Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy.

BACKGROUND: Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]). METHODS AND RESULTS: A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045). CONCLUSIONS: The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study

Finite-size scaling considerations on the ground state microcanonical temperature in entropic sampling simulations

In this work we discuss the behavior of the microcanonical temperature $\frac{\partial S(E)}{\partial E}$ obtained by means of numerical entropic sampling studies. It is observed that in almost all cases the slope of the logarithm of the density of states $S(E)$ is not infinite in the ground state, since as expected it should be directly related to the inverse temperature $\frac{1}{T}$. Here we show that these finite slopes are in fact due to finite-size effects and we propose an analytic expression $a\ln(bL)$ for the behavior of $\frac{\varDelta S}{\varDelta E}$ when $L\rightarrow\infty$. To test this idea we use three distinct two-dimensional square lattice models presenting second-order phase transitions. We calculated by exact means the parameters $a$ and $b$ for the two-states Ising model and for the $q=3$ and $4$ states Potts model and compared with the results obtained by entropic sampling simulations. We found an excellent agreement between exact and numerical values. We argue that this new set of parameters $a$ and $b$ represents an interesting novel issue of investigation in entropic sampling studies for different models

Mineralocorticoid receptor antagonists eplerenone and spironolactone modify adrenal cortex morphology and physiology

Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, n = 18) and normotensive rats (WKY, n = 18) were randomly exposed to a daily dose of spironolactone (n = 6), eplerenone (n = 6), or no drug (n = 6) over 28 days. After that, aldosterone, corticosterone, and 11-deoxycorticosterone plasma concentrations were quantified. Adrenal glands were subjected to morphological analysis to assess lipid droplets content, capsular width, cell proliferation, and steroidogenic proteins expression. The adrenal cortex in untreated SHR showed higher lipid droplet content as than in WKY. In SHR, MRA treatment was associated with higher circulating aldosterone levels and Ki-67 expression in aldosterone-secreting cells. In WKY, the only difference observed after MRA spironolactone treatment was a narrower capsule. There was no difference in abundance of steroidogenic enzyme between groups. In conclusion, MRAs modify adrenal gland function and morphology in SHR. The effects observed within the adrenal glomerulosa with aldosterone-secreting cell proliferation and higher circulating aldosterone levels suggests that MRA treatment provokes activation of the renin angiotensin system. The prognostic value of hyperaldosteronism secondary to MRAs blockade requires further investigation.Funding: This research was funded by the Associação dos Amigos do Serviço de Endocrinologia do Hospital de São João (2020–2021). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by the Foundation for Science and Technology (FCT)-Portugal (UIDB/00215/2020 and UIDP/00215/2020—approval date: 2019)

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation (“cytokine storm”) induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo, changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs

Formation of Lipofuscin-Like Autofluorescent Granules in the Retinal Pigment Epithelium Requires Lysosome Dysfunction

PURPOSE: We aim to characterize the pathways required for autofluorescent granule (AFG) formation by RPE cells using cultured monolayers. METHODS: We fed RPE monolayers in culture with a single pulse of photoreceptor outer segments (POS). After 24 hours the cells started accumulating AFGs that were comparable to lipofuscin in vivo. Using this model, we used a variety of light and electron microscopical techniques, flow cytometry and Western blot to analyze the formation of AFGs. We also generated a mutant RPE line lacking cathepsin D by gene editing. RESULTS: AFGs seem to derive from incompletely digested POS-containing phagosomes and after 3 days are surrounded by a single membrane positive for lysosome markers. We show by various methods that lysosome-phagosome fusion is required for AFG formation, and that impairment of lysosomal pH or catalytic activity, particularly cathepsin D activity, enhances AF accumulation. CONCLUSIONS: We conclude that lysosomal dysfunction results in incomplete POS degradation and enhanced AFG accumulation

Substrate texture properties induce triatomine probing on bitten warm surfaces

<p>Abstract</p> <p>Background</p> <p>In this work we initially evaluated whether the biting process of <it>Rhodnius prolixus </it>relies on the detection of mechanical properties of the substrate. A linear thermal source was used to simulate the presence of a blood vessel under the skin of a host. This apparatus consisted of an aluminium plate and a nickel-chrome wire, both thermostatized and presented at 33 and 36°C, respectively. To evaluate whether mechanical properties of the substrate affect the biting behaviour of bugs, this apparatus was covered by a latex membrane. Additionally, we evaluated whether the expression of probing depends on the integration of bilateral thermal inputs from the antennae.</p> <p>Results</p> <p>The presence of a latex cover on a thermal source induced a change in the biting pattern shown by bugs. In fact, with latex covered sources it was possible to observe long bites that were never performed in response to warm metal surfaces. The total number of bites was higher in intact versus unilaterally antennectomized insects. These bites were significantly longer in intact than in unilaterally antennectomized insects.</p> <p>Conclusions</p> <p>Our results suggest that substrate recognition by simultaneous input through thermal and mechanical modalities is required for triggering maxillary probing activity.</p

Yeasts and wine off-flavours: a technological perspective

Review article. Part of the special issue "Wine microbiology and safety: from the vineyard to the bottle (Microsafety Wine)", 19-20 Nov. 2009, ItalyIn wine production, yeasts have both beneficial and detrimental activities. Saccharomyces cerevisiae is the yeast mainly responsible for turning grape juice into wine but this species and several others may also show undesirable effects in wines. Among such effects, technologists are particularly concerned with the production of offflavours that may occur during all stages of winemaking. Typical spoiling activities include the production of ethyl acetate by apiculate yeasts before fermentation, hydrogen sulphide by S. cerevisiae during fermentation phases, acetaldehyde by film-forming yeasts during bulk storage, and volatile phenols by Dekkera bruxellensis during storage or after bottling. The occurrence of these hazards depends on the technological operations designed to obtain a given type of wine and most can be avoided by current preventive or curative measures. On the contrary, good manufacturing practices must be strengthened to deal with the problem of volatile phenol production in red wines. Appropriate monitoring of D. bruxellensis populations and quantification of 4-ethylphenol is advised during storage, particularly when oak barrels are used, and absence of viable cells must be guaranteed in bottled wines. This work, which is based on our experience at winery level, aims to provide information on appropriate technological strategies to deal with the problem of off-flavours produced by yeasts

Minimal intervention in dentistry : which is the best approach for silorane composite restoration repairs?

This study aimed to evaluate surface treatments, adhesives and composites for repairing silorane based restorations. One hundred and twenty truncated cones (2 mm smaller diameter and 4 mm larger diameter) made of silorane composite were divided in 12 g

Reproducibility of global and segmental myocardial strain using cine DENSE at 3 T: a multicenter cardiovascular magnetic resonance study in healthy subjects and patients with heart disease

BACKGROUND: While multiple cardiovascular magnetic resonance (CMR) methods provide excellent reproducibility of global circumferential and global longitudinal strain, achieving highly reproducible segmental strain is more challenging. Previous single-center studies have demonstrated excellent reproducibility of displacement encoding with stimulated echoes (DENSE) segmental circumferential strain. The present study evaluated the reproducibility of DENSE for measurement of whole-slice or global circumferential (Ecc), longitudinal (Ell) and radial (Err) strain, torsion, and segmental Ecc at multiple centers. METHODS: Six centers participated and a total of 81 subjects were studied, including 60 healthy subjects and 21 patients with various types of heart disease. CMR utilized 3 T scanners, and cine DENSE images were acquired in three short-axis planes and in the four-chamber long-axis view. During one imaging session, each subject underwent two separate DENSE scans to assess inter-scan reproducibility. Each subject was taken out of the scanner and repositioned between the scans. Intra-user, inter-user-same-site, inter-user-different-site, and inter-user-Human-Deep-Learning (DL) comparisons assessed the reproducibility of different users analyzing the same data. Inter-scan comparisons assessed the reproducibility of DENSE from scan to scan. The reproducibility of whole-slice or global Ecc, Ell and Err, torsion, and segmental Ecc were quantified using Bland-Altman analysis, the coefficient of variation (CV), and the intraclass correlation coefficient (ICC). CV was considered excellent for CV ≤ 10%, good for 10%  40. ICC values were considered excellent for ICC > 0.74, good for ICC 0.6 < ICC ≤ 0.74, fair for ICC 0.4 < ICC ≤ 0.59, poor for ICC < 0.4. RESULTS: Based on CV and ICC, segmental Ecc provided excellent intra-user, inter-user-same-site, inter-user-different-site, inter-user-Human-DL reproducibility and good-excellent inter-scan reproducibility. Whole-slice Ecc and global Ell provided excellent intra-user, inter-user-same-site, inter-user-different-site, inter-user-Human-DL and inter-scan reproducibility. The reproducibility of torsion was good-excellent for all comparisons. For whole-slice Err, CV was in the fair-good range, and ICC was in the good-excellent range. CONCLUSIONS: Multicenter data show that 3 T CMR DENSE provides highly reproducible whole-slice and segmental Ecc, global Ell, and torsion measurements in healthy subjects and heart disease patients