Aims/hypothesis
Seroconversion to islet autoantibodies precedes type 1 diabetes. This study aimed to identify periods of high seroconversion incidence, which could be targeted for mechanistic and ...therapeutic studies.
Methods
Incidence of islet autoantibodies was calculated in 1,650 genetically at-risk children followed with measurements of islet autoantibodies and thyroid autoantibodies at age 9 months and 2, 5, 8, 11, 14 and 17 years. Peak incidence periods were confirmed in a second cohort of 150 children followed until age 6 years with three-monthly samples up to age 3 years.
Results
Islet autoantibody incidence (per 1,000 person-years) was 18.5 until age 9 months, 21 from 9 months to 2 years and <10 for intervals after age 2 years. The second cohort confirmed peak incidence around age 9 months and demonstrated an absence of seroconversion before this age. Seroconversion to insulin autoantibodies occurred earlier than other autoantibodies (
p
< 0.01 against glutamic acid decarboxylase GAD-, insulinoma-associated protein 2 IA-2- and zinc transporter 8 ZnT8-autoantibodies). Early peak seroconversion incidence was most evident in children with high-risk
HLA DR3/4-DQ8
or
DR4/4-DQ8
genotypes.
Conclusion
The age period 9 months to 2 years is associated with a high incidence of activation of type 1 diabetes-associated autoimmunity in genetically at-risk children and should be targeted for effective primary prevention strategies.
Objectives
Little is known about the experiences of women who travel within Europe for abortion care from countries with relatively liberal laws. This paper aims to assess the primary reasons for ...travel among a sample of women who travelled from European countries with relatively liberal abortion laws to obtain abortion care mainly in the UK and the Netherlands.
Design
Multi‐country, 5‐year mixed methods study on barriers to legal abortion and travel for abortion.
Setting
UK, the Netherlands and Spain.
Population or Sample
We present quantitative data from 204 surveys, and qualitative data from 30 in‐depth interviews with pregnant people who travelled to the UK, the Netherlands and Spain from countries where abortion is legal on broad grounds within specific gestational age (GA) limits.
Methods
Mixed‐methods.
Main outcome measures
GA when presenting at abortion clinic, primary reason for abortion‐related travel.
Results
Study participants overwhelmingly reported travelling for abortion because they had exceeded GA limits in their country of residence. Participants also reported numerous delays and barriers to receiving care.
Conclusions
Our findings highlight the need for policies that support access to abortion throughout pregnancy and illustrate that early access to it is necessary but not sufficient to meet people’s reproductive health needs.
Funding
This study is funded by the European Research Council (ERC).
Tweetable
This study shows that GA limits drive women from EU countries where abortion is legal to seek abortions abroad.
Tweetable
This study shows that GA limits drive women from EU countries where abortion is legal to seek abortions abroad.
Reactive oxygen species (ROS) are chemically reactive molecules that are naturally produced within biological systems. Research has focused extensively on revealing the multi‐faceted and complex ...roles that ROS play in living tissues. In regard to the good side of ROS, this article explores the effects of ROS on signalling, immune response and other physiological responses. To review the potentially bad side of ROS, we explain the consequences of high concentrations of molecules that lead to the disruption of redox homeostasis, which induces oxidative stress damaging intracellular components. The ugly effects of ROS can be observed in devastating cardiac, pulmonary, neurodegenerative and other disorders. Furthermore, this article covers the regulatory enzymes that mitigate the effects of ROS. Glutathione peroxidase, superoxide dismutase and catalase are discussed in particular detail. The current understanding of ROS is incomplete, and it is imperative that future research be performed to understand the implications of ROS in various therapeutic interventions.
Road deposited sediments (RDS) are a valuable environmental medium for characterizing contaminant levels in urban areas; and their associated potentially toxic elements (PTEs) can directly impact ...both human and aquatic health. In this study, RDS were collected from 15 co-located industrial and residential roads throughout Singapore to determine the effect of land use on contaminant levels. A second pilot study was designed to quantify the efficiency of road sweeping in removing different RDS grain size fractions from industrial and residential roads. The fine fraction (<63 μm) of all RDSs was analyzed for over 40 elements. Eleven elements that reflect geogenic and anthropogenic sources were examined in detail (Al, Co, Cr, Cu, Fe, Ni, Pb, Sb, Sc, Si, and Zn). Industrial RDS had statistically higher concentrations of Co, Cr, Fe, and Ni than residential RDS. Potentially toxic elements Cu, Pb, Sb, and Zn were enriched >10-fold at all locations compared to upper continental crust values. Concentrations of Cu, Pb and Zn exceeded aquatic sediment probable effect concentration levels, suggesting they could generate a toxic response in bottom-dwelling aquatic organisms. Traffic was equally heavy at both industrial and residential sites, but large trucks and machinery comprised a larger proportion of the traffic in the industrial areas. Traffic was not significantly correlated with the PTE (i.e., Cu, Pb, Sb and Zn) concentrations. Plausible anthropogenic contaminant sources include vehicles (e.g., brake and tire wear, vehicle emissions) and several industrial activities including metal works, oil processing, and waste incineration. Street sweeping was effective in removal of large organic debris and inorganic RDS, but it was ineffective in removing the geochemically important fraction, i.e., <125 μm.
► Co, Cr, Fe, and Ni were higher in industrial than residential RDS. ► Cu, Pb, Sb, and Zn of anthropogenic origins were not statistically different in residential and industrial RDS. ► Cu, Pb and Zn were found in levels which could generate a toxicity response in aquatic organisms. ► While heavy vehicles were more common on industrial roads, there was no significant relationship between vehicular types and elemental concentrations.
Gut microbiota modulates metabolic and immunoregulatory axes and contributes to the pathophysiology of diseases with inflammatory components, such as atherosclerosis, diabetes mellitus, and ischemic ...stroke. Inflammation is emerging as a critical player in the pathophysiology of an intracranial aneurysm. Therefore, we hypothesized that the gut microbiota affects aneurysm formation by modulating inflammation. We induced intracranial aneurysms in mice by combining systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Depletion of the gut microbiota was achieved via an oral antibiotic cocktail of vancomycin, metronidazole, ampicillin, and neomycin. Antibiotics were given 3 weeks before aneurysm induction and either continued until the end of the experiment or stopped 1 day before aneurysm induction. We also assessed the effects of the gut microbiota depletion on macrophage infiltration and mRNA levels of inflammatory cytokines. Gut microbiota depletion by antibiotics reduced the incidence when antibiotics were started 3 weeks before aneurysm induction and continued until the end of the experiment (83% versus 6%, P<0.001). Even when antibiotics were stopped 1 day before aneurysm induction, the gut microbiota depletion significantly reduced the incidence of aneurysms (86% versus 28%, P<0.05). Both macrophage infiltration and mRNA levels of inflammatory cytokines were reduced with gut microbiota depletion. These findings suggest that the gut microbiota contributes to the pathophysiology of aneurysms by modulating inflammation. Human studies are needed to determine the exact contribution of the gut microbiota to the pathophysiology of aneurysm formation and disease course in humans.
Abstract
Aims
Cardiac inflammation has been suggested to be regulated by the sympathetic nervous system (SNS). However, due to the lack of methodology to surgically eliminate the myocardial SNS in ...mice, neuronal control of cardiac inflammation remains ill-defined. Here, we report a procedure for local cardiac sympathetic denervation in mice and tested its effect in a mouse model of heart failure post-myocardial infarction.
Methods and results
Upon preparation of the carotid bifurcation, the right and the left superior cervical ganglia were localized and their pre- and postganglionic branches dissected before removal of the ganglion. Ganglionectomy led to an almost entire loss of myocardial sympathetic innervation in the left ventricular anterior wall. When applied at the time of myocardial infarction (MI), cardiac sympathetic denervation did not affect acute myocardial damage and infarct size. In contrast, cardiac sympathetic denervation significantly attenuated chronic consequences of MI, including myocardial inflammation, myocyte hypertrophy, and overall cardiac dysfunction.
Conclusion
These data suggest a critical role for local sympathetic control of cardiac inflammation. Our model of myocardial sympathetic denervation in mice should prove useful to further dissect the molecular mechanisms underlying cardiac neural control.
Aims
Children and adolescents with a family history of diabetes are at increased risk of overweight, but little is known about the potentially beneficial effects of physical activity on these ...children. The objective of this study was to investigate the association between moderate to vigorous physical activity (MVPA) and metabolic and inflammatory risks in children and adolescents with a family background of Type 1 diabetes or gestational diabetes.
Methods
Valid MVPA measurements, made with accelerometers, were available from 234 participants (median age, 10.2 years) who had a first‐degree relative with either Type 1 or gestational diabetes. Anthropometric and metabolic measurements were made and cytokines measured, and were correlated with MVPA measurements, with stepwise adjustment for confounding factors, in a cross‐sectional analysis.
Results
MVPA was negatively associated with insulin and C‐peptide during challenge with an oral glucose tolerance test. MVPA was also significantly positively associated with the insulin sensitivity index, whereas no consistently significant associations were found between MVPA and BMI, blood pressure or cytokine levels.
Discussion
Our findings indicate that physical activity may have beneficial effects on insulin and C‐peptide metabolism in children and adolescents with a family background of diabetes, but show no evidence of a protective association with other health‐related outcomes.
What's new?
Children and adolescents with a family history of diabetes are at increased risk of overweight, obesity and Type 2 diabetes during their lifetimes. However, there is only limited knowledge about the potentially beneficial effects of physical activity in these children.
Our findings indicate that moderate to vigorous physical activity is associated with lower insulin and C‐peptide levels during challenge with oral glucose tolerance tests in children and adolescents with a family background of diabetes mellitus.
The promotion of physical activity may lower the metabolic risk in these children.
Feast-famine response proteins are a widely conserved class of global regulators in prokaryotes, the most highly studied of which is the Escherichia coli leucine-responsive regulatory protein (Lrp). ...Lrp senses the environmental nutrition status and subsequently regulates up to one-third of the genes in E. coli, either directly or indirectly. Lrp exists predominantly as octamers and hexadecamers (16mers), where leucine is believed to shift the equilibrium toward the octameric state. In this study, we analyzed the effects of three oligomerization state mutants of Lrp in terms of their ability to bind to DNA and regulate gene expression in response to exogenous leucine. We find that oligomerization beyond dimers is required for Lrp's regulatory activity and that, contrary to previous speculation, exogenous leucine modulates Lrp activity at its target promoters exclusively by inhibiting Lrp binding to DNA. We also show evidence that Lrp binding bridges DNA over length scales of multiple kilobases, revealing a new range of mechanisms for Lrp-mediated transcriptional regulation.
Leucine-responsive regulatory protein (Lrp) is one of the most impactful regulators in E. coli and other bacteria. Lrp senses nutrient conditions and responds by controlling strategies for virulence, cellular motility, and nutrient acquisition. Despite its importance and being evolutionarily highly conserved across bacteria and archaea, several mysteries remain regarding Lrp, including how it actually responds to leucine to change its regulation of targets. Previous studies have led to the hypothesis that Lrp switches between two states, an octamer (8 Lrp molecules together) and a hexadecamer (16 Lrp molecules together), upon exposure to leucine; these are referred to as different oligomerization states. Here, we show that contrary to previous expectations, it is Lrp's propensity to bind DNA, rather than its oligomerization state, that is directly affected by leucine in the cell's environment. Our new understanding of Lrp activity will aid in identifying and disrupting pathways used by bacteria to cause disease.
Birth by Cesarean section increases the risk of developing type 1 diabetes later in life. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of ...islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system. To investigate Cesarean section effects, we analyzed longitudinal gene expression profiles from peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes. For islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns. We identified the pentose phosphate pathway and pyrimidine metabolism - both involved in nucleotide synthesis and cell proliferation - to be differentially expressed in children born by Cesarean section and after islet autoimmunity. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. Moreover, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes. In conclusion, we identified shared molecular changes relating to immune cell activation in children born by Cesarean section and children who developed autoimmunity. Our results serve as a starting point for further investigations on how a type 1 diabetes risk factor impacts the young immune system at a molecular level.
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