Protocol for a 20-year follow-up after a randomized controlled trial of a Mediterranean diet in pregnancy:maternal and offspring risk factors for cardiovascular disease

Background: An inadequate maternal diet during pregnancy can impair offspring health and may increase the risk of cardiovascular disease later in life. The purpose of the proposed study is to assess the risk factors associated with cardiovascular disease in both mothers and their offspring 20 years following their participation in a Mediterranean diet intervention trial during pregnancy.Methods: The “Cardiovascular Risk Reduction Diet In Pregnancy” (CARRDIP) study was a randomized controlled trial performed between 1999 and 2001. The participants were randomized to adhere to either a Mediterranean diet or their regular diet during pregnancy. An extensive amount of data such as diet information, ultrasound measurements, anthropometry, and biomarkers from these mothers during pregnancy and their offspring in the neonatal period were collected. The mother–offspring pairs (n = 269) from the CARRDIP study will be invited to participate in a clinical examination and blood sample collection. This follow-up study, conducted 20 years after the original CARRDIP study, will investigate cardiovascular risk factors in mothers and offspring. The primary outcome will be the blood pressure of the offspring. In addition, the study will explore various aspects of cardiovascular health, including metabolic and inflammatory status, clinical history, and body composition of the participants.Discussion: Previous studies investigating the effects of nutrition during pregnancy on maternal and offspring health have been either observational studies, animal studies, or randomized controlled trials with a follow-up period of less than 5 years. This project aims to study the long-term effects of dietary intervention during pregnancy on maternal and offspring cardiovascular risk markers.Clinical Trial Registration: Clinicaltrials.gov, identifier (NCT05030922)

Sample size requirements to detect the effect of a group of genetic variants in case-control studies

<p>Abstract</p> <p>Background</p> <p>Because common diseases are caused by complex interactions among many genetic variants along with environmental risk factors, very large sample sizes are usually needed to detect such effects in case-control studies. Nevertheless, many genetic variants act in well defined biologic systems or metabolic pathways. Therefore, a reasonable first step may be to detect the effect of a group of genetic variants before assessing specific variants.</p> <p>Methods</p> <p>We present a simple method for determining approximate sample sizes required to detect the average joint effect of a group of genetic variants in a case-control study for multiplicative models.</p> <p>Results</p> <p>For a range of reasonable numbers of genetic variants, the sample size requirements for the test statistic proposed here are generally not larger than those needed for assessing marginal effects of individual variants and actually decline with increasing number of genetic variants in many situations considered in the group.</p> <p>Conclusion</p> <p>When a significant effect of the group of genetic variants is detected, subsequent multiple tests could be conducted to detect which individual genetic variants and their combinations are associated with disease risk. When testing for an effect size in a group of genetic variants, one can use our global test described in this paper, because the sample size required to detect an effect size in the group is comparatively small. Our method could be viewed as a screening tool for assessing groups of genetic variants involved in pathogenesis and etiology of common complex human diseases.</p

Risk of Stillbirth in the Relation to Water Disinfection By-Products: A Population-Based Case-Control Study in Taiwan

Background: Few epidemiological studies that have assessed the relation between water disinfection by-products (DBPs) and the risk of stillbirth provide inconsistent results. The objective was to assess the relation between exposure to water disinfection by-products and the risk of stillbirth. Methods: We conducted a population-based case-control study of 3,289 cases of stillbirth and a random sample of 32,890 control subjects from 396,049 Taiwanese newborns in 2001–2003 using information from the Birth Registry and Waterworks Registry in Taiwan. We compared the risk of stillbirth in four disinfection by-product exposure categories based on the levels of total trihalomethanes (TTHMs) representing high (TTHMs 20+ mg/L), medium (TTHMs 10–19 mg/L), low exposure (TTHMs 5–9 mg/L), and 0–4 mg/L as the reference category. In addition, we conducted a meta-analysis of the results from the present and 5 previous studies focusing on stillbirth. Findings: In logistic regression analysis adjusting for gender, maternal age, plurality, conception of season and population density of the municipality where the mother lived during pregnancy, the odds ratio (OR) for stillbirth was 1.10 (95 % CI 1.00–1.21) for medium exposure and 1.06 (95 % 0.96–1.17) for high exposure compared to reference category. In the metaanalysis, the summary odds ratio for stillbirth (1.11, 95 % CI: 1.03, 1.19) was consistently elevated. Conclusions: The present study is consistent with the hypothesis that the risk of stillbirth is related to prenatal exposure t

Increased Level of Extracellular ATP at Tumor Sites: In Vivo Imaging with Plasma Membrane Luciferase

There is growing awareness that tumour cells build up a "self-advantageous" microenvironment that reduces effectiveness of anti-tumour immune response. While many different immunosuppressive mechanisms are likely to come into play, recent evidence suggests that extracellular adenosine acting at A2A receptors may have a major role in down-modulating the immune response as cancerous tissues contain elevated levels of adenosine and adenosine break-down products. While there is no doubt that all cells possess plasma membrane adenosine transporters that mediate adenosine uptake and may also allow its release, it is now clear that most of extracellularly-generated adenosine originates from the catabolism of extracellular ATP. METHODOLOGY/PRINCIPAL FINDINGS: Measurement of extracellular ATP is generally performed in cell supernatants by HPLC or soluble luciferin-luciferase assay, thus it generally turns out to be laborious and inaccurate. We have engineered a chimeric plasma membrane-targeted luciferase that allows in vivo real-time imaging of extracellular ATP. With this novel probe we have measured the ATP concentration within the tumour microenvironment of several experimentally-induced tumours. CONCLUSIONS/SIGNIFICANCE: Our results show that ATP in the tumour interstitium is in the hundreds micromolar range, while it is basically undetectable in healthy tissues. Here we show that a chimeric plasma membrane-targeted luciferase allows in vivo detection of high extracellular ATP concentration at tumour sites. On the contrary, tumour-free tissues show undetectable extracellular ATP levels. Extracellular ATP may be crucial for the tumour not only as a stimulus for growth but also as a source of an immunosuppressive agent such as adenosine. Our approach offers a new tool for the investigation of the biochemical composition of tumour milieu and for development of novel therapies based on the modulation of extracellular purine-based signalling

CD36 Participates in PrP106–126-Induced Activation of Microglia

Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106–126 (PrP106–126). We first examined the time course of CD36 mRNA expression upon exposure to PrP106–126 in BV2 microglia. We then analyzed different parameters of microglial activation in PrP106–126-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP106–126. The results showed that PrP106–126 treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP106–126-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP106–126-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP106–126 –treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP106–126. Together, these results suggest that CD36 is involved in PrP106–126-induced microglial activation and that the participation of CD36 in the interaction between PrP106–126 and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling

Dietary calcium and zinc deficiency risks are decreasing but remain prevalent

Globally, more than 800 million people are undernourished while >2 billion people have one or more chronic micronutrient deficiencies (MNDs). More than 6% of global mortality and morbidity burdens are associated with undernourishment and MNDs. Here we show that, in 2011, 3.5 and 1.1 billion people were at risk of calcium (Ca) and zinc (Zn) deficiency respectively due to inadequate dietary supply. The global mean dietary supply of Ca and Zn in 2011 was 684 ± 211 and 16 ± 3 mg capita−1 d−1 (±SD) respectively. Between 1992 and 2011, global risk of deficiency of Ca and Zn decreased from 76 to 51%, and 22 to 16%, respectively. Approximately 90% of those at risk of Ca and Zn deficiency in 2011 were in Africa and Asia. To our knowledge, these are the first global estimates of dietary Ca deficiency risks based on food supply. We conclude that continuing to reduce Ca and Zn deficiency risks through dietary diversification and food and agricultural interventions including fortification, crop breeding and use of micronutrient fertilisers will remain a significant challenge

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Burden of rotavirus gastroenteritis in the Middle Eastern and North African pediatric population

<p>Abstract</p> <p>Background</p> <p>Rotavirus gastroenteritis (RVGE) is the most common cause of severe childhood diarrhea worldwide. Objectives were to estimate the burden of RVGE among children less than five years old in the Middle East (Bahrain, Iran, Iraq, Israel, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Syria, UAE, Yemen), North Africa (Algeria, Egypt, Libya, Morocco, Tunisia) and Turkey.</p> <p>Methods</p> <p>A comprehensive literature search was conducted in major databases on the epidemiology and burden of rotavirus among children less than five years old between 1999 and 2009. Data from each country was extracted and compared.</p> <p>Results</p> <p>The search identified 43 studies. RVGE was identified in 16-61% of all cases of acute gastroenteritis, with a peak in the winter. RVGE-related hospitalization rates ranged from 14% to 45%, compared to 14%-28% for non-RVGE. Annually, RVGE caused up to 112 fatalities per 100,000 in certain countries in the region. Hospitalization costs ranged from $1.8 to$4.6 million annually, depending on the country. The most recent literature available showed that G1P[8] was the most prevalent genotype combination in 8 countries (range 23%-56%). G2P[4] was most prevalent in 4 countries (26%-48%). G9P[8] and G4P[8] were also frequently detected.</p> <p>Conclusions</p> <p>RVGE is a common disease associated with significant morbidity, mortality, and economic burden. Given the variety and diverse rotavirus types in the region, use of a vaccine with broad and consistent serotype coverage would be important to help decrease the burden of RVGE in the Middle East and North Africa.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Regression of target organ damage in children and adolescents with primary hypertension

We assessed the effects of 12 months of non-pharmacological and pharmacological therapy on 24-h ambulatory blood pressure, regression of target organ damage (TOD) and metabolic abnormalities in 86 children (14.1 ± 2.4 years) with primary hypertension. Twenty-four hour systolic and diastolic blood pressure (BP) decreased (130 ± 8 vs 126 ± 8, 73 ± 7 vs 70 ± 7, p = 0.0001 and 0.004 respectively). Body mass index (BMI) did not change, but waist-to-hip (0.85 ± 0.07 vs 0.83 ± 0.05, p = 0.01) and waist-to-height ratio (WHtR; 0.49 ± 0.07 vs 0.48 ± 0.05, p = 0.008) decreased. Left ventricular mass index (LVMi; 38.5 ± 10.7 vs 35.2 ± 7.5 g/m2.7, p = 0.0001), prevalence of left ventricular hypertrophy (46.5% vs 31.4%; p = 0.0001), carotid intima-media thickness (cIMT; 0.44 ± 0.05 vs 0.42 ± 0.04 mm, p = 0.0001), wall cross sectional area (WCSA; 7.5 ± 1.3 vs 6.9 ± 1.2 mm2, p = 0.002), hsCRP (1.1 ± 1.0 vs 0.7 ± 0.7 mg/l, p = 0.002), and LDL-cholesterol (115 ± 33 vs 107 ± 26 mg/dl, p = 0.001) decreased. Patients who had lowered BP had a lower cIMT at the second examination (0.41 ± 0.04 vs 0.43 ± 0.04 mm, p = 0.04) and lower initial hsCRP values (0.9 ± 0.7 vs 1.5 ± 1.3 mg/l, p = 0.04) in comparison to non-responders. Regression analysis revealed that the main predictor of LVMi decrease was a decrease in abdominal fat expressed as a decrease in waist circumference (WC) (R2 = 0.280, β = 0.558, p = 0.005), for WCSA-SDS a decrease in WC (R2 = 0.332, β = 0.611, p = 0.009) and for a cIMT-SDS decrease the main predictor was a decrease in hsCRP concentrations (R2 = 0.137, β = 0.412, p = 0.03). Standard antihypertensive treatment lowered BP and led to regression of TOD in hypertensive children. Lean body mass increase and decrease in abdominal obesity correlated with TOD regression