 5-min Apgar scores. High cumulative distress reduced the expression of placental HSD11B2 mRNA and increased the expression of placental NR3C1 mRNA. These data support a role for prenatal distress as a risk factor for altered obstetric outcomes. The alterations in placental gene expression support a role for altered placental glucocorticoid signalling in the relationship between maternal prenatal distress and adverse outcomes