Relation of mitral valve morphology and motion to mitral regurgitation severity in patients with mitral valve prolapse

<p>Abstract</p> <p>Background</p> <p>Mitral valve thickness is used as a criterion to distinguish the classical from the non-classical form of mitral valve prolapse (MVP). Classical form of MVP has been associated with higher risk of mitral regurgitation (MR) and concomitant complications. We sought to determine the relation of mitral valve morphology and motion to mitral regurgitation severity in patients with MVP.</p> <p>Methods</p> <p>We prospectively analyzed transthoracic echocardiograms of 38 consecutive patients with MVP and various degrees of MR. In the parasternal long-axis view, leaflets length, diastolic leaflet thickness, prolapsing depth, billowing area and non-coaptation distance between both leaflets were measured.</p> <p>Results</p> <p>Twenty patients (53%) and 18 patients (47%) were identified as having moderate to severe and mild MR respectively (ERO = 45 ± 27 mm²vs. 5 ± 7 mm², p < 0.001). Diastolic leaflet thickness was similar in both groups (5.5 ± 0.9 mm vs. 5.3 ± 1 mm, p = 0.57). On multivariate analysis, the non-coaptation distance (OR 7.9 per 1 mm increase; 95% CI 1.72-37.2) was associated with significant MR. Thick mitral valve leaflet as traditionally reported (≥ 5 mm) was not associated with significant MR (OR 0.9; 95% CI 0.2-3.4).</p> <p>Conclusions</p> <p>In patients with MVP, thick mitral leaflet is not associated with significant MR. Leaflet thickness is probably not as important in risk stratification as previously reported in patients with MVP. Other anatomical and geometrical features of the mitral valve apparatus area appear to be much more closely related to MR severity.</p

Molecular Evolution of the Two-Component System BvgAS Involved in Virulence Regulation in Bordetella

The whooping cough agent Bordetella pertussis is closely related to Bordetella bronchiseptica, which is responsible for chronic respiratory infections in various mammals and is occasionally found in humans, and to Bordetella parapertussis, one lineage of which causes mild whooping cough in humans and the other ovine respiratory infections. All three species produce similar sets of virulence factors that are co-regulated by the two-component system BvgAS. We characterized the molecular diversity of BvgAS in Bordetella by sequencing the two genes from a large number of diverse isolates. The response regulator BvgA is virtually invariant, indicating strong functional constraints. In contrast, the multi-domain sensor kinase BvgS has evolved into two different types. The pertussis type is found in B. pertussis and in a lineage of essentially human-associated B. bronchiseptica, while the bronchiseptica type is associated with the majority of B. bronchiseptica and both ovine and human B. parapertussis. BvgS is monomorphic in B. pertussis, suggesting optimal adaptation or a recent population bottleneck. The degree of diversity of the bronchiseptica type BvgS is markedly different between domains, indicating distinct evolutionary pressures. Thus, absolute conservation of the putative solute-binding cavities of the two periplasmic Venus Fly Trap (VFT) domains suggests that common signals are perceived in all three species, while the external surfaces of these domains vary more extensively. Co-evolution of the surfaces of the two VFT domains in each type and domain swapping experiments indicate that signal transduction in the periplasmic region may be type-specific. The two distinct evolutionary solutions for BvgS confirm that B. pertussis has emerged from a specific B. bronchiseptica lineage. The invariant regions of BvgS point to essential parts for its molecular mechanism, while the variable regions may indicate adaptations to different lifestyles. The repertoire of BvgS sequences will pave the way for functional analyses of this prototypic system

Therapeutic Efficacy of Potent Neutralizing HIV-1-Specific Monoclonal Antibodies in SHIV-Infected Rhesus Monkeys

HIV-1-specific monoclonal antibodies (mAbs) with extraordinary potency and breadth have recently been described. In humanized mice, combinations of mAbs have been shown to suppress viremia, but the therapeutic potential of these mAbs has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific mAbs, as well as the single glycan-dependent mAb PGT121, resulted in a rapid and precipitous decline of plasma viremia to undetectable levels in rhesus monkeys chronically infected with the pathogenic virus SHIV-SF162P3. A single mAb infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa, and lymph nodes without the development of viral resistance. Moreover, following mAb administration, host Gag-specific T lymphocyte responses exhibited improved functionality. Virus rebounded in the majority of animals after a median of 56 days when serum mAb titers had declined to undetectable levels, although a subset of animals maintained long-term virologic control in the absence of further mAb infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific mAbs in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of mAb therapy for HIV-1 in humans

Computer-assisted proofs for radially symmetric solutions of PDEs

We obtain radially symmetric solutions of some nonlinear (geo- metric) partial differential equations via a rigorous computer-assisted method. We introduce all main ideas through examples, accessible to non-experts. The proofs are obtained by solving for the coefficients of the Taylor series of the solutions in a Banach space of geometrically decaying sequences. The tool that allows us to advance from numerical simulations to mathematical proofs is the Banach contraction theorem

Computer-assisted proofs for radially symmetric solutions of PDEs

We obtain radially symmetric solutions of some nonlinear (geo- metric) partial differential equations via a rigorous computer-assisted method. We introduce all main ideas through examples, accessible to non-experts. The proofs are obtained by solving for the coefficients of the Taylor series of the solutions in a Banach space of geometrically decaying sequences. The tool that allows us to advance from numerical simulations to mathematical proofs is the Banach contraction theorem

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease