Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Aims/hypothesis: Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFß1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia.
Methods: Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term.
Results: Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n?=?26) vs those without hypertensive complications (diabetic normotensive, n?=?95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p?<?0.05) and the normal rise of PlGF during pregnancy was blunted (p?<?0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r2?=?42%, p?<?0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p?<?0.0001).
Conclusions/interpretation: Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

Plasma Lipoproteins and Preeclampsia in Women with Type 1 Diabetes: A Prospective Study

Context: In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown.

Objectives: The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM.

Design and Settings: We conducted a multicenter prospective study in T1DM pregnancy.

Patients: We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 1.9, 21.6 1.5, and 31.5 1.7 wk gestation (means SD)] and at term (37.6 2.0 wk). Nondiabetic normotensive pregnant women (n 21) were included for reference.

Main Outcome Measures: Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE.

Results: In women with vs. without subsequent PE, at the first and/or second study visits: lowdensity lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P 0.05); peripheral lipoprotein lipolysis was decreased (P0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset.

Conclusions: Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk.

Association Study of 167 Candidate Genes for Schizophrenia Selected by a Multi-Domain Evidence-Based Prioritization Algorithm and Neurodevelopmental Hypothesis

Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this
ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted.

Response of farmland biodiversity to the introduction of bioenergy crops: effects of local factors and surrounding landscape context

The recent growth in bioenergy crop cultivation, stimulated by the need to implement measures to reduce net CO emissions, is driving major land-use changes with consequences for biodiversity and ecosystem service provision. Although the type of bioenergy crop and its associated management is likely to affect biodiversity at the local (field) scale, landscape context and its interaction with crop type may also influence biodiversity on farms. In this study, we assessed the impact of replacing conventional agricultural crops with two model bioenergy crops (either oilseed rape Brassica napus or Miscanthus × giganteus) on vascular plant, bumblebee, solitary bee, hoverfly and carabid beetle richness, diversity and abundance in 50 sites in Ireland. We assessed whether within-field biodiversity was also related to surrounding landscape structure. We found that local- and landscape-scale variables correlated with biodiversity in these agricultural landscapes. Overall, the differences between the bioenergy crops and the conventional crops on farmland biodiversity were mostly positive (e.g. higher vascular plant richness in Miscanthus planted on former conventional tillage, higher solitary bee abundance and richness in Miscanthus and oilseed rape compared with conventional crops) or neutral (e.g. no differences between crop types for hoverflies and bumblebees). We showed that these crop type effects were independent of (i.e. no interactions with) the surrounding landscape composition and configuration. However, surrounding landscape context did relate to biodiversity in these farms, negatively for carabid beetles and positively for hoverflies. Although we conclude that the bioenergy crops compared favourably with conventional crops in terms of biodiversity of the taxa studied at the field scale, the effects of large-scale planting in these landscapes could result in very different impacts. Maintaining ecosystem functioning and the delivery of ecosystem services will require a greater understanding of impacts at the landscape scale to ensure the sustainable development of climate change mitigation measures.

Neonatal intensive care and late preterm infants:Health and family functioning at three years

Background: Late preterm infants (LPIs), born at 34 + 0 to 36 + 6 weeks of gestation contribute a significant proportion of all neonatal intensive care (NIC) admissions and are regarded as being at risk of adverse outcomes compared to term-born infants.

Aim: To explore the health outcomes and family functioning of LPIs who required neonatal intensive care, at three years of age.

Study design and subjects: This cohort study included 225 children born late preterm, between 1 January and 31 December 2006 in Northern Ireland. Children admitted for NIC (study group, n = 103) were compared with children who did not require NIC or who required special care only for up to three days (comparison group, n = 122).

Outcome measures
Health outcomes were measured using the Health Status Questionnaire, health service usage by parent report and family functioning using the PedsQL™ Family Impact Module.

Results: LPIs who required NIC revealed similar health outcomes at three years in comparison to those who did not. Despite this, more parents of LPIs who required NIC reported visiting their GP and medical specialists during their child's third year of life. Differences in family functioning were also observed with mothers of LPIs who required NIC reporting, significantly lower levels of social and physical functioning, increased difficulties with communication and increased levels of worry.

Conclusions: LPIs were observed to have similar health outcomes at three years of age regardless of NIC requirement. The increase in GP and medical specialist visits and family functioning difficulties observed among those infants who required NIC merits further investigation.

Abbreviations: LPI, late preterm infant; NIC, neonatal intensive care; HSQ, Health Status Questionnaire; GP, general practitioner

Field-Isolated Genotypes of Mycobacterium bovis Vary in Virulence and Influence Case Pathology but Do Not Affect Outbreak Size

Strains of many infectious agents differ in fundamental epidemiological parameters including transmissibility, virulence and pathology. We investigated whether genotypes of Mycobacterium bovis (the causative agent of bovine tuberculosis, bTB) differ significantly in transmissibility and virulence, combining data from a nine-year survey of the genetic structure of the M. bovis population in Northern Ireland with detailed records of the cattle population during the same period. We used the size of herd breakdowns as a proxy measure of transmissibility and the proportion of skin test positive animals (reactors) that were visibly lesioned as a measure of virulence. Average breakdown size increased with herd size and varied depending on the manner of detection (routine herd testing or tracing of infectious contacts) but we found no significant variation among M. bovis genotypes in breakdown size once these factors had been accounted for. However breakdowns due to some genotypes had a greater proportion of lesioned reactors than others, indicating that there may be variation in virulence among genotypes. These findings indicate that the current bTB control programme may be detecting infected herds sufficiently quickly so that differences in virulence are not manifested in terms of outbreak sizes. We also investigated whether pathology of infected cattle varied according to M. bovis genotype, analysing the distribution of lesions recorded at post mortem inspection. We concentrated on the proportion of cases lesioned in the lower respiratory tract, which can indicate the relative importance of the respiratory and alimentary routes of infection. The distribution of lesions varied among genotypes and with cattle age and there were also subtle differences among breeds. Age and breed differences may be related to differences in susceptibility and husbandry, but reasons for variation in lesion distribution among genotypes require further investigation. © 2013 Wright et al.

Natural variation of rice strigolactone biosynthesis is associated with the deletion of two MAX1 orthologs

Rice (Oryza sativa) cultivar Azucena--belonging to the Japonica subspecies--exudes high strigolactone (SL) levels and induces high germination of the root parasitic plant Striga hermonthica. Consistent with the fact that SLs also inhibit shoot branching, Azucena is a low-tillering variety. In contrast, Bala, an Indica cultivar, is a low-SL producer, stimulates less Striga germination, and is highly tillered. Using a Bala × Azucena F6 population, a major quantitative trait loci--qSLB1.1--for the exudation of SL, tillering, and induction of Striga germination was detected on chromosome 1. Sequence analysis of the corresponding locus revealed a rearrangement of a 51- to 59-kbp stretch between 28.9 and 29 Mbp in the Bala genome, resulting in the deletion of two cytochrome P450 genes--SLB1 and SLB2--with high homology to the Arabidopsis SL biosynthesis gene, MAX1. Both rice genes rescue the Arabidopsis max1-1 highly branched mutant phenotype and increase the production of the SL, ent-2'-epi-5-deoxystrigol, when overexpressed in Bala. Furthermore, analysis of this region in 367 cultivars of the publicly available Rice Diversity Panel population shows that the rearrangement at this locus is a recurrent natural trait associated with the Indica/Japonica divide in rice.

Behavioural outcomes at 3 years of age among late preterm infants admitted to neonatal intensive care: a cohort study

Objective: Examine the behavioural outcomes at age 3 years of late preterm infants (LPIs) who were admitted to neonatal intensive care (NIC) in comparison with LPIs who were not admitted.
Method: This cohort study prospectively recruited 225 children born late preterm (34–36+6 weeks gestation) in 2006 in Northern Ireland, now aged 3 years. Two groups were compared: LPIs who received NIC (study; n=103) and LPIs who did not receive NIC (control; n=122). Parents/guardians completed the Child Behaviour Checklist/1½-5. Descriptive maternal and infant data were also collected.
Results: As expected LPI children admitted to NIC had higher medical risk than the non-admitted comparison group (increased caesarean section, born at earlier gestation, lower birth weight and an episode of resuscitation at birth). LPIs admitted to NIC scored higher on the Child Behaviour Checklist/1½-5 compared with those who were not admitted indicating more behavioural problems; this was statistically significant for the Aggressive Behaviour Subscale (z=−2.36) and the Externalising Problems Scale (z=−2.42). The group difference on the Externalising Problems Scale was no longer significant after controlling for gender, gestational age and deprivation score.
Conclusions: This study provides valuable data on the behaviour at age 3 years of LPIs admitted to NIC compared with LPIs not admitted to NIC. Further research would be beneficial to explore medical and psychosocial explanations for observed differences between groups using large prospective cohort studies.

Detectability of bovine TB using the tuberculin skin test does not vary significantly according to pathogen genotype within Northern Ireland

Strains of many infectious diseases differ in parameters that influence epidemic spread, for example virulence, transmissibility, detectability and host specificity. Knowledge of inter-strain variation can be exploited to improve management and decrease disease incidence. Bovine tuberculosis (bTB) is increasingly prevalent among farmed cattle in the UK, exerting a heavy economic burden on the farming industry and government. We aimed to determine whether strains of Mycobacterium bovis (the causative agent of bTB) identified and classified using genetic markers (spoligotyping and multi-locus VNTR analysis) varied in response to the tuberculin skin test; this being the primary method of bTB detection used in the UK. Inter-strain variation in detectability of M. bovis could have important implications for disease control. The skin test is based on a differential delayed type hypersensitivity (DTH) response to intradermal injections of purified protein derivative (PPD) from M. bovis (PPD-B) and Mycobacterium avium (PPD-A). We searched for an association between skin test response (PPD-B skin rise minus PPD-A skin rise) and M. bovis genotype at the disclosing test in culture-confirmed cases using a field dataset consisting of 21,000 isolates belonging to 63 genotypes of M. bovis from cattle in Northern Ireland. We found no substantial variation among genotypes (estimated responses clustered tightly around the mean) controlling for animal sex, breed and test effects. We also estimated the ratio of skin test detected to undetected cases (i.e. cases only detected at abattoir). The skin test detection ratio varied among abattoirs with some detecting a greater proportion of cases than others but this variation was unrelated to the community composition of genotypes within each abattoir catchment. These two lines of evidence indicate that M. bovis genotypes in Northern Ireland have similar detectability using the skin test.

Predictors and dynamics of postpartum relapses in women with multiple sclerosis

Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)