Long-term follow-up of balloon-expandable valves according to the implantation strategy: insight from the DIRECTAVI trial.

BACKGROUND: Safety and feasibility of transcatheter aortic valve replacement (TAVR) without balloon aortic valvuloplasty (BAV) using the SAPIEN 3 balloon-expandable device has been previously demonstrated. The impact on long-term valve hemodynamic performances and outcomes remains however unknown. We evaluate long-term clinical and hemodynamic results according to the implant strategy (direct TAVR vs BAV pre-TAVR) in patients included in the DIRECTAVI randomized trial (NCT02729519). METHODS: Clinical and echocardiographic follow-up until January 2023 was performed for all patients included in the DIRECTAVI trial since 2016 (n = 228). The primary endpoint was incidence of moderate/severe hemodynamic valve deterioration (HVD), according to the Valve Academic Research defined Consortium-3 criteria (increase in mean gradient ≥10 mmHg resulting in a final mean gradient ≥20 mmHg, or new/worsening aortic regurgitation of 1 grade resulting in ≥ moderate aortic regurgitation). RESULTS: Median follow-up was 3.8 (2.2-4.7) years. Mean age at follow-up was 87 ± 6.7 years. No difference in incidence of HVD in the direct implantation group compared to the BAV group was found (incidence of 1.97 per 100 person-years and 1.45 per 100 person-years, respectively, P = 0.6). Prevalence of predicted prothesis-patient mismatch was low (n = 13 [11.4%] in the direct TAVR group vs n = 15 [13.2%] in BAV group) and similar between both groups (P = .7). Major outcomes including death, stroke, hospitalization for heart failure and pacemaker implantation were similar between both groups, (P = .4, P = .7, P = .3, and P = .3 respectively). CONCLUSION: Direct implantation of the balloon-expandable device in TAVR was not associated with an increased risk of moderate/severe HVD or major outcomes up to 6-year follow-up. These results guarantee wide use of direct balloon-expandable valve implantation, when feasible. CLINICAL TRIALS REGISTRATION NUMBER: NCT05140317.

Two-in-one: A case report of a touchy TAVI procedure with a new valve.

Implantation of a second transcatheter heart valve (THV) into a primary THV is a bail-out situation, but may be necessary. An 85-year-old woman was referred with severe symptomatic aortic stenosis (AS). Echocardiography showed a moderately calcified AS. Computed tomography resulted in an average annular diameter of 22.3 mm and an area of 371 mm2 , leading to M-sized ACURATE NEO implantation. Deployment of the upper valve part was uneventful. During lower valve part deployment, the valve dived into the left ventricle outflow tract with the stabilization arches above the annular plane. With the SAFARI guidewire in place, a second M-sized ACURATE NEO was implanted higher inside the first displaced valve. Deployment was straightforward, with no aortic leak, no mitral regurgitation and the patient had normal hemodynamic parameters. Follow-up was uneventful. Positioning a second ACURATE NEO into a failing primary ACURATE NEO is feasible and safe, with favorable short and longer-term outcome.

A four-leaf clover: A case report of quadricuspid aortic valve stenosis.

BACKGROUND: We present the case of a patient with severe quadricuspid aortic valve (QAV) stenosis who underwent treatment with transcatheter aortic valve implantation (TAVI). CASE SUMMARY: An 87-year-old woman was referred to our department with severe aortic stenosis. Computed tomography angiography revealed a QAV with four separate equal-sized leaflets, similar in appearance to a four-leaf clover. The patient underwent successful implantation of a 23 mm Edwards Sapien 3 transcatheter valve via left transfemoral access. The valve positioning across the aortic annulus was fluoroscopically challenging due to difficulty visualizing all four cusps in only one two-dimensional view and to the position of the left main coronary artery, which was very low. The immediate result of the TAVI was good, with no aortic regurgitation and no coronary damage. Follow-up to 6 months was free of event. CONCLUSION: This case demonstrates that QAV stenosis can be treated using TAVI with good clinical outcomes.

PAR-4/LKB1 regulates DNA replication during asynchronous division of the early C. elegans embryo.

Regulation of cell cycle duration is critical during development, yet the underlying molecular mechanisms are still poorly understood. The two-cell stage Caenorhabditis elegans embryo divides asynchronously and thus provides a powerful context in which to study regulation of cell cycle timing during development. Using genetic analysis and high-resolution imaging, we found that deoxyribonucleic acid (DNA) replication is asymmetrically regulated in the two-cell stage embryo and that the PAR-4 and PAR-1 polarity proteins dampen DNA replication dynamics specifically in the posterior blastomere, independently of regulators previously implicated in the control of cell cycle timing. Our results demonstrate that accurate control of DNA replication is crucial during C. elegans early embryonic development and further provide a novel mechanism by which PAR proteins control cell cycle progression during asynchronous cell division.

Optimizing pacemaker longevity with pacing mode and settings programming: results from a pacemaker multicenter registry.

BACKGROUND: This study aimed to describe the influence on dual-chamber devices' expected longevity of devices' settings. METHODS: Data from patients implanted with dual chamber devices (Symphony™, SORIN CRM SAS, Clamart, France) from 2003 to 2006 were collected in registries. Programmer files were retrieved: device-estimated longevity, assessed through algorithm prediction, was analyzed according to device settings. RESULTS: One thousand sixty-eight recipients of dual chamber pacemaker in sinus rhythm (75.3±11.1 years, 54.5% male, ventricular block 30%, brady-tachy syndrome 21%, and sinus node dysfunction 49%) were followed up to 14.2±12.1 months (ranging from first quartile Q1: 2.9 months to fourth quartile Q4: 49.3 months) after implantation. DDD with automatic mode conversion and minimized ventricular pacing (SafeR) modes were programmed in 34.3%, 2.9%, and 62.8% of the patients, respectively. The mean total longevity estimated by the device was 134.1±31.5 months (11.2±2.6 years). Significant increase in longevity was observed in devices undergoing at least one reprogramming (134.4±31.4 months) versus device presenting no reprogramming (103.4±32.3 months, P=0.0005). The parameters associated with the major increase in mean longevity were the mode (mean longevity increase of +23.9 months in SafeR as compared to DDD mode, P<0.0001) and the atrial (A) and ventricular (V) amplitudes (mean longevity increase of +29.6 and +26.9 months for a decrease of less than 1V in A and V outputs respectively, P<0.0001). CONCLUSION: This study provides information on dual chamber pacemakers' longevity and highlights the impact of devices' reprogramming on expected longevities.

Two structurally similar fungal prions efficiently cross-seed in vivo but form distinct polymers when coexpressed.

HET-s is a prion protein of the filamentous fungus Podospora anserina. An orthologue of this protein, called FgHET-s has been identified in Fusarium graminearum. The region of the FgHET-s protein corresponding to the prion forming domain of HET-s, forms amyloid fibrils in vitro. These fibrils seed HET-s(218-289) fibril formation in vitro and vice versa. The amyloid fold of HET-s(218-289) and FgHET-s(218-289) are remarkably similar although they share only 38% identity. The present work corresponds to the functional characterization of the FgHET-s(218-289) region as a prion forming domain in vivo. We show that FgHET-s(218-289) is capable of prion propagation in P. anserina and is able to substitute for the HET-s PFD in the full-length HET-s protein. In accordance with the in vitro cross-seeding experiments, we detect no species barrier between P. anserina and F. graminearum PFDs. We use the yeast Saccharomyces cerevisiae as a host to compare the prion performances of the two orthologous PFDs. We find that FgHET-s(218-289) leads to higher spontaneous prion formation rates and mitotic prion stability than HET-s(218-289). Then we analysed the outcome of HET-s(218-289)/FgHET-s(218-289) coexpression. In spite of the cross-seeding ability of HET-s(218-289) and FgHET-s(218-289), in vivo, homotypic polymerization is favoured over mixed fibril formation.

PAR-4/LKB1 mobilizes nonmuscle myosin through anillin to regulate C. elegans embryonic polarization and cytokinesis.

BACKGROUND: The serine/threonine kinase LKB1 regulates cell growth and polarity in metazoans, and loss of LKB1 function is implicated in the development of some epithelial cancers. Despite its fundamental role, the mechanism by which LKB1 regulates polarity establishment and/or maintenance is unclear. In the present study, we use the nematode C. elegans to investigate the role of the LKB1 ortholog PAR-4 in actomyosin contractility, a cellular process essential for polarity establishment and cell division in the early embryo. RESULTS: Using high-resolution time-lapse imaging of GFP-tagged nonmuscle myosin II (NMY-2), we found that par-4 mutations reduce actomyosin contractility during polarity establishment, leading to the mispositioning of anterior PAR proteins and to defects in contractile ring ingression during cytokinesis. Fluorescence recovery after photobleaching analysis revealed that the mobility of a cortical population of NMY-2 was reduced in par-4 mutants. Interestingly, the contractility defects of par-4 mutants depend on the reciprocal activity of ANI-1 and ANI-2, two C. elegans homologs of the actin cytoskeletal scaffold protein anillin. CONCLUSION: Because loss of PAR-4 promoted inappropriate accumulation of ANI-2 at the cell cortex, we propose that PAR-4 controls C. elegans embryonic polarity by regulating the activity of anillin family scaffold proteins, thus enabling turnover of cortical myosin and efficient actomyosin contractility. This work provides the first description of a cellular mechanism by which PAR-4/LKB1 mediates cell polarization.

Solid-state NMR spectroscopy reveals that E. coli inclusion bodies of HET-s(218-289) are amyloids.

Protein deposition frequently occurs as inclusion bodies (IBs) during heterologous protein expression in E. coli. The structure of these E. coli IBs of the prion-forming domain from the fungal prion HET-s is the same as that previously determined for fibrils assembled in vitro, and show prion infectivity. These results demonstrate that the IBs of HET-s(218-289) are amyloids.

The ESCRT-III protein CeVPS-32 is enriched in domains distinct from CeVPS-27 and CeVPS-23 at the endosomal membrane of epithelial cells.

BACKGROUND INFORMATION: Within the endocytic pathway, the ESCRT (endosomal sorting complex required for transport) machinery is essential for the biogenesis of MVBs (multivesicular bodies). In yeast, ESCRTs are recruited at the endosomal membrane and are involved in cargo sorting into intralumenal vesicles of the MVBs. RESULTS: In the present study, we characterize the ESCRT-III protein CeVPS-32 (Caenorhabditis elegans vacuolar protein sorting 32) and its interactions with CeVPS-27, CeVPS-23 and CeVPS-4. In contrast with other CevpsE (class E vps) genes, depletion of Cevps-32 is embryonic lethal with severe defects in the remodelling of epithelial cell shape during organogenesis. Furthermore, Cevps-32 animals display an accumulation of enlarged early endosomes in epithelial cells and an accumulation of autophagosomes. The CeVPS-32 protein is enriched in epithelial tissues and in residual bodies during spermatid maturation. We show that CeVPS-32 and CeVPS-27/Hrs (hepatocyte-growth-factor-regulated tyrosine kinase substrate) are enriched in distinct subdomains at the endosomal membrane. CeVPS-27-positive subdomains are also enriched for the ESCRT-I protein CeVPS-23/TSG101 (tumour susceptibility gene 101). The formation of CeVPS-27 subdomains is not affected by the depletion of CeVPS-23, CeVPS-32 or the ATPase CeVPS-4. CONCLUSION: Our results suggest that the formation of membrane subdomains is essential for the maturation of endosomes.

Role of Hsp104 in the propagation and inheritance of the [Het-s] prion.

The chaperones of the ClpB/HSP100 family play a central role in thermotolerance in bacteria, plants, and fungi by ensuring solubilization of heat-induced protein aggregates. In addition in yeast, Hsp104 was found to be required for prion propagation. Herein, we analyze the role of Podospora anserina Hsp104 (PaHsp104) in the formation and propagation of the [Het-s] prion. We show that DeltaPaHsp104 strains propagate [Het-s], making [Het-s] the first native fungal prion to be propagated in the absence of Hsp104. Nevertheless, we found that [Het-s]-propagon numbers, propagation rate, and spontaneous emergence are reduced in a DeltaPaHsp104 background. In addition, inactivation of PaHsp104 leads to severe meiotic instability of [Het-s] and abolishes its meiotic drive activity. Finally, we show that DeltaPaHSP104 strains are less susceptible than wild type to infection by exogenous recombinant HET-s(218-289) prion amyloids. Like [URE3] and [PIN(+)] in yeast but unlike [PSI(+)], [Het-s] is not cured by constitutive PaHsp104 overexpression. The observed effects of PaHsp104 inactivation are consistent with the described role of Hsp104 in prion aggregate shearing in yeast. However, Hsp104-dependency appears less stringent in P. anserina than in yeast; presumably because in Podospora prion propagation occurs in a syncitium.

Prion and non-prion amyloids of the HET-s prion forming domain.

HET-s is a prion protein of the fungus Podospora anserina. A plausible structural model for the infectious amyloid fold of the HET-s prion-forming domain, HET-s(218-289), makes it an attractive system to study structure-function relationships in amyloid assembly and prion propagation. Here, we report on the diversity of HET-s(218-289) amyloids formed in vitro. We distinguish two types formed at pH 7 from fibrils formed at pH 2, on morphological grounds. Unlike pH 7 fibrils, the pH 2 fibrils show very little if any prion infectivity. They also differ in ThT-binding, resistance to denaturants, assembly kinetics, secondary structure, and intrinsic fluorescence. Both contain 5 nm fibrils, either bundled or disordered (pH 7) or as tightly twisted protofibrils (pH 2). We show that electrostatic interactions are critical for the formation and stability of the infectious prion fold given in the current model. The altered properties of the amyloid assembled at pH 2 may arise from a perturbation in the subunit fold or fibrillar stacking.

Prion proteins as genetic material in fungi.

Prions are infectious proteins. Several prions have been identified in fungi where they behave as non-Mendelian cytoplasmic genetic elements. Most of these prions propagate as self-perpetuating amyloid aggregates thus providing an example of structural heredity. In yeast, prion propagation requires the Hsp104 disaggregase presumably to sheer amyloid assemblies and generate more fiber ends. Recent work in yeast shows that amyloid structure polymorphism underlies the prion strain phenomenon and influences species barriers. Structural models for the amyloid form of several fungal prion proteins are now available. All propose a cross beta-organization with parallel beta-sheets. Whether or not some of the fungal prions might be beneficial to their host is still a debated issue.

Methods for the in vivo and in vitro analysis of [Het-s] prion infectivity.

Prions have been described in mammals and fungi. The [Het-s] infectious genetic element of the filamentous fungus Podospora anserina is the prion form of the HET-s protein. This protein is involved in the control of a cell death reaction termed heterokaryon incompatibility. The infectious form of HET-s corresponds to a self-perpetuating amyloid. The purpose of the present paper is to describe the techniques that can be used to analyse [Het-s] prion propagation in vivo and HET-s amyloid aggregation in vitro. In addition, we report several methods that can be used to infect Podospora with recombinant HET-s amyloid.

Ambra Grisea, Castoreum, Mephitis / Ambra Grisea, Castoreum, Mephitis

Le sujet de ce travail est pour le moins inhabituel mais interessant, d'une part par la definition d'une concretion et celle d'une excretion, mais aussi et surtout par un discours sur des... (AU)

Pluralisme et constitutions / Pluralisme and constitutions

Le pluralisme est globalement tres utile pour la therapeutique homeopathique. La matiere medicale s'enrichit de plus en plus et necessite une classification des medicaments, en groupes... (AU)

Un cas particulier: les migraines

La migraine est confondue dans le public avec le " mal de tête". Elle est la plus courante des céphalées. Sa description a été faite en Mésopotamie, environ 3000 ans avant notr ère. Elle est l´objet d´études scientifiques, depuis cette époque jusqu´à nos jours.(AU)

Le pluralisme / The pluralism

Les homeopathes peuvent etre classes, selon ma reflexion, dans les categories des enthousiastes, des interesses, ou des indifferents aux problemes techniques et biologiques, satisfaits de leur pratique. Et pourquoi...((AU)

L'andropause / The andropause

Il y a quelques decennies, je lisais un livre consacre a l'andropause, et je notais avec une certaine fierte que j'avais la chance d'etre un homme, car l'auteur declarait, sans preuve, qu'elle... (AU)

Crotalus horridus / Crotalus horridus

Ce serpent est couramment appele "serpent a sonnettes". Il provoque une sorte de repulsion et de peur chez certains hommes ou femmes, parce qu'il est mortel. (AU)