Cardiac computed tomography for the detection of cardiac amyloidosis

A 67-year-old Caucasian man presented with atrial flutter on routine 12-lead electrocardiography (ECG). Following appropriate anticoagulation, he successfully underwent atrial flutter ablation. Echocardiography during the admission showed concentric left ventricular (LV) hypertrophy with severely impaired LV systolic function, particularly longitudinal (Figure 1A, video 1), and biatrial dilatation. Due to episodes of non-sustained ventricular tachycardia, he was fitted with an implantable cardioverter-defibrillator (ICD). The ECG QRS complexes on peripheral leads were small compared to the structural wall thickening on echocardiography (Figure 1B) raising the suspicion of cardiac amyloidosis. Preliminary evaluation excluded a plasma cell dyscrasia (negative serum free light chains changes and urinary Bence-Jones protein). Serum amyloid P component (SAP) scintigraphy was negative for visceral organ uptake and bone tracer scintigraphy (Technetium-DPD) was positive with Perugini Grade 2-3 uptake (Figure 1C), consistent with a diagnosis of cardiac transthyretin amyloidosis (ATTR). Cardiac magnetic resonance (CMR) was contra-indicated due to the non-conditional ICD (Figure 1D). After giving fully informed written consent, cardiac computed tomography (CCT) was performed as part of a research study, using a three step protocol (Figure 1E) as previously described1, allowing calculation of the extracellular volume fraction (ECV) from pre- and 5-minutes post-contrast images. The septal ECV, calculated from a co-registered, segmented myocardial mask displaying pixel-by-pixel ECV values, was in the amyloid spectrum elevated at 63% (Figure 1F), Gene sequencing revealed a heterozygous V122I mutation, confirming the diagnosis of familial amyloid cardiomyopathy (ATTR)

A vine copula mixed effect model for trivariate meta-analysis of diagnostic test accuracy studies accounting for disease prevalence

A bivariate copula mixed model has been recently proposed to synthesize diagnostic test accuracy studies and it has been shown that it is superior to the standard generalized linear mixed model in this context. Here, we call trivariate vine copulas to extend the bivariate meta-analysis of diagnostic test accuracy studies by accounting for disease prevalence. Our vine copula mixed model includes the trivariate generalized linear mixed model as a special case and can also operate on the original scale of sensitivity, specificity, and disease prevalence. Our general methodology is illustrated by re-analyzing the data of two published meta-analyses. Our study suggests that there can be an improvement on trivariate generalized linear mixed model in fit to data and makes the argument for moving to vine copula random effects models especially because of their richness, including reflection asymmetric tail dependence, and computational feasibility despite their three dimensionality

A comparison of the metabolic effects of sustained strenuous activity in polar environments on men and women

This study investigates differences in pre- to post-expedition energy expenditure, substrate utilisation and body composition, between the all-male Spear17 (SP-17) and all-female Ice Maiden (IM) transantarctic expeditions (IM: N = 6, 61 days, 1700 km; SP-17: N = 5, 67 days, 1750 km). Energy expenditure and substrate utilisation were measured by a standardised 36 h calorimetry protocol; body composition was determined using air displacement plethysmography. Energy balance calculation were used to assess the physical challenge. There was difference in the daily energy expenditure (IM: 4,939 kcal day−1; SP-17: 6,461 kcal day−1, p = 0.004); differences related to physical activity were small, but statistically significant (IM = 2,282 kcal day−1; SP-17 = 3,174 kcal day−1; p = 0.004). Bodyweight loss was modest (IM = 7.8%, SP-17 = 6.5%; p > 0.05) as was fat loss (IM = 30.4%, SP-17 = 40.4%; p > 0.05). Lean tissue weight change was statistically significant (IM = − 2.5%, SP-17 = + 1.0%; p = 0.05). No difference was found in resting or sleeping energy expenditure, normalised to lean tissue weight (p > 0.05); nor in energy expenditure when exercising at 80, 100 and 120 steps min−1, normalised to body weight (p > 0.05). Similarly, no difference was found in the change in normalised substrate utilisation for any of the activities (p > 0.05). Analysis suggested that higher daily energy expenditures for the men in Spear-17 was the result of higher physical demands resulting in a reduced demand for energy to thermoregulate compared to the women in Ice Maiden. The lack of differences between men and women in the change in energy expenditure and substrate utilisation, suggests no sex difference in response to exposure to extreme environments

A Three-Dimensional B.I.E.M. Program

The program PECET (Boundary Element Program in Three-Dimensional Elasticity) is presented in this paper. This program, written in FORTRAN V and implemen ted on a UNIVAC 1100,has more than 10,000 sentences and 96 routines and has a lot of capabilities which will be explained in more detail. The object of the program is the analysis of 3-D piecewise heterogeneous elastic domains, using a subregionalization process and 3-D parabolic isopara, metric boundary elements. The program uses special data base management which will be described below, and the modularity followed to write it gives a great flexibility to the package. The Method of Analysis includes an adaptive integration process, an original treatment of boundary conditions, a complete treatment of body forces, the utilization of a Modified Conjugate Gradient Method of solution and an original process of storage which makes it possible to save a lot of memory

Regulation of Mycobacterium tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway

Tuberculosis (TB) disease in HIV co-infected patients contributes to increased mortality by activating innate and adaptive immune signaling cascades that stimulate HIV-1 replication, leading to an increase in viral load. Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages. We show that NFAT5 gene and protein expression are strongly induced by MTb, which is a Toll-like receptor (TLR) ligand, and that an intact NFAT5 binding site in the viral promoter of R5-tropic HIV-1 subtype B and subtype C molecular clones is required for efficent induction of HIV-1 replication by MTb. Furthermore, silencing by RNAi of key components of the TLR pathway in human monocytes, including the downstream signaling molecules MyD88, IRAK1, and TRAF6, significantly inhibits MTb-induced NFAT5 gene expression. Thus, the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct interaction with the viral promoter. These findings also demonstrate a general role for NFAT5 in TLR- and MTb-mediated control of gene expression

Assessing the reliability of retrospective reports of adverse childhood experiences among adolescents with documented childhood maltreatment

The literature suggests that childhood maltreatment is related to a higher probability of developing psychopathology and disease in adulthood. However, some authors have questioned the reliability of self-reports of maltreatment, suggesting that psychopathology at the time of evaluation affects self-reports. We evaluated the reliability of the self-reports of 79 young adults who were identified in childhood by Child Protective Services by comparing two moments of evaluation. Psychological and physical symptoms were tested to evaluate their interference with the reports. We found good to excellent agreement, with no significant correlation between the changes in self-reported experiences and the changes in physical and psychological symptoms, suggesting that the reliability of reports is not related to the health state at the time of the report

Exclusion of NFAT5 from Mitotic Chromatin Resets Its Nucleo-Cytoplasmic Distribution in Interphase

The transcription factor NFAT5 is a major inducer of osmoprotective genes and is required to maintain the proliferative capacity of cells exposed to hypertonic stress. In response to hypertonicity, NFAT5 translocates to the nucleus, binds to regulatory regions of osmoprotective genes and activates their transcription. Besides stimulus-specific regulatory mechanisms, the activity of transcription factors in cycling cells is also regulated by the passage through mitosis, when most transcriptional processes are downregulated. It was not known whether mitosis could be a point of control for NFAT5.Using confocal microscopy we observed that NFAT5 was excluded from chromatin during mitosis in both isotonic and hypertonic conditions. Analysis of NFAT5 deletions showed that exclusion was mediated by the carboxy-terminal domain (CTD). NFAT5 mutants lacking this domain showed constitutive binding to mitotic chromatin independent of tonicity, which caused them to localize in the nucleus and remain bound to chromatin in the subsequent interphase without hypertonic stimulation. We analyzed the contribution of the CTD, DNA binding, and nuclear import and export signals to the subcellular localization of this factor. Our results indicated that cytoplasmic localization of NFAT5 in isotonic conditions required both the exclusion from mitotic DNA and active nuclear export in interphase. Finally, we identified several regions within the CTD of NFAT5, some of them overlapping with transactivation domains, which were separately capable of causing its exclusion from mitotic chromatin.Our results reveal a multipart mechanism regulating the subcellular localization of NFAT5. The transactivating module of NFAT5 switches its function from an stimulus-specific activator of transcription in interphase to an stimulus-independent repressor of binding to DNA in mitosis. This mechanism, together with export signals acting in interphase, resets the cytoplasmic localization of NFAT5 and prevents its nuclear accumulation and association with DNA in the absence of hypertonic stress

Ideological Labels in America

This paper extends Ellis and Stimson’s (Ideology in America. New York: Cambridge UniversityPress, 2012) study of the operational-symbolic paradox using issue-level measures of ideological incongruence based on respondent positions and symbolic labels for these positions across 14 issues. Like Ellis and Stimson, we find that substantial numbers—over 30 %—of Americans experience conflicted conservatism. Our issue-level data reveal, furthermore, that conflicted conservatism is most common on the issues of education and welfare spending. In addition, we also find that 20 % of Americans exhibit conflicted liberalism. We then replicate Ellis and Stimson’s finding that conflicted conservatism is associated with low sophistication and religiosity, but also find that it is associated with being socialized in a post-1960s generation and using Fox News as a main news source. Finally, we show the important role played by identities, with both conflicted conservatism and conflicted liberalism linked with partisan and ideological identities, and conflicted liberalism additionally associated with ethnic identities

Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice

<p>Abstract</p> <p>Background</p> <p>The transcription factor NFAT5/TonEBP regulates the response of mammalian cells to hypertonicity. However, little is known about the physiopathologic tonicity thresholds that trigger its transcriptional activity in primary cells. Wilkins et al. recently developed a transgenic mouse carrying a luciferase reporter (9xNFAT-Luc) driven by a cluster of NFAT sites, that was activated by calcineurin-dependent NFATc proteins. Since the NFAT site of this reporter was very similar to an optimal NFAT5 site, we tested whether this reporter could detect the activation of NFAT5 in transgenic cells.</p> <p>Results</p> <p>The 9xNFAT-Luc reporter was activated by hypertonicity in an NFAT5-dependent manner in different types of non-transformed transgenic cells: lymphocytes, macrophages and fibroblasts. Activation of this reporter by the phorbol ester PMA plus ionomycin was independent of NFAT5 and mediated by NFATc proteins. Transcriptional activation of NFAT5 in T lymphocytes was detected at hypertonic conditions of 360–380 mOsm/kg (isotonic conditions being 300 mOsm/kg) and strongly induced at 400 mOsm/kg. Such levels have been recorded in plasma in patients with osmoregulatory disorders and in mice deficient in aquaporins and vasopressin receptor. The hypertonicity threshold required to activate NFAT5 was higher in bone marrow-derived macrophages (430 mOsm/kg) and embryonic fibroblasts (480 mOsm/kg). Activation of the 9xNFAT-Luc reporter by hypertonicity in lymphocytes was insensitive to the ERK inhibitor PD98059, partially inhibited by the PI3-kinase inhibitor wortmannin (0.5 μM) and the PKA inhibitor H89, and substantially downregulated by p38 inhibitors (SB203580 and SB202190) and by inhibition of PI3-kinase-related kinases with 25 μM LY294002. Sensitivity of the reporter to FK506 varied among cell types and was greater in primary T cells than in fibroblasts and macrophages.</p> <p>Conclusion</p> <p>Our results indicate that NFAT5 is a sensitive responder to pathologic increases in extracellular tonicity in T lymphocytes. Activation of NFAT5 by hypertonicity in lymphocytes was mediated by a combination of signaling pathways that differed from those required in other cell types. We propose that the 9xNFAT-Luc transgenic mouse model might be useful to study the physiopathological regulation of both NFAT5 and NFATc factors in primary cells.</p