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”

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

Oxidative stress in pre-eclampsia; have we been looking in the wrong place?

Pre-eclampsia is a disorder of late pregnancy. It is a major cause of maternal and perinatal morbidity and mortality, accounting for nearly 18% of all maternal deaths worldwide; an estimated 77,000 maternal deaths per year [1]. Poor placentation is considered to be an initial cause of the placental ischemia [2]. Placental ischemia in turn gives rise to oxidative stress in the placenta and leads to shedding of syncytiotrophoblast debris into the maternal circulation provoking a systemic maternal inflammatory response and release of sFLT and sENG causing maternal vascular endothelial dysfunction. The ubiquitous nature of the maternal vascular endothelium accounts for the diverse multi-system nature of pre-eclampsia. Currently there is no treatment for pre-eclampsia except delivery of the placenta and the baby, with the attendant risk of iatrogenic prematurity and significant neonatal morbidity and mortality. As a result, intensive research endeavours have focused on defining the molecular mechanisms of pre-eclampsia and the identification of new pre-symptomatic biomarkers of the condition. This review focuses on the role of elevated oxidative stress in the pathology of pre-eclampsia and potential therapeutic agents targeting oxidative stress that may prevent or ameliorate this disorder

Rapid prototyping and validation of FS-FBMC dynamic spectrum radio with simulink and ZynqSDR

This paper presents the research carried out in developing and targeting a novel real-time Dynamic Spectrum Access (DSA) Frequency Spread Filter Bank Multicarrier (FS-FBMC) transmitter prototype to programmable ‘ZynqSDR’ Software Defined Radio (SDR) hardware, and introduces a series of experiments used to validate the design’s ‘cognitive’ DSA capabilities. This transmitter is a proof of concept, that uses DSA techniques to enable Secondary Users (SUs) to access the band traditionally used for FM Radio broadcasting (88-108 MHz), and establish data communication channels in vacant parts of the FM Radio Primary User (PU) spectrum using a multicarrier modulation scheme with a Non Contiguous (NC) channel mask. Once implemented on the hardware, the transmitter is subjected to various FM Radio environments sampled from around Central Scotland, and it is demonstrated that it can dynamically adapt its NC transmitter mask in real time to protect the FM Radio signals it detects. A video is presented of this dynamic on-hardware spectral reconfiguration, and the reader is encouraged to view the video to appreciate the responsiveness of the design. An investigation into potential FBMC guardband sizes is carried out, with initial findings indicating a guardband of 200 kHz (either side of an FM Radio station) is required in order to prevent interference with the PUs. This paper also demonstrates the capabilities of the MATLAB®/ Simulink ZynqSDR workflow, and provides a case study and reference design that we feel other researchers working in this field can benefit from

Early cost-effectiveness analysis of screening for preeclampsia in nulliparous women:A modelling approach in European high-income settings

BACKGROUND: Preeclampsia causes substantial maternal and perinatal morbidity and mortality and significant societal economic impact. Effective screening would facilitate timely and appropriate prevention and management of preeclampsia. OBJECTIVES: To develop an early cost-effectiveness analysis to assess both costs and health outcomes of a new screening test for preeclampsia from a healthcare payer perspective, in the United Kingdom (UK), Ireland, the Netherlands and Sweden. METHODS: A decision tree over a 9-month time horizon was developed to explore the cost-effectiveness of the new screening test for preeclampsia compared to the current screening strategy. The new test strategy is being developed so that it can stratify healthy low risk nulliparous women early in pregnancy to either a high-risk group with a risk of 1 in 6 or more of developing preeclampsia, or a low-risk group with a risk of 1 in 100 or less. The model simulated 25 plausible scenarios in a hypothetical cohort of 100,000 pregnant women, in which the sensitivity and specificity of the new test were varied to set a benchmark for the minimum test performance that is needed for the test to become cost-effective. The input parameters and costs were mainly derived from published literature. The main outcome was incremental costs per preeclampsia case averted, expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty. RESULTS: Base case results showed that the new test strategy would be more effective and less costly compared to the current situation in the UK. In the Netherlands, the majority of scenarios would be cost-effective from a threshold of €50,000 per preeclampsia case averted, while in Ireland and Sweden, the vast majority of scenarios would be considered cost-effective only when a threshold of €100,000 was used. In the best case analyses, ICERs were more favourable in all four participating countries. Aspirin effectiveness, prevalence of preeclampsia, accuracy of the new screening test and cost of regular antenatal care were identified as driving factors for the cost-effectiveness of screening for preeclampsia. CONCLUSION: The results indicate that the new screening test for preeclampsia has potential to be cost-effective. Further studies based on proven accuracy of the test will confirm whether the new screening test is a cost-effective additional option to the current situation

What is to blame for postnatal pelvic floor dysfunction in primiparous women — Pre-pregnancy or intrapartum risk factors?

Background: The aetiology of pelvic floor dysfunction (PFD) is still poorly understood. However childbearing is recognized as a major risk factor. Objectives: To elucidate the natural history of PFD by investigating the impact of the mode of delivery on postnatal pelvic floor dysfunction in primiparas, when PFD existing before the first pregnancy is taken into consideration. Study design: 4P-study (Prevalence and Predictors of Pelvic floor dysfunction in Primips) is a prospective cohort study, nested within the Screening for Pregnancy Endpoints (SCOPE) study set in a tertiary referral teaching hospital with 9000 deliveries annually. Established and proposed risk factors for urinary, fecal, prolapse and sexual dysfunction and the severity of symptoms for each of these outcomes were assessed using the Australian Pelvic Floor Questionnaire in 1482 nulliparous women, who each completed the questionnaire in early pregnancy. Of these, 1060 (72%) repeated the questionnaire 12 months postpartum. Outcomes were analyzed using multivariate ordinal logistic regression. Results: Significant (p < 0.05) risk factors for postpartum PFD were pre-pregnancy presence of similar symptoms Odds Ratio (OR) (5.0–30.0), smoking (OR 2.2–4.6), recurrent UTI (OR 2.2–17.3), high hip circumference (OR1.4–1.6), vigorous exercising (OR 3.1–17.9), induction of labor (OR 1.5–2.3), forceps delivery (OR 1.8–8.8), and 3rd degree perineal tear (OR 2.4–2.7). Cesarean section was associated with a lower risk of stress urinary incontinence (OR 0.3–0.5). Other common pre-pregnancy significant (p < 0.05) risk factors for various PFD types prior to the first pregnancy were: diagnosed depression – (OR 1.6–2.1), high BMI (OR 3.1), strenuous exercising (OR 1.3–2.2), recurrent UTI (OR 1.5–2.5) and lower educational achievement (OR 1.5–1.6). Conclusions: Pre-pregnancy PFD was mainly associated with modifiable risk factors such as smoking and exercising. The main risk factor for postpartum PFD was the presence of similar symptoms prior to pregnancy, followed by anthropometric and intrapartum factors. Hip circumference seems to be a better predictor of PFD compared to BMI. When pre-pregnancy PFD was included in the analysis, Cesarean section was protective only for stress urinary incontinence, while delivery by forceps increased the risk of prolapse

Infant formula feeding practices in a prospective population based study

Background: It is recommended that formula-fed infants are given standard whey-based infant formula throughout the first year of life, unless otherwise advised by healthcare professionals. To our knowledge it has not yet been explored if parents are using a whey-based infant formula throughout the first 12 months of life. Reasons for parental choice of formula are also unknown. Therefore, the objective of this paper was to describe parental administration of whey-based and non whey-based infant formula in the first year of life. Methods: Data collected as part of the Cork BASELINE Birth Cohort Study examined infant feeding practices at 2, 6 and 12 months of age. Descriptive analysis explored infant feeding practices and parental reasons for changing from a whey-based to a non whey-based infant formula. Multiple logistic regression investigated parental and infant characteristics associated with the use of whey-based infant formula. Results: In total, 62.4%, 40.4% and 12.8% parent(s) at 2, 6 and 12 months, respectively, gave their infant whey-based infant formula. No parental or infant characteristic was found to consistently influence the use of whey-based infant formula. The most common reason reported by parent(s) for changing their infant’s formula to a non whey-based formula was that they perceived their baby as being hungry. Conclusion: The majority of parent(s) commence their infants on whey-based formula, but most change to non whey-based formula before 12 months of age. Parental perception of infant satiety and not healthcare advice was the most common reason for changing from a whey-based to a non whey-based infant formula. Additional research is now required to investigate the effect of whey-based and non whey-based infant formula on infant growth