Quantitative analysis of mitral valve morphology in atrial functional mitral regurgitation using real-time 3-dimensional echocardiography atrial functional mitral regurgitation

Background

Atrial fibrillation (AF) can result in atrial functional mitral regurgitation (MR), but the mechanism remains controversial. Few data about the relationship between the 3-dimensional morphology of the MV and the degree of MR in AF exist.

Methods

Real-time 3-dimensional transesophageal echocardiography (3D-TEE) of the MV was acquired in 168 patients with AF (57.7% persistent AF), including 25 (14.9%) patients with moderate to severe MR (the MR+ group) and 25 patients without AF as controls. The 3-dimensional geometry of the MV apparatus was acquired using dedicated quantification software.

Results

Compared with the group of patients with no or mild MR (the MR- group) and the controls, the MR+ group had a larger left atrium (LA), a more dilated mitral annulus (MA), a reduced annular height to commissural width ratio (AHCWR), indicating flattening of the annular saddle shape, and greater leaflet surfaces and tethering. MR severity was correlated with the MA area (r²?=?0.43, P?<?0.01) and the annulus circumference (r²?=?0.38, P?<?0.01). A logistic regression analysis indicated that the MA area (OR: 1.02, 95% CI: 1.01–1.03, P?<?0.01), AHCWR (OR: 0.24, 95% CI: 0.14–0.35, P?=?0.04) and MV tenting volume (OR: 3.24, 95% CI: 1.16–9.08, P?=?0.03) were independent predictors of MR severity in AF patients.

Conclusions

The mechanisms of “atrial functional MR” are complex and include dilation of the MA, flattening of the annular saddle shape and greater leaflet tethering.

     

Artemether Does Not Turn α Cells into β Cells

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Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme

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A membrane fusion protein,Ykt6, regulates epithelial cell migration via microRNA-mediated suppression of Junctional Adhesion Molecule A

Vesicle trafficking regulates epithelial cell migration by remodeling matrix adhesions and delivering signaling molecules to the migrating leading edge. Membrane fusion, which is driven by soluble N-ethylmaleimide-sensitive factor associated receptor (SNARE) proteins, is an essential step of vesicle trafficking. Mammalian SNAREs represent a large group of proteins, but few have been implicated in the regulation of cell migration. Ykt6 is a unique SNARE existing in equilibrium between active membrane-bound and inactive cytoplasmic pools, and mediating vesicle trafficking between different intracellular compartments. The biological functions of this protein remain poorly understood. In the present study, we found that Ykt6 acts as a negative regulator of migration and invasion of human prostate epithelial cells. Furthermore, Ykt6 regulates the integrity of epithelial adherens and tight junctions. The observed anti-migratory activity of Ykt6 is mediated by a unique mechanism involving the expressional upregulation of microRNA 145, which selectively decreases the cellular level of Junctional Adhesion Molecule (JAM) A. This decreased JAM-A expression limits the activity of Rap1 and Rac1 small GTPases, thereby attenuating cell spreading and motility. The described novel functions of Ykt6 could be essential for the regulation of epithelial barriers, epithelial repair, and metastatic dissemination of cancer cells.     

Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors

Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity.     

Case Series: Report of the First Two Human Indigenous Cases of <Emphasis Type="Italic">Cryptococcus gattii</Emphasis> Infection in Eastern Canada

We report the two first cases of human C. gattii meningoencephalitis acquired on the Canadian east coast, from the province of Quebec. Unlike C. neoformans, C. gattii is not known to have an established ecological niche on the North American east coast. C. gattii has recently been responsible for major outbreaks in British Columbia, Canada, and in the American pacific northwest. However, no human cases acquired in other Canadian provinces have been reported to our knowledge. The source of acquisition remains unclear for both patients but since neither had traveled outside of the province of Quebec, we discuss the possibilities of environmental and animal-associated acquisition, as well as the possible established endemicity in new areas. These cases add to the growing reported human and animal cases in areas previously not thought to be endemic for C. gattii.     

Soil system budgets of N,Si and P in an agricultural irrigated watershed: surplus,differential export and underlying mechanisms

Ongoing socio-economic and climatic changes can differentially affect the biogeochemistry of the key nutrients nitrogen (N), silica (Si), and phosphorus (P) by altering their soil budgets, their transfer to aquatic environments and their ecological stoichiometry. This may lead to cascade consequences for aquatic communities and biogeochemical processes. Soil budgets, river export, and N, Si, and P ecological stoichiometry were assessed in a heavy impacted basin (Mincio River, Italy) in two decades (1991–2000; 2001–2010). The main aim was to analyse element-specific mechanisms of terrestrial-aquatic transport and retention within aquatic habitats. Budget results suggest a net accumulation (inputs exceeding outputs) of all nutrients in agricultural lands, mainly due to livestock manure, with a reduction for N (196 kg N ha^?1 year^?1 in 2000, and 132 kg N ha^?1 year^?1 in 2010), and constant values for Si (up to 3 kg Si ha^?1 year^?1) and P (43 kg P ha^?1 year^?1) along the study period. River export of N and P accounted for 3–27% and?~?2% of N and P soil net accumulation, respectively, while Si export was significantly greater (25 kg Si ha^?1 year^?1) than Si net accumulation on farmlands. The stoichiometry of net nutrient accumulation in soils was not reflected by the stoichiometry of nutrient riverine export, due to element-specific mechanisms. We speculate that N and Si vertical and horizontal mobilization is increased by the irrigation loop, while P retention is favored by limited erosion due to limited slopes in the Mincio River basin. The simultaneous analysis of N, Si and P allows us to better understand the different paths, transformation and retention mechanisms at the watershed scale.