Micellar nanocarriers of hydroxytyrosol are protective against parkinson’s related oxidative stress in an in vitro hcmec/d3‐sh‐sy5y co‐culture system

Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson’s disease (PD). Due to issues such as rapid metabolism, HT is unlikely to reach the brain at therapeutic concentrations required for a clinical effect. We have previously developed micellar nanocarriers from Pluronic F68® (P68) and dequalinium (DQA) which have suita-ble characteristics for brain delivery of antioxidants and iron chelators. The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferox-amine (DFO), and assess their physical characteristics and ability to pass the blood–brain barrier and protect against rotenone in a cellular hCMEC/D3‐SH‐SY5Y co‐culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). P68 + DQA nanoformulation enhanced the mean blood–brain barrier (BBB) passage of HT by 50% (p < 0.0001, n = 6). This resulted in increased protection against rotenone induced cyto-toxicity and oxidative stress by up to 12% and 9%, respectively, compared to the corresponding free drug treatments (p < 0.01, n = 6). This study demonstrates for the first time the incorporation of HT and HT + DFO into P68 + DQA nanocarriers and successful delivery of these nanocarriers across a BBB model to protect against PD‐related oxidative stress. These nanocarriers warrant further investigation to evaluate whether this enhanced neuroprotection is exhibited in in vivo PD models

N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson's Disease

Oxidative stress is a key mediator in the development and progression of Parkinson’s disease (PD). The antioxidant N-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD

Antimicrobial peptide capsids of de novo design

The spread of bacterial resistance to antibiotics poses the need for antimicrobial discovery. With traditional search paradigms being exhausted, approaches that are altogether different from antibiotics may offer promising and creative solutions. Here, we introduce a de novo peptide topology that-by emulating the virus architecture-assembles into discrete antimicrobial capsids. Using the combination of high-resolution and real-time imaging, we demonstrate that these artificial capsids assemble as 20-nm hollow shells that attack bacterial membranes and upon landing on phospholipid bilayers instantaneously (seconds) convert into rapidly expanding pores causing membrane lysis (minutes). The designed capsids show broad antimicrobial activities, thus executing one primary function-they destroy bacteria on contact

International standards for fetal brain structures based on serial ultrasound measurements from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project.

OBJECTIVE: To create prescriptive growth standards for five fetal brain structures, measured by ultrasound, from healthy, well-nourished women, at low risk of impaired fetal growth and poor perinatal outcomes, taking part in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. METHODS: This was a complementary analysis of a large, population-based, multicentre, longitudinal study. We measured, in planes reconstructed from 3-dimensional (3D) ultrasound volumes of the fetal head at different time points in pregnancy, the size of the parieto-occipital fissure (POF), Sylvian fissure (SF), anterior horn of the lateral ventricle (AV), atrium of the posterior ventricle (PV) and cisterna magna (CM). The sample analysed was randomly selected from the overall FGLS population, ensuring an equal distribution amongst the eight diverse participating sites and of 3D ultrasound volumes across pregnancy (range: 15 - 36 weeks' gestation). Fractional polynomials were used to the construct standards. Growth and development of the infants were assessed at 1 and 2 years of age to confirm their adequacy for constructing international standards. RESULTS: From the entire FGLS cohort of 4321 women, 451 (10.4%) were randomly selected. After exclusions, 3D ultrasound volumes from 442 fetuses born without congenital malformations were used to create the charts. The fetal brain structures of interest were identified in 90% of cases. All structures showed increasing size with gestation and increasing variability for the POF, SF, PV and CM. The 3rd , 5th , 50th , 95th and 97th smoothed centile are presented. The 5th centile of POF and SF were 2.8 and 4.3 at 22 weeks and 4.2 and 9.4mm at 32 weeks respectively. The 95th centile of PV and CM were 8.5 and 7.4 at 22 weeks and 8.5 and 9.4mm at 32 weeks respectively. CONCLUSIONS: We have produced prescriptive size standards for fetal brain structures based on prospectively enrolled pregnancies at low risk of abnormal outcomes. We recommend these as international standards for the assessment of measurements obtained by ultrasound from fetal brain structures

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients

Background: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design: 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826Not peer reviewedPublisher PD

International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project

Background: In 2006, WHO produced international growth standards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee. Using the same methods and conceptual approach, the Fetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21st Project, aimed to develop international growth and size standards for fetuses. Methods: The multicentre, population-based FGLS assessed fetal growth in geographically defined urban populations in eight countries, in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided. We used ultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown–rump length in the first trimester. The five primary ultrasound measures of fetal growth—head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length—were obtained every 5 weeks (within 1 week either side) from 14 weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. Findings: We screened 13 108 women commencing antenatal care at less than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations (the analysis population). We documented very low maternal and perinatal mortality and morbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetal growth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th, and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and −2·69 mm (3·2) for head circumference; 0·83 mm (0·9), −0·05 mm (0·8), and −0·84 mm (1·0) for biparietal diameter; 0·63 mm (1·2), 0·04 mm (1·1), and −1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm (3·2), and −4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and −0·65 mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curves according to gestational age for these ultrasound measures, representing the international standards for fetal growth. Interpretation: We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations. Funding: Bill & Melinda Gates Foundation

Structurally plastic peptide capsules for synthetic antimicrobial viruses

A conceptual design for artificial antimicrobial viruses is described. The design emulates viral assembly and function to create self-assembling peptide capsules that promote efficient gene delivery and silencing in mammalian cells. Unlike viruses, however, the capsules are antimicrobial, which allows them to exhibit a dual biological function: gene transport and antimicrobial activity. Unlike other antimicrobials, the capsules act as pre-concentrated antimicrobial agents that elicit rapid and localised membrane-disrupting responses by converting into individual pores at their precise landing positions on membranes. The concept holds promise for engineering virus-like scaffolds with biologically tuneable properties

Postnatal growth standards for preterm infants: the Preterm Postnatal Follow-up Study of the INTERGROWTH-21(st) Project.

BACKGROUND: Charts of size at birth are used to assess the postnatal growth of preterm babies on the assumption that extrauterine growth should mimic that in the uterus. METHODS: The INTERGROWTH-21(st) Project assessed fetal, newborn, and postnatal growth in eight geographically defined populations, in which maternal health care and nutritional needs were met. From these populations, the Fetal Growth Longitudinal Study selected low-risk women starting antenatal care before 14 weeks' gestation and monitored fetal growth by ultrasonography. All preterm births from this cohort were eligible for the Preterm Postnatal Follow-up Study, which included standardised anthropometric measurements, feeding practices based on breastfeeding, and data on morbidity, treatments, and development. To construct the preterm postnatal growth standards, we selected all live singletons born between 26 and before 37 weeks' gestation without congenital malformations, fetal growth restriction, or severe postnatal morbidity. We did analyses with second-degree fractional polynomial regression models in a multilevel framework accounting for repeated measures. Fetal and neonatal data were pooled from study sites and stratified by postmenstrual age. For neonates, boys and girls were assessed separately. FINDINGS: From 4607 women enrolled in the study, there were 224 preterm singleton births, of which 201 (90%) were enrolled in the Preterm Postnatal Follow-up Study. Variance component analysis showed that only 0·2% and 4·0% of the total variability in postnatal length and head circumference, respectively, could be attributed to between-site differences, justifying pooling the data from all study sites. Preterm growth patterns differed from those for babies in the INTERGROWTH-21(st) Newborn Size Standards. They overlapped with the WHO Child Growth Standards for term babies by 64 weeks' postmenstrual age. INTERPRETATION: Our data have yielded standards for postnatal growth in preterm infants. These standards should be used for the assessment of preterm infants until 64 weeks' postmenstrual age, after which the WHO Child Growth Standards are appropriate. Size-at-birth charts should not be used to measure postnatal growth of preterm infants. FUNDING: Bill & Melinda Gates Foundation

Predicting mental imagery based BCI performance from personality, cognitive profile and neurophysiological patterns

Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy— EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants’ BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants’ performance with a mean error of less than 3 points. This study determined how users’ profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user