Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy.

Inherited retinal diseases (IRDs) are a heterogeneous group of blinding disorders, which result in dysfunction or death of the light-sensing cone and rod photoreceptors. Despite individual IRDs (Inherited retinal disease) being rare, collectively, they affect up to 1:2000 people worldwide, causing a significant socioeconomic burden, especially when cone-mediated central vision is affected. This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD (Inherited retinal disease), to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methylation and acetylation in healthy and diseased cones. Furthermore, continuous administration of GSK-J4 in retinal explants increased cone survival. Our results suggest that IRD (Inherited retinal disease)-affected cones respond positively to epigenetic modulation of histones, indicating the potential of this approach in developing a broad class of novel therapies to slow cone degeneration.

Differential Gene Expression of Lymphocytes Stimulated with Rhinovirus A and C in Children with Asthma.

Rationale: Individuals with asthma have heightened antibody responses to rhinoviruses (RVs), although those specific for RV-C are lower than responses specific for RV-A, suggesting poor immunity to this species.Objectives: To ascertain and compare T-cell memory responses induced by RV-A and RV-C in children with and without asthma.Methods: Peripheral blood mononuclear cells from 17 children with asthma and 19 control subjects without asthma were stimulated in vitro with peptide formulations to induce representative species-specific responses to RV-A and RV-C. Molecular profiling (RNA sequencing) was used to identify enriched pathways and upstream regulators.Measurements and Main Results: Responses to RV-A showed higher expression of IFNG and STAT1 compared with RV-C, and significant expression of CXCL9, 10, and 11 was not found for RV-C. There was no reciprocal increase of T-helper cell type 2 (Th2) cytokine genes or the Th2 chemokine genes CCL11, CCL17, and CCL22. RV-C induced higher expression of CCL24 (eotaxin-2) than RV-A in the responses of children with and without asthma. Upstream regulator analysis showed both RV-A and, although to a lesser extent, RV-C induced predominant Th1 and inflammatory cytokine expression. The responses of children with asthma compared with those without asthma were lower for both RV-A and RV-C while retaining the pattern of gene expression and upstream regulators characteristic of each species. All groups showed activation of the IL-17A pathway.Conclusions: RV-C induced memory cells with a lower IFN-γ-type response than RV-A without T-helper cell type 2 (Th2) upregulation. Children with asthma had lower recall responses than those without asthma while largely retaining the same gene activation profile for each species. RV-A and RV-C, therefore, induce qualitatively different T-cell responses.

Mode of birth and risk of infection-related hospitalisation in childhood: A population cohort study of 7.17 million births from 4 high-income countries.

BACKGROUND: The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates. METHODS AND FINDINGS: We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available. CONCLUSIONS: In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated.

Reticulon-1 and Reduced Migration toward Chemoattractants by Macrophages Differentiated from the Bone Marrow of Ultraviolet-Irradiated and Ultraviolet-Chimeric Mice.

The ability of macrophages to respond to chemoattractants and inflammatory signals is important for their migration to sites of inflammation and immune activity and for host responses to infection. Macrophages differentiated from the bone marrow (BM) of UV-irradiated mice, even after activation with LPS, migrated inefficiently toward CSF-1 and CCL2. When BM cells were harvested from UV-irradiated mice and transplanted into naive mice, the recipient mice (UV-chimeric) had reduced accumulation of elicited monocytes/macrophages in the peritoneal cavity in response to inflammatory thioglycollate or alum. Macrophages differentiating from the BM of UV-chimeric mice also had an inherent reduced ability to migrate toward chemoattractants in vitro, even after LPS activation. Microarray analysis identified reduced reticulon-1 mRNA expressed in macrophages differentiated from the BM of UV-chimeric mice. By using an anti-reticulon-1 Ab, a role for reticulon-1 in macrophage migration toward both CSF-1 and CCL2 was confirmed. Reticulon-1 subcellular localization to the periphery after exposure to CSF-1 for 2.5 min was shown by immunofluorescence microscopy. The proposal that reduced reticulon-1 is responsible for the poor inherent ability of macrophages to respond to chemokine gradients was supported by Western blotting. In summary, skin exposure to erythemal UV radiation can modulate macrophage progenitors in the BM such that their differentiated progeny respond inefficiently to signals to accumulate at sites of inflammation and immunity.

UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow-Differentiated Dendritic Cells.

A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow (BM) of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with BM from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the BM of nonirradiated mice, those from UV-irradiated mice produced more lactate, consumed more glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4-dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from BM of UV-irradiated mice. UV-induced prostaglandin E2 has been implicated as an intermediary in the effects of UV radiation on BM cells. DCs differentiating from BM cells pulsed in vitro for 2 hours with dimethyl prostaglandin E2 were functionally similar to those from the BM of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice.

Official ERS technical standards: Global Lung Function Initiative reference values for the carbon monoxide transfer factor for Caucasians.

There are numerous reference equations available for the single-breath transfer factor of the lung for carbon monoxide (T LCO); however, it is not always clear which reference set should be used in clinical practice. The aim of the study was to develop the Global Lung Function Initiative (GLI) all-age reference values for T LCOData from 19 centres in 14 countries were collected to define T LCO reference values. Similar to the GLI spirometry project, reference values were derived using the LMS (lambda, mu, sigma) method and the GAMLSS (generalised additive models for location, scale and shape) programme in R.12 660 T LCO measurements from asymptomatic, lifetime nonsmokers were submitted; 85% of the submitted data were from Caucasians. All data were uncorrected for haemoglobin concentration. Following adjustments for elevation above sea level, gas concentration and assumptions used for calculating the anatomic dead space volume, there was a high degree of overlap between the datasets. Reference values for Caucasians aged 5-85 years were derived for T LCO, transfer coefficient of the lung for carbon monoxide and alveolar volume.This is the largest collection of normative T LCO data, and the first global reference values available for T LCO.

Integrated analyses of zebrafish miRNA and mRNA expression profiles identify miR-29b and miR-223 as potential regulators of optic nerve regeneration.

BACKGROUND: Unlike mammals, zebrafish have the ability to regenerate damaged parts of their central nervous system (CNS) and regain functionality of the affected area. A better understanding of the molecular mechanisms involved in zebrafish regeneration may therefore provide insight into how CNS repair might be induced in mammals. Although many studies have described differences in gene expression in zebrafish during CNS regeneration, the regulatory mechanisms underpinning the differential expression of these genes have not been examined. RESULTS: We used microarrays to analyse and integrate the mRNA and microRNA (miRNA) expression profiles of zebrafish retina after optic nerve crush to identify potential regulatory mechanisms that underpin central nerve regeneration. Bioinformatic analysis identified 3 miRNAs and 657 mRNAs that were differentially expressed after injury. We then combined inverse correlations between our miRNA expression and mRNA expression, and integrated these findings with target predictions from TargetScan Fish to identify putative miRNA-gene target pairs. We focused on two over-expressed miRNAs (miR-29b and miR-223), and functionally validated seven of their predicted gene targets using RT-qPCR and luciferase assays to confirm miRNA-mRNA binding. Gene ontology analysis placed the miRNA-regulated genes (eva1a, layna, nefmb, ina, si:ch211-51a6.2, smoc1, sb:cb252) in key biological processes that included cell survival/apoptosis, ECM-cytoskeleton signaling, and heparan sulfate proteoglycan binding, CONCLUSION: Our results suggest a key role for miR-29b and miR-223 in zebrafish regeneration. The identification of miRNA regulation in a zebrafish injury model provides a framework for future studies in which to investigate not only the cellular processes required for CNS regeneration, but also how these mechanisms might be regulated to promote successful repair and return of function in the injured mammalian brain.

Gene dysregulation in acute HIV-1 infection - early transcriptomic analysis reveals the crucial biological functions affected.

Introduction: Transcriptomic analyses from early human immunodeficiency virus (HIV) infection have the potential to reveal how HIV causes widespread and lasting damage to biological functions, especially in the immune system. Previous studies have been limited by difficulties in obtaining early specimens. Methods: A hospital symptom-based screening approach was applied in a rural Mozambican setting to enrol patients with suspected acute HIV infection (Fiebig stage I-IV). Blood samples were collected from all those recruited, so that acute cases and contemporaneously recruited, uninfected controls were included. PBMC were isolated and sequenced using RNA-seq. Sample cellular composition was estimated from gene expression data. Differential gene expression analysis was completed, and correlations were determined between viral load and differential gene expression. Biological implications were examined using Cytoscape, gene set enrichment analysis, and enrichment mapping. Results: Twenty-nine HIV infected subjects one month from presentation and 46 uninfected controls were included in this study. Subjects with acute HIV infection demonstrated profound gene dysregulation, with 6131 (almost 13% of the genome mapped in this study) significantly differentially expressed. Viral load was correlated with 1.6% of dysregulated genes, in particular, highly upregulated genes involved in key cell cycle functions, were correlated with viremia. The most profoundly upregulated biological functions related to cell cycle regulation, in particular, CDCA7 may drive aberrant cell division, promoted by overexpressed E2F family proteins. Also upregulated were DNA repair and replication, microtubule and spindle organization, and immune activation and response. The interferome of acute HIV was characterized by broad activation of interferon-stimulated genes with antiviral functions, most notably IFI27 and OTOF. BCL2 downregulation alongside upregulation of several apoptotic trigger genes and downstream effectors may contribute to cycle arrest and apoptosis. Transmembrane protein 155 (TMEM155) was consistently highly overexpressed during acute infection, with roles hitherto unknown. Discussion: Our study contributes to a better understanding of the mechanisms of early HIV-induced immune damage. These findings have the potential to lead to new earlier interventions that improve outcomes.

Ndrg1 in development and maintenance of the myelin sheath.

CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.

Hepatic iron loading in mice increases cholesterol biosynthesis.

UNLABELLED: Iron and cholesterol are both essential metabolites in mammalian systems, and too much or too little of either can have serious clinical consequences. In addition, both have been associated with steatosis and its progression, contributing, inter alia, to an increase in hepatic oxidative stress. The interaction between iron and cholesterol is unclear, with no consistent evidence emerging with respect to changes in plasma cholesterol on the basis of iron status. We sought to clarify the role of iron in lipid metabolism by studying the effects of iron status on hepatic cholesterol synthesis in mice with differing iron status. Transcripts of seven enzymes in the cholesterol biosynthesis pathway were significantly up-regulated with increasing hepatic iron (R(2) between 0.602 and 0.164), including those of the rate-limiting enzyme, 3-hydroxy-3-methylglutarate-coenzyme A reductase (Hmgcr; R(2) = 0.362, P < 0.002). Hepatic cholesterol content correlated positively with hepatic iron (R(2) = 0.255, P < 0.007). There was no significant relationship between plasma cholesterol and either hepatic cholesterol or iron (R(2) = 0.101 and 0.014, respectively). Hepatic iron did not correlate with a number of known regulators of cholesterol synthesis, including sterol-regulatory element binding factor 2 (Srebf2; R(2) = 0.015), suggesting that the increases seen in the cholesterol biosynthesis pathway are independent of Srebf2. Transcripts of genes involved in bile acid synthesis, transport, or regulation did not increase with increasing hepatic iron. CONCLUSION: This study suggests that hepatic iron loading increases liver cholesterol synthesis and provides a new and potentially important additional mechanism by which iron could contribute to the development of fatty liver disease or lipotoxicity.

The familial risk of infection-related hospitalization in children: A population-based sibling study.

OBJECTIVE: To assess the risk of severe childhood infections within families, we conducted a sibling analysis in a population-based cohort study with genealogical linkage. We investigated the sibling risk of hospitalization with common infections, a marker of severity. We hypothesized that having siblings hospitalized for infection would increase the proband's risk of admission with infection. STUDY DESIGN: We used population data on Western Australian live-born singletons and their siblings between 1980 and 2014. Measures of infection were infection-related hospitalizations from discharge diagnostic codes. Exposure was having a sibling who had an infection-related hospitalization. Outcomes were infection-related hospitalizations in the child/proband. Probands were followed until an infection-related hospitalization admission (up to the first three), death, 18th birthday, or end of 2014, whichever occurred first. Infection risks were estimated by adjusted Cox proportional hazard models for multiple events. RESULTS: Of 512,279 probands, 142,915 (27.9%) had infection-related hospitalizations; 133,322 (26.0%) had a sibling with a previous infection-related hospitalization (i.e. exposed). Median interval between sibling and proband infection-related hospitalizations was 1.4 years (inter-quartile range 0.5-3.7). Probands had a dose-dependent increase in risk if sibling/s had 1, 2, or 3+ infection-related hospitalizations (adjusted hazard ratio, aHR 1.41, 95% CI 1.39-1.43; aHR 1.65, 1.61-1.69; aHR 1.83, 1.77-1.90, respectively). Among siblings with the same clinical infection type, highest sibling risks were for genitourinary (aHR 2.06, 1.68-2.53), gastrointestinal (aHR 2.07, 1.94-2.19), and skin/soft tissue infections (aHR 2.34, 2.15-2.54). Overall risk of infection-related hospitalization was higher in children with more siblings and with older siblings. CONCLUSION: In this population-based study, we observed an increased risk of infection-related hospitalization in children whose siblings were previously hospitalized for infection. Public health interventions may be particularly relevant in families of children hospitalized with infection.

Maternal prenatal stress exposure and sex-specific risk of severe infection in offspring.

BACKGROUND: Maternal stressful life events during pregnancy have been associated with immune dysregulation and increased risk for asthma and atopy in offspring. Few studies have investigated whether prenatal stress is associated with increased overall or specific infectious diseases in childhood, nor explored sex differences. We sought to examine the relationship between the nature and timing of maternal stress in pregnancy and hospitalisation with infection in offspring. METHODS: Between 1989 and 1992, exposure data on stressful life events were collected from pregnant women (Gen1) in the Raine Study at 18 and 34 weeks' gestation and linked to statutory state-wide hospital morbidity data. We examined associations between the number, category and timing of maternal prenatal stress events and overall and clinical groups of offspring (Gen2) infection-related hospitalisation until age 16 years, adjusting for maternal age, education, and smoking in pregnancy in addition to the presence of siblings at birth. RESULTS: Of 2,141 offspring with complete stress in pregnancy data available, 1,089 had at least one infection-related hospitalisation, with upper respiratory tract infections the most common (n = 556). Each additional stressful life event during pregnancy was associated with increased risk in male offspring for hospitalisation with all infection types. There was little evidence of these associations in girls. CONCLUSIONS: Increased exposure to stressful life events in utero is associated with sex-specific infection-related hospitalisations in childhood. Prenatal stress may adversely affect early immune development for boys and increase the risk of more severe infections. Mechanistic understanding would inform preventative interventions.

Celestial3D: a novel method for 3D visualization of familial data.

SUMMARY: Traditional two-dimensional (2D) software programs for drawing pedigrees are limited when dealing with extended pedigrees. In successive generations, the number of individuals grows exponentially, leading to an unworkable amount of space required in the horizontal direction for 2D displays. In addition, it is not always possible to place closely related individuals near each other due to the lack of space in 2Ds. To address these issues we have developed three-dimensional (3D) pedigree drawing techniques to enable clearer visualization of extended pedigrees. Currently no other methods are available for displaying extended pedigrees in 3Ds. We have made freely available a software tool--'Celestial3D'--that implements these novel techniques. AVAILABILITY: Freely available to non-commercial users.

SimHap GUI: an intuitive graphical user interface for genetic association analysis.

BACKGROUND: Researchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the SimHap package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool. RESULTS: We have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the SimHap R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress. CONCLUSION: SimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.

Investigating the association between K198N coding polymorphism in EDN1 and hypertension, lipoprotein levels, the metabolic syndrome and cardiovascular disease.

Endothelin-1 is a potent vasoconstrictor in the body. Previous studies have identified associations between the coding polymorphism K198N and hypertension, systolic blood pressure and HDL levels. We sought to examine the evidence for these associations and, additionally, the association between K198N, insulin resistance, metabolic syndrome and coronary artery disease (CAD). We used generalised linear modelling to test K198N for association with hypertension and systolic blood pressure, lipid levels, insulin resistance scores and metabolic syndrome in a general cross-sectional community sample. Mean carotid intima media thickness and risk of carotid plaque were examined in the general population sample, and Gensini score was examined in a sample of patients with CAD. A case/control sample was used to examine the association of K198N with risk of CAD. There was no significant evidence for association between K198N and hypertension, systolic blood pressure, lipid levels, insulin resistance or metabolic syndrome in either population. The minor allele was marginally associated with increased mean IMT levels (P = 0.02) in the general population sample, although not with CAD in the case/control study or with the severity of disease in patients with CAD. In conclusion, we found no robust evidence for the associations between K198N and hypertension, systolic blood pressure or HDL levels seen in previous studies.

Association of PARL rs3732581 genetic variant with insulin levels, metabolic syndrome and coronary artery disease.

PARL (presenilin-associated rhomboid-like) is a mitochondrial protein involved in mitochondrial membrane remodelling, and maps to a quantitative trait locus (3q27) associated with metabolic traits. Recently the rs3732581 (Leu262Val) variant was found to be associated with increased levels of plasma insulin, a finding not replicated in a larger cohort. The aim of the current study was to investigate the associations between rs3732581 and levels of plasma insulin, metabolic syndrome (MetS) and its components, and cardiovascular disease. The CUPID population consisted of 556 subjects with angiographically proven CAD and the CUDAS cohort consisted of 1,109 randomly selected individuals from Perth, Western Australia. Samples were genotyped using mutation-specific PCR. No significant associations were observed between rs3732581 and levels of plasma insulin, glucose, BMI or MetS in either population. However, carriers of the minor allele had significantly lower mean intima-media thickness (IMT) [0.69 mm, 95% CI (0.69, 0.70 mm); P = 0.004], compared with major allele homozygotes [mean IMT = 0.71 mm, 95% CI (0.70, 0.72 mm)] in the CUDAS population. Further analysis using a recessive model showed homozygous carriers of the minor allele were predisposed to CAD [OR 1.55, 95% CI (1.11, 2.16); P = 0.01]. Despite the functional evidence for a role of PARL in regulating insulin levels, no association with rs3732581 was found in the current study. Additionally, there were no associations with glucose levels, BMI or MetS. There were significant effects of the variant on mean IMT and risk of CAD. A role for PARL in metabolic conditions cannot be excluded and more comprehensive genetic studies are warranted.

Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population.

The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) in the Interleukin-1 (IL-1) gene family are associated with central obesity and metabolic syndrome in a coronary heart disease population. The IL-1 alpha C-889T (rs1800587) and IL-1 beta +3954 (rs1143634) SNPs were studied in a Western Australian coronary heart disease (CHD) population (N = 556). Subjects who were TT homozygous at either SNP had larger waist circumference (IL-1 alpha: 1.8 cm greater, P = 0.04; IL-1 beta: 4 cm greater, P = 0.0004) compared with major allele homozygotes. Individuals with two copies of the IL-1 alpha:IL-1 beta T:T haplotype had greater waist circumference (4.7 cm greater, P = 0.0001) compared to other haplotypes. There was a significant interaction between the IL-1 beta SNP and BMI level on waist circumference (P = 0.01). When the cohort was stratified by median BMI, TT carriers for IL-1 beta with above median BMI had greater waist circumference (6.1 cm greater, P = 0.007) compared to baseline carriers, whilst no significant association was seen in the below median group. Similarly, when the cohort was stratified by median fibrinogen level (IL-1 alpha interaction P = 0.01; IL-1 beta interaction P = 0.04), TT carriers for both SNPs in the above median fibrinogen group had greater waist circumference (IL-1 alpha 2.7 cm greater, P = 0.007; IL-1 beta 3.3 cm greater, P = 0.003) compared with major allele homozygotes. This association was not seen in the below median group. Also, we found a trend of increased metabolic syndrome for IL-1 beta TT homozygotes (P = 0.07). In conclusion, our findings suggest that in a CHD population IL-1 gene polymorphisms may be involved in increased central obesity, and the genetic influences are more evident among patients who have a higher level of obesity or inflammatory markers.

Incidence of and risk factors for hospitalisations due to vascular complications: A population-based type 1 diabetes cohort (n=1316) followed into early adulthood.

AIM: To determine the incidence of hospitalisations and risk factors for vascular complications experienced during early adulthood in patients with childhood onset type 1 diabetes. METHODS: A population-based childhood onset type 1 diabetes cohort was identified from a statewide register (1992-2012). Data linkage was used to identify a matched comparison cohort. Hospital admissions data were extracted to follow up both cohorts into early adulthood (1975-2012). RESULTS: The type 1 diabetes cohort (n=1316) had a mean age of diagnosis of 9.5years, 49.5% were women and mean age at the end of follow-up was 26.3years (range 18-38). Within the type 1 diabetes cohort 32 (2.4%) were hospitalised with a vascular complication during early adulthood. Poor glycaemic control during paediatric management was associated with a significant increase in risk for ophthalmic complication with 19.4% (n=12/62) of those with a mean HbA1c >12% (108mmol/mol) diagnosed compared to 0.72% (n=5/696) of those with mean HbA1c <9% (75mmol/mol), adjusted hazard ratio 8.4 (95% CI 2.0, 34.7). CONCLUSION: Severe vascular complications requiring hospital admission continue to be observed during early adulthood. Both women and those with poor glycaemic control are at increased risk of requiring a hospital admission for these complications during early adulthood.

The Global Lung Function Initiative (GLI) Network: bringing the world's respiratory reference values together.

The Global Lung Function Initiative (GLI) Network has become the largest resource for reference values for routine lung function testing ever assembled. This article addresses how the GLI Network came about, why it is important, and its current challenges and future directions. It is an extension of an article published in Breathe in 2013 [1], and summarises recent developments and the future of the GLI Network. KEY POINTS: The Global Lung Function Initiative (GLI) Network was established as a result of international collaboration, and altruism between researchers, clinicians and industry partners. The ongoing success of the GLI relies on network members continuing to work together to further improve how lung function is reported and interpreted across all age groups around the world.The GLI Network has produced standardised lung function reference values for spirometry and gas transfer tests.GLI reference equations should be adopted immediately for spirometry and gas transfer by clinicians and physiologists worldwide.The recently established GLI data repository will allow ongoing development and evaluation of reference values, and will offer opportunities for novel research. EDUCATIONAL AIMS: To highlight the advances made by the GLI Network during the past 5 years.To highlight the importance of using GLI reference values for routine lung function testing (e.g. spirometry and gas transfer tests).To discuss the challenges that remain for developing and improving reference values for lung function tests.

JLIN: a java based linkage disequilibrium plotter.

BACKGROUND: A great deal of effort and expense are being expended internationally in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Techniques such as Linkage Disequilibrium mapping are being increasingly used to examine and compare markers across increasingly large datasets. Visualisation techniques are becoming essential to analyse the ever-growing volume of data and results available with any given analysis. RESULTS: JLIN (Java LINkage disequilibrium plotter) is a software package designed for customisable, intuitive visualisation of Linkage Disequilibrium (LD) across all common computing platforms. Customisation allows the user to choose particular visualisations, statistical measures and measurement ranges. JLIN also allows the user to export images of the LD visualisation in several common document formats. CONCLUSION: JLIN allows the user to visually compare and contrast the results of a range of statistical measures on the input dataset(s). These measures include the commonly used D' and r2 statistics and empirical p-values. JLIN has a number of unique and novel features that improve on existing LD visualisation tools.