Recurrent episodes of Takotsubo cardiomyopathy in systemic sclerosis

Systemic sclerosis is an autoimmune disease characterized by fibrosis and small vessel vasculopathy, which affects various organ systems, such as the heart. Takotsubo cardiomyopathy is a transient cardiomyopathy in reaction to an emotional or physical trigger. There may be clinical and pathogenetic overlap between Takotsubo cardiomyopathy and primary systemic sclerosis heart disease, and some patients with systemic sclerosis have been diagnosed with recurrent Takotsubo cardiomyopathy. Our large systemic sclerosis clinical cohort was reviewed to identify cases diagnosed with Takotsubo cardiomyopathy. The clinical features, laboratory and imaging results were reviewed and evaluated to perform a comparison between cases. We identified five patients with systemic sclerosis, all female (age 68.6 ± 5.7 years), who were diagnosed with Takotsubo cardiomyopathy. Two of these patients had recurrent episodes: one case with a history of multiple episodes and the other with one recurrence. Typical features included repolarization abnormalities on the electrocardiogram and transient left ventricular dysfunction observed using echocardiography or cardiac magnetic resonance imaging. Our findings build upon previous reports and observations that systemic sclerosis may cause Takotsubo cardiomyopathy. To our knowledge, this is the largest case series of Takotsubo syndrome in patients with systemic sclerosis. This association may provide novel insights into the aetiopathogenesis of Takotsubo cardiomyopathy as part of primary systemic sclerosis heart involvement

Two-dimensional projections of an hypercube

We present a method to project a hypercube of arbitrary dimension on the plane, in such a way as to preserve, as well as possible, the distribution of distances between vertices. The method relies on a Montecarlo optimization procedure that minimizes the squared difference between distances in the plane and in the hypercube, appropriately weighted. The plane projections provide a convenient way of visualization for dynamical processes taking place on the hypercube.Comment: 4 pages, 3 figures, Revtex

Chronic glucokinase activation reduces glycaemia and improves glucose tolerance in high-fat diet fed mice.

Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8weeks. In the long-term study, GKA71 was provided in the diet for 4weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with increased insulin secretion after intravenous glucose both in control and high-fat fed mice. Chronic GK activation significantly reduced basal plasma glucose and insulin, and improved glucose tolerance despite reduced insulin secretion after intravenous glucose, suggesting improved insulin sensitivity. Isolated islets from chronically GKA71-treated mice displayed augmented insulin secretion at 8.3mmol/l glucose, without affecting glucose oxidation. High-fat diet fed mice had reduced glycogen and increased triglyceride in liver compared to control mice, and these parameters were not altered by long-term GK activation. We conclude that GK activation in high-fat diet-fed mice potently reduces glycaemia and improves glucose tolerance, with combined effect both to stimulate insulin secretion from islets and improve insulin sensitivity

Dynamic prediction of pulmonary hypertension in systemic sclerosis using landmark analysis

OBJECTIVE: Pulmonary hypertension (PH) is a serious complication of systemic sclerosis (SSc). We explore prediction of short-term risk for PH using serial pulmonary function tests (PFTs) and other disease features. METHODS: Subjects with SSc, disease onset≥10 years prior to data retrieval, available autoantibody specificity and PFTs were included. Mixed effects modelling was used to describe change in PFTs over time. Landmarking was utilized to include serial assessments and stratified Cox proportional hazards regression analysis with landmarks as strata was used to develop the PH prediction models. RESULTS: We analysed 1247 SSc patients, 16.3% male, 35.8% with dcSSc. Anticentromere, anti-topoisomerase and anti-RNA polymerase antibodies were observed in 29.8%, 22.0% and 11.4% respectively and PH developed in 13.6%. Over time diffusing capacity for carbon monoxide (DLco) and carbon monoxide transfer coefficient (Kco) declined in all SSc patients (up to 1.5%/year) but demonstrated much greater annual decline (up to 4.5% and 4.8% respectively) in the 5-7 years preceding PH diagnosis. Comparison between multivariable models including either DLco, Kco or FVC/DLco ratio, demonstrated that both absolute values and change over preceding year in those measurements associate strongly with risk of PH (HR 0.93 and 0.76 for Kco and its change; HR 0.90 and 0.96 for DLco and its change; and HR 1.08 and 2.01 for FVC/DLco ratio and its change; p<0.001 for all). The Kco based model had the greatest discriminating ability (Harrell's C 0.903). CONCLUSION: Our findings strongly support the importance of PFT trends over time in identifying patients at risk of PH. This article is protected by copyright. All rights reserved

Collagen X Biomarker (CXM), Linear Growth, and Bone Development in a Vitamin D Intervention Study in Infants

Publisher Copyright: © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Collagen X biomarker (CXM) is suggested to be a biomarker of linear growth velocity. However, early childhood data are limited. This study examines the relationship of CXM to the linear growth rate and bone development, including the possible modifying effects of vitamin D supplementation. We analyzed a cohort of 276 term-born children participating in the Vitamin D Intervention in Infants (VIDI) study. Infants received 10 μg/d (group-10) or 30 μg/d (group-30) vitamin D3 supplementation for the first 2 years of life. CXM and length were measured at 12 and 24 months of age. Tibial bone mineral content (BMC), volumetric bone mineral density (vBMD), cross-sectional area (CSA), polar moment of inertia (PMI), and periosteal circumference (PsC) were measured using peripheral quantitative computed tomography (pQCT) at 12 and 24 months. We calculated linear growth as length velocity (cm/year) and the growth rate in length (SD unit). The mean (SD) CXM values were 40.2 (17.4) ng/mL at 12 months and 38.1 (12.0) ng/mL at 24 months of age (p = 0.12). CXM associated with linear growth during the 2-year follow-up (p = 0.041) but not with bone (p = 0.53). Infants in group-30 in the highest tertile of CXM exhibited an accelerated mean growth rate in length compared with the intermediate tertile (mean difference [95% CI] −0.50 [−0.98, −0.01] SD unit, p = 0.044) but not in the group-10 (p = 0.062) at 12 months. Linear association of CXM and growth rate until 12 months was weak, but at 24 months CXM associated with both length velocity (B for 1 increment of √CXM [95% CI] 0.32 [0.12, 0.52] cm/yr, p = 0.002) and growth rate in length (0.20 [0.08, 0.32] SD unit, p = 0.002). To conclude, CXM may not reliably reflect linear growth from birth to 12 months of age, but its correlation with growth velocity improves during the second year of life.Peer reviewe

On the statistical mechanics of prion diseases

We simulate a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant prion protein misfolding and aggregation. Our simulations lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self averaging. We model `species barriers' to prion infection and assess a related treatment protocol.Comment: 5 Pages, 3 eps figures (submitted to Physical Review Letters

Calibrating and testing tissue equivalent proportional counters with 37Ar

A method for testing and calibrating tissue equivalent proportional counters with37Ar is described.37Ar is produced by exposure of argon in its normal isotope composition to thermal neutrons. It is shown that - up to volume ratios of 0.01 of argon to the tissue equivalent gas - there is no appreciable effect of the argon admixture on the function of the proportional counter. Conventional calibration methods with characteristic x-rays or with -particles require modifications of the detectors, and they test only small sub-volumes in the counters. In contrast, argon permits calibrations and tests of the resolution that are representative for the entire counter volume and that do not require changes in detector construction. The method is equally applicable to multi-element proportional counters; it is here exemplified by its application to a long cylindrical counter of simplified design that is part of such a multi-element configuration

Annotation of two large contiguous regions from the Haemonchus contortus genome using RNA-seq and comparative analysis with Caenorhabditis elegans

The genomes of numerous parasitic nematodes are currently being sequenced, but their complexity and size, together with high levels of intra-specific sequence variation and a lack of reference genomes, makes their assembly and annotation a challenging task. Haemonchus contortus is an economically significant parasite of livestock that is widely used for basic research as well as for vaccine development and drug discovery. It is one of many medically and economically important parasites within the strongylid nematode group. This group of parasites has the closest phylogenetic relationship with the model organism Caenorhabditis elegans, making comparative analysis a potentially powerful tool for genome annotation and functional studies. To investigate this hypothesis, we sequenced two contiguous fragments from the H. contortus genome and undertook detailed annotation and comparative analysis with C. elegans. The adult H. contortus transcriptome was sequenced using an Illumina platform and RNA-seq was used to annotate a 409 kb overlapping BAC tiling path relating to the X chromosome and a 181 kb BAC insert relating to chromosome I. In total, 40 genes and 12 putative transposable elements were identified. 97.5% of the annotated genes had detectable homologues in C. elegans of which 60% had putative orthologues, significantly higher than previous analyses based on EST analysis. Gene density appears to be less in H. contortus than in C. elegans, with annotated H. contortus genes being an average of two-to-three times larger than their putative C. elegans orthologues due to a greater intron number and size. Synteny appears high but gene order is generally poorly conserved, although areas of conserved microsynteny are apparent. C. elegans operons appear to be partially conserved in H. contortus. Our findings suggest that a combination of RNA-seq and comparative analysis with C. elegans is a powerful approach for the annotation and analysis of strongylid nematode genomes

Why highly expressed proteins evolve slowly

Much recent work has explored molecular and population-genetic constraints on the rate of protein sequence evolution. The best predictor of evolutionary rate is expression level, for reasons which have remained unexplained. Here, we hypothesize that selection to reduce the burden of protein misfolding will favor protein sequences with increased robustness to translational missense errors. Pressure for translational robustness increases with expression level and constrains sequence evolution. Using several sequenced yeast genomes, global expression and protein abundance data, and sets of paralogs traceable to an ancient whole-genome duplication in yeast, we rule out several confounding effects and show that expression level explains roughly half the variation in Saccharomyces cerevisiae protein evolutionary rates. We examine causes for expression's dominant role and find that genome-wide tests favor the translational robustness explanation over existing hypotheses that invoke constraints on function or translational efficiency. Our results suggest that proteins evolve at rates largely unrelated to their functions, and can explain why highly expressed proteins evolve slowly across the tree of life.Comment: 40 pages, 3 figures, with supporting informatio