From small to big molecules: how do we prevent and delay the progression of age-related neurodegeneration?

Age-related neurodegeneration in the brain and retina is complicated. It comprises a series of events encompassing different modes of degeneration in neurons, as well as inflammation mediated by glial cells. Systemic inflammation and risk factors can contribute to disease progression. Age-related conditions such as Alzheimer's disease (AD), Parkinson's disease (PD) and Age-related Macular Degeneration (AMD) affect patients for 5 to 20 years and are highly associated with risk factors such as hyperhomocysteinaemia, hypercholesterolaemia, hypertension, and symptoms of mood disorder. The long duration of the degeneration and the wide array of systemic factors provide the opportunity for nutraceutical intervention to prevent or delay disease progression. Small molecules such as phenolic compounds are candidates for neuroprotection because they have anti-oxidant activities and can modulate intracellular signaling pathways. Bigger entities such as oligosaccharides and polysaccharides have often been neglected because of their complex structure. However, certain big molecules can provide neuroprotective effects. They may also have a wide spectrum of action against risk factors. In this review we use an integrative approach to the potential uses of nutraceutical products to prevent age-related neurodegeneration. These include direct effects of phenolic compounds and polysaccharides on neurons to antagonize various neurodegenerative mechanisms in AD, PD and AMD, and indirect effects of these compounds on peripheral disease-related risk factors.postprin

Making Sense of a New Transport System: An Ethnographic Study of the Cambridgeshire Guided Busway

An increase in public transport use has the potential to contribute to improving population health, and there is growing interest in innovative public transport systems. Yet how new public transport infrastructure is experienced and integrated (or not) into daily practice is little understood. We investigated how the Cambridgeshire Guided Busway, UK, was used and experienced in the weeks following its opening, using the method of participant observation (travelling on the busway and observing and talking to passengers) and drawing on Normalization Process Theory to interpret our data. Using excerpts of field notes to support our interpretations, we describe how the ease with which the new transport system could be integrated into existing daily routines was important in determining whether individuals would continue to use it. It emerged that there were two groups of passengers with different experiences and attitudes. Passengers who had previously travelled frequently on regular bus services did not perceive the new system to be an improvement; consequently, they were frustrated that it was differentiated from and not coherent with the regular system. In contrast, passengers who had previously travelled almost exclusively by car appraised the busway positively and perceived it to be a novel and superior form of travel. Our rich qualitative account highlights the varied and creative ways in which people learn to use new public transport and integrate it into their everyday lives. This has consequences for the introduction and promotion of future transport innovations. It is important to emphasise the novelty of new public transport, but also the ways in which its use can become ordinary and routine. Addressing these issues could help to promote uptake of other public transport interventions, which may contribute to increasing physical activity and improving population health. © 2013 Jones et al

Effective suckling in relation to naked maternal-infant body contact in the first hour of life: an observation study

Background Best practice guidelines to promote breastfeeding suggest that (i) mothers hold their babies in naked body contact immediately after birth, (ii) babies remain undisturbed for at least one hour and (iii) breastfeeding assistance be offered during this period. Few studies have closely observed the implementation of these guidelines in practice. We sought to evaluate these practices on suckling achievement within the first hour after birth. Methods Observations of seventy-eight mother-baby dyads recorded newborn feeding behaviours, the help received by mothers and birthing room practices each minute, for sixty minutes. Results Duration of naked body contact between mothers and their newborn babies varied widely from 1 to 60 minutes, as did commencement of suckling (range = 10 to 60 minutes). Naked maternal-infant body contact immediately after birth, uninterrupted for at least thirty minutes did not predict effective suckling within the first hour of birth. Newborns were four times more likely to sustain deep rhythmical suckling when their chin made contact with their mother’s breast as they approached the nipple (OR 3.8; CI 1.03 - 14) and if their mothers had given birth previously (OR 6.7; CI 1.35 - 33). Infants who had any naso-oropharyngeal suctioning administered at birth were six times less likely to suckle effectively (OR .176; CI .04 - .9). Conclusion Effective suckling within the first hour of life was associated with a collection of practices including infants positioned so their chin can instinctively nudge the underside of their mother’s breast as they approach to grasp the nipple and attach to suckle. The best type of assistance provided in the birthing room that enables newborns to sustain an effective latch was paying attention to newborn feeding behaviours and not administering naso-oropharyngeal suction routinely

Integration of vitamin A supplementation with the expanded program on immunization does not affect seroconversion to oral poliovirus vaccine in infants.

Childhood immunization programs may provide infrastructure for delivering vitamin A supplements to infants in developing countries. The effect of giving vitamin A, an immune enhancer, on antibody responses to trivalent oral poliovirus vaccine (TOPV) is unknown. A randomized, double-blind, placebo-controlled clinical trial was conducted to determine the effect of giving

Placental Pathology Contributes to Impaired Volumetric Brain Development in Neonates With Congenital Heart Disease

BACKGROUND: Neonates with congenital heart disease are at risk for impaired brain development in utero, predisposing children to postnatal brain injury and adverse long-term neurodevelopmental outcomes. Given the vital role of the placenta in fetal growth, we assessed the incidence of placental pathology in fetal congenital heart disease and explored its association with total and regional brain volumes, gyrification, and brain injury after birth. METHODS AND RESULTS: Placentas from 96 term singleton pregnancies with severe fetal congenital heart disease were prospectively analyzed for macroscopic and microscopic pathology. We applied a placental pathology severity score to relate placental abnormalities to neurological outcome. Postnatal, presurgical magnetic resonance imaging was used to analyze brain volumes, gyrification, and brain injuries. Placental analyses revealed the following abnormalities: maternal vascular malperfusion lesions in 46%, nucleated red blood cells in 37%, chronic inflammatory lesions in 35%, delayed maturation in 30%, and placental weight below the 10th percentile in 28%. Severity of placental pathology was negatively correlated with cortical gray matter, deep gray matter, brainstem, cerebellar, and total brain volumes (r=-0.25 to -0.31, all P<0.05). When correcting for postmenstrual age at magnetic resonance imaging in linear regression, this association remained significant for cortical gray matter, cerebellar, and total brain volume (adjusted R2=0.25-0.47, all P<0.05). CONCLUSIONS: Placental pathology occurs frequently in neonates with severe congenital heart disease and may contribute to impaired brain development, indicated by the association between placental pathology severity and reductions in postnatal cortical, cerebellar, and total brain volumes

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Peer reviewe

Farkas-Type Results for Vector-Valued Functions with Applications

The main purpose of this paper consists of providing characterizations of the inclusion of the solution set of a given conic system posed in a real locally convex topological space into a variety of subsets of the same space defined by means of vector-valued functions. These Farkas-type results are used to derive characterizations of the weak solutions of vector optimization problems (including multiobjective and scalar ones), vector variational inequalities, and vector equilibrium problems.This research was partially supported by MINECO of Spain and FEDER of EU, Grant MTM2014-59179-C2-1-P, by the project DP160100854 from the Australian Research Council, and by the project B2015-28-04: “A new approach to some classes of optimization problems” from the Vietnam National University - HCM city, Vietnam

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant)

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Avoiding bias from weak instruments in Mendelian randomization studies

Background Mendelian randomization is used to test and estimate the magnitude of a causal effect of a phenotype on an outcome by using genetic variants as instrumental variables (IVs). Estimates of association from IV analysis are biased in the direction of the confounded, observational association between phenotype and outcome. The magnitude of the bias depends on the F-statistic for the strength of relationship between IVs and phenotype. We seek to develop guidelines for the design and analysis of Mendelian randomization studies to minimize bias. Methods IV analysis was performed on simulated and real data to investigate the effect on bias of size of study, number and choice of instruments and method of analysis. Results Bias is shown to increase as the expected F-statistic decreases, and can be reduced by using parsimonious models of genetic association (i.e. not over-parameterized) and by adjusting for measured covariates. Using data from a single study, the causal estimate of a unit increase in log-transformed C-reactive protein on fibrinogen (mmol/l) is shown to increase from À0.005 (P ¼ 0.99) to 0.792 (P ¼ 0.00003) due to injudicious choice of instrument. Moreover, when the observed F-statistic is larger than expected in a particular study, the causal estimate is more biased towards the observational association and its standard error is smaller. This correlation between causal estimate and standard error introduces a second source of bias into meta-analysis of Mendelian randomization studies. Bias can be alleviated in meta-analyses by using individual level data and by pooling genetic effects across studies. Conclusions Weak instrument bias is of practical importance for the design and analysis of Mendelian randomization studies. Post hoc choice of instruments, genetic models or data based on measured F-statistics can exacerbate bias. In particular, the commonly cited rule of thumb that F410 avoids bias in IV analysis is misleading