The effects of remodeling with heart failure on mode of initiation of ventricular fibrillation and its spatiotemporal organization

Purpose The effect of the heart failure substrate on the initiation of ventricular fibrillation (VF) and its resulting mechanism is not known. The objective of this study was to determine the effects of substrate on VF initiation and its spatiotemporal organization in the heart failure model. Methods Optical action potentials were recorded from LV wedge preparations either from structurally normal hearts (control, n = 11) or from congestive heart failure (CHF; n = 7), at the epicardial surface, endocardial surface which included a papillary muscle, and a transmural cross section. Action potential duration (APD80) was determined, and VF was initiated. A fast Fourier transform was calculated, and the dominant frequency (DF) was determined. Results The CHF group showed increased VF vulnerability (69 vs 26 %, p < 0.03), and every mapped surface showed an APD80 gradient which included islands of higher APDs on the transmural surface (M cells) which was not observed in controls. VF in the CHF group was characterized by stable, discrete, high-DF areas that correlated to either foci or spiral waves located on the transmural surface at the site of the papillary muscle. Overall, the top 10 % of DFs correlated to an APD of 101 ms while the bottom 10 % of DFs correlated to an APD of 126 ms (p < 0.01). Conclusions In the CHF model, APD gradients correlated with an increased vulnerability to VF, and the highest stable DFs were located on the transmural surface which was not seen in controls. This indicates that the CHF substrate creates unique APD and DF characteristics

Moderate Champagne consumption promotes an acute improvement in acute endothelial-independent vascular function in healthy human volunteers

Epidemiological studies have suggested an inverse correlation between red wine consumption and the incidence of CVD. However, Champagne wine has not been fully investigated for its cardioprotective potential. In order to assess whether acute and moderate Champagne wine consumption is capable of modulating vascular function, we performed a randomised, placebo-controlled, cross-over intervention trial. We show that consumption of Champagne wine, but not a control matched for alcohol, carbohydrate and fruit-derived acid content, induced an acute change in endothelium-independent vasodilatation at 4 and 8 h post-consumption. Although both Champagne wine and the control also induced an increase in endothelium-dependent vascular reactivity at 4 h, there was no significant difference between the vascular effects induced by Champagne or the control at any time point. These effects were accompanied by an acute decrease in the concentration of matrix metalloproteinase (MMP-9), a significant decrease in plasma levels of oxidising species and an increase in urinary excretion of a number of phenolic metabolites. In particular, the mean total excretion of hippuric acid, protocatechuic acid and isoferulic acid were all significantly greater following the Champagne wine intervention compared with the control intervention. Our data suggest that a daily moderate consumption of Champagne wine may improve vascular performance via the delivery of phenolic constituents capable of improving NO bioavailability and reducing matrix metalloproteinase activity

Migration Transforms the Conditions for the Achievement of the Sustainable Development Goals

Migration is transformative both for those who move and for the places and economies of source and destination. The global stock of migrants, depending on definition, is approximately 750 million people: to assume that the world is static and that migration is a problem to be managed is inaccurate. Since migration is a major driving force of planetary and population health, we argue that it must be more directly incorporated into planning for sustainable development, with a focus on the extent and way in which the Sustainable Development Goals (SDGs) incorporate the transformative reality of migration

Assessment of farmers' compliance in implementing recommended cow comfort changes and their effects on lying time, stall and cow cleanliness within smallholder dairy farms in Kenya

Our study aimed to evaluate farmers' compliance in implementing recommendations of farm-specific cow comfort changes, and the effects of these changes on lying time, stall cleanliness and cow cleanliness using a randomized controlled trial carried out on 100 smallholder dairy farms in Kenya, with 62 and 11 farms remaining in the intervention and control groups, respectively. On the first farm visit, data loggers were attached on lactating cows to determine lying time and questionnaires utilized to collect baseline data. Three days later, stall design and management recommendations were given to the intervention group of farmers orally and in written form. After an average of 39 ± 7 days, data loggers were re-attached, compliance was assessed, and a post-intervention questionnaire was administered to the intervention group on the third visit. Three days subsequent to the first and third visits, data loggers were removed from all cows. Data were analysed in Stata 14.2® using proportion tests and Kruskal-Wallis rank tests to compare cleanliness scores and lying time, respectively. Interaction effects between treatment groups and visits were assessed using multivariable mixed linear and logistic regression models. While 46 of the 62 intervention farmers (74%) made at least one recommended change to cow comfort, 63% of the 324 overall recommendations were implemented. The odds of a recommendation being implemented were significantly higher when:1) major recommendations were given relative to minor recommendations (OR = 6.28); 2) recommendations were related to floor characteristics (floor softness and flatness) in comparison to recommendations related to stall design (OR = 3.14). The odds of compliance were lower on: 1) farms where the farm-hands received the recommendations compared to farms that had the female principal farmer receive the recommendations (OR = 0.01); 2) farms that had recommended changes related to roof, alley and sharps fixes relative to stall design fixes (OR = 0.13). Post-intervention, stall, udder and upper hind-leg cleanliness scores improved significantly (p < 0.0001, p = 0.021 and p = 0.017, respectively) in the intervention farms but not in the control farms. There was no significant difference in lying times between intervention and control farms, with 0.6 and 0.2 h/day increases being recorded in the intervention and control groups, from the 10.9 and 10.4 h/day at baseline, respectively. Giving farm-specific cow comfort recommendations to smallholder dairy farmers in Kenya, and providing them with a participatory role in the formulation and implementation of improvement recommendations ensured good acceptance and a high degree of implementation, and led to a subsequent improvement in cow comfort and cleanliness

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

Evidence for shock-heated gas in the Taffy Galaxies and Bridge from Optical Emission-Line IFU spectroscopy

We present optical IFU observations of the Taffy system (UGC 12914/15); named for the radio emission that stretches between the two galaxies. Given that these gas rich galaxies are believed to have recently collided head-on, the pair exhibits a surprisingly normal total (sub-LIRG) IR luminosity ($\mathrm{L_{FIR} \sim 4.5 \times 10^{10}}$ L$_\odot$). Previous observations have demonstrated that a large quantity of molecular and neutral gas have been drawn out of the galaxies into a massive multi-phase bridge. We present, for the first time, spatially resolved spectroscopy of the ionized gas in the system. The results show that the ionized gas is highly disturbed kinematically, with gas spread in two main filaments between the two galaxies. The line profiles exhibit widespread double components in both the bridge and parts of the disks of the galaxies. We investigate the spatial distribution of the excitation properties of the ionized gas using emission-line diagnostic diagrams, and conclude that large quantities (up to 40$\%$) of the emission from the entire system is consistent with gas heated in $\sim$200 \kms\ shocks. While the shocked gas is mainly associated with the bridge, there is a significant amount of shocked gas associated with both galaxies. Confirming other multi-wavelength indicators, the results suggest that the effects of shocks and turbulence can continue to be felt in a high-speed galaxy collision long after the collision has occurred. The persistence of shocks in the Taffy system may explain the relatively low current star formation rates in the system as a whole.Comment: 19 pages, 13 figures. Accepted for publication in Ap

Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-β signaling pathway.

Skeletal muscle and bone homeostasis are regulated by members of the myostatin/GDF-11/activin branch of the transforming growth factor-β superfamily, which share many regulatory components, including inhibitory extracellular binding proteins and receptors that mediate signaling. Here, we present the results of genetic studies demonstrating a critical role for the binding protein follistatin (FST) in regulating both skeletal muscle and bone. Using an allelic series corresponding to varying expression levels of endogenous Fst, we show that FST acts in an exquisitely dose-dependent manner to regulate both muscle mass and bone density. Moreover, by employing a genetic strategy to target Fst expression only in the posterior (caudal) region of the animal, we show that the effects of Fst loss are mostly restricted to the posterior region, implying that locally produced FST plays a much more important role than circulating FST with respect to regulation of muscle and bone. Finally, we show that targeting receptors for these ligands specifically in osteoblasts leads to dramatic increases in bone mass, with trabecular bone volume fraction being increased by 12- to 13-fold and bone mineral density being increased by 8- to 9-fold in humeri, femurs, and lumbar vertebrae. These findings demonstrate that bone, like muscle, has an enormous inherent capacity for growth that is normally kept in check by this signaling system and suggest that the extent to which this regulatory mechanism may be used throughout the body to regulate tissue mass may be more significant than previously appreciated

N-Terminal Pro-B-Type Natriuretic Peptide and Microsize Myocardial Infarction Risk in the Reasons for Geographic and Racial Differences in Stroke Study

Background: N-terminal pro B-type peptide (NT-proBNP) has been associated with risk of myocardial infarction (MI), but less is known about the relationship between NT-proBNP and very small non ST-elevation MI, also known as microsize MI. These events are now routinely detectable with modern troponin assays and are emerging as a large proportion of all MI. Here, we sought to compare the association of NT-proBNP with risk of incident typical MI and microsize MI in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Methods: The REGARDS Study is a national cohort of 30,239 US community-dwelling black and white adults aged ≥ 45 years recruited from 2003 to 2007. Expert-adjudicated outcomes included incident typical MI (definite/probable MI with peak troponin ≥ 0.5 μg/L), incident microsize MI (definite/probable MI with peak troponin \u3c 0.5 μg/L), and incident fatal CHD. Using a case-cohort design, we estimated the hazard ratio of the outcomes as a function of baseline NT-proBNP. Competing risk analyses tested whether the associations of NT-proBNP differed between the risk of incident microsize MI and incident typical MI as well as if the association of NT-proBNP differed between incident non-fatal microsize MI and incident non-fatal typical MI, while accounting for incident fatal coronary heart disease (CHD) as well as heart failure (HF). Results: Over a median of 5 years of follow-up, there were 315 typical MI, 139 microsize MI, and 195 incident fatal CHD. NT-proBNP was independently and strongly associated with all CHD endpoints, with significantly greater risk observed for incident microsize MI, even after removing individuals with suspected HF prior to or coincident with their incident CHD event. Conclusion: NT-proBNP is associated with all MIs, but is a more powerful risk factor for microsize than typical MI