Infliximab for the treatment of intravenous immunoglobulin resistant Kawasaki disease complicated by coronary artery aneurysms: a case report

This case report describes an 8 year old boy with IVIG resistant Kawasaki disease complicated by severe bilateral coronary artery aneurysms successfully treated with infliximab, a monoclonal antibody against tumour necrosis factor alpha

Variable Radio Sources in the Galactic Plane

Using three epochs of VLA observations of the Galactic Plane in the first quadrant taken ~15 years apart, we have conducted a search for a population of variable Galactic radio emitters in the flux density range 1-100 mJy at 6 cm. We find 39 variable sources in a total survey area of 23.2 sq deg. Correcting for various selection effects and for the extragalactic variable population of active galactic nuclei, we conclude there are ~1.6 Galactic sources per sq deg which vary by more than 50% on a time scale of years (or shorter). We show that these sources are much more highly variable than extragalactic objects; more than 50% show variability by a factor >2 compared to <10% for extragalactic objects in the same flux density range. We also show that the fraction of variable sources increases toward the Galactic center (another indication that this is a Galactic population), and that the spectral indices of many of these sources are flat or inverted. A small number of the variables are coincident with mid-IR sources and two are coincident with X-ray emitters, but most have no known counterparts at other wavelengths. Intriguingly, one lies at the center of a supernova remnant, while another appears to be a very compact planetary nebula; several are likely to represent activity associated with star formation regions. We discuss the possible source classes which could contribute to the variable cohort and followup observations which could clarify the nature of these sources.Comment: 11 pages, 7 figures; to be published in the Astronomical Journal; data available on MAGPIS website at http://third.ucllnl.org/gps

A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Genome-wide association studies (GWAS), relying on hundreds of thousands of individuals, have revealed > 200 genomic loci linked to metabolic disease (MD). Loss of insulin sensitivity (IS) is a key component of MD and we hypothesized that discovery of a robust IS transcriptome would help reveal the underlying genomic structure of MD. Using 1,012 human skeletal muscle samples, detailed physiology and a tissue-optimized approach for the quantification of coding (> 18,000) and non-coding (> 15,000) RNA (ncRNA), we identified 332 fasting IS-related genes (CORE-IS). Over 200 had a proven role in the biochemistry of insulin and/or metabolism or were located at GWAS MD loci. Over 50% of the CORE-IS genes responded to clinical treatment; 16 quantitatively tracking changes in IS across four independent studies (P = 0.0000053: negatively: AGL, G0S2, KPNA2, PGM2, RND3 and TSPAN9 and positively: ALDH6A1, DHTKD1, ECHDC3, MCCC1, OARD1, PCYT2, PRRX1, SGCG, SLC43A1 and SMIM8). A network of ncRNA positively related to IS and interacted with RNA coding for viral response proteins (P < 1 × 10−48), while reduced amino acid catabolic gene expression occurred without a change in expression of oxidative-phosphorylation genes. We illustrate that combining in-depth physiological phenotyping with robust RNA profiling methods, identifies molecular networks which are highly consistent with the genetics and biochemistry of human metabolic disease

iGEMS : an integrated model for identification of alternative exon usage events

DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with (n = 9) or without (n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (similar to 90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3'UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5-10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.Peer reviewe

A practical and time-efficient high-intensity interval training program modifies cardio-metabolic risk factors in adults with risk factors for type ii diabetes

Introduction: Regular physical activity (PA) can reduce the risk of developing type 2 diabetes, but adherence to time-orientated (150 min week−1 or more) PA guidelines is very poor. A practical and time-efficient PA regime that was equally efficacious at controlling risk factors for cardio-metabolic disease is one solution to this problem. Herein, we evaluate a new time-efficient and genuinely practical high-intensity interval training (HIT) protocol in men and women with pre-existing risk factors for type 2 diabetes.Materials and methods: One hundred eighty-nine sedentary women (n = 101) and men (n = 88) with impaired glucose tolerance and/or a body mass index >27 kg m−2 [mean (range) age: 36 (18–53) years] participated in this multi-center study. Each completed a fully supervised 6-week HIT protocol at work-loads equivalent to ~100 or ~125% V˙O2 max. Change in V˙O2 max was used to monitor protocol efficacy, while Actiheart™ monitors were used to determine PA during four, weeklong, periods. Mean arterial (blood) pressure (MAP) and fasting insulin resistance [homeostatic model assessment (HOMA)-IR] represent key health biomarker outcomes.Results: The higher intensity bouts (~125% V˙O2 max) used during a 5-by-1 min HIT protocol resulted in a robust increase in V˙O2 max (136 participants, +10.0%, p < 0.001; large size effect). 5-by-1 HIT reduced MAP (~3%; p < 0.001) and HOMA-IR (~16%; p < 0.01). Physiological responses were similar in men and women while a sizeable proportion of the training-induced changes in V˙O2 max, MAP, and HOMA-IR was retained 3 weeks after cessation of training. The supervised HIT sessions accounted for the entire quantifiable increase in PA, and this equated to 400 metabolic equivalent (MET) min week−1. Meta-analysis indicated that 5-by-1 HIT matched the efficacy and variability of a time-consuming 30-week PA program on V˙O2 max, MAP, and HOMA-IR.Conclusion: With a total time-commitment o

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP. KEYWORDS: Craniopharyngioma; IL1-β; Inflammasome; MAPK/ERK pathway; Odontogenesis; Paracrine signalling; Trametini

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation