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Any patient with a herpes zoster infection of the mandibular branch of the trigeminal nerve should benefit from early oral monitoring, especially in elderly population where traumatic dental prostheses are common, because osteonecrosis can occur., Herpes zoster infection is a rare and little‐known etiology of osteonecrosis of the maxilla. Only a few cases have reported in the international literature. We present a rare case of right mandibular osteonecrosis following herpes zoster infection in the mandibular branch of the trigeminal nerve.

International audience; Available online xxxx Hemodynamic forces have been known for a long time to regulate cardiogenic processes such as cardiac valve development. During embryonic development in vertebrates, the outflow tract (OFT) adjacent to the ventricle comes under increasing hemodynamic load as cardiogenesis proceeds. Consequently, extracellular matrix components are produced in this region as the cardiac cushions form which will eventually give rise to the aortic valves. The proteoglycan AGGRECAN is a key component of the aortic valves and is frequently found to be deregulated in a variety of aortic valve diseases. Here we demonstrate that aggrecan expression in the OFT of developing zebrafish embryos is hemodynamically dependent, a process presumably mediated by mechanosensitive channels. Furthermore, knockdown or knockout of aggrecan leads to failure of the OFT to develop resulting in ste-nosis. Based on these findings we analysed the expression of AGGRECAN in human bicuspid aortic valves (BAV). We found that in type 0 BAV there was a significant reduction in the expression of AGGRECAN. Our data indicate that aggrecan is required for OFT development and when its expression is reduced this is associated with BAV in humans.

Among the aortic valve diseases, the bicuspid aortic valve (BAV) occurs when the aortic valve has two leaflets (cusps), rather than three, and represents the most common form of congenital cardiac malformation, affecting 1&ndash, 2% of the population. Despite recent advances, the etiology of BAV is poorly understood. We have recently shown that Krox20 is expressed in endothelial and cardiac neural crest derivatives that normally contribute to aortic valve development and that lack of Krox20 in these cells leads to aortic valve defects including partially penetrant BAV formation. Dysregulated expression of endothelial nitric oxide synthase (Nos3) is associated with BAV. To investigate the relationship between Krox20 and Nos3 during aortic valve development, we performed inter-genetic cross. While single heterozygous mice had normal valve formation, the compound Krox20+/&minus, Nos3+/&minus, mice had BAV malformations displaying an in vivo genetic interaction between these genes for normal valve morphogenesis. Moreover, in vivo and in vitro experiments demonstrate that Krox20 directly binds to Nos3 proximal promoter to activate its expression. Our data suggests that Krox20 is a regulator of nitric oxide in endothelial-derived cells in the development of the aortic valve and concludes on the interaction of Krox20 and Nos3 in BAV formation.

Introduction Bicuspid aortic-valve (BAV) is the most common congenital malformation. Complications include aortic stenosis and regurgitation, endocarditis, aortic dilatation and dissection. Although BAV is associated with early valve degeneration, its pathophysiology remains unknown. Purpose The objective of this study was to examine at clinical, histological and molecular levels, a cohort of BAV patients with pure aortic regurgitation (AR-BAV). Methods From 2011 to 2018, patients with BAV were prospectively included. We performed histological and transcriptomic analysis of explanted BAV and compared differences between characteristics of prolapsed leaflet and non-prolapsed leaflet, using a normal tricuspid valve leaflet at reference. Aortic-valves from patients with long term left ventricular assist device (LVAD) were used as a model of acquired aortic regurgitation. Results A total of 350 patients with BAV were included. Among 316 patients (90%) with dysfunctional BAV, 66 (21%) presented severe AR-BAV. Mechanism of AR was prolapse in 37 patients (56%). Histologically, analysis of 2 explanted AR-BAV showed disorganization of extracellular matrix, loss of laminar structure and proteoglycans accumulation on prolapsed leaflet. Inversely, trilaminar structure of the non-prolapsed aortic leaflet was preserved. Transcriptomic analysis revealed upregulation of genes involved in extracellular matrix homeostasis and downregulation of endothelial cell markers on the prolapsed leaflet. The aortic-valve LVAD analysis found histological and molecular results similar to those described in BAV prolapsed leaflet and was associated with occurrence AR. Conclusion AR-BAV is a mood of BAV dysfunction that occurs in young male subjects, as a consequence of myxomatous degeneration similar to that described in mitral valve prolapse. LVAD model suggests that altered hemodynamic environment could account for the acquired nature of valve degeneration.

Genetically modified mice have advanced our understanding of valve development and related pathologies. Yet, little is known regarding human valvulogenesis in health and diseases. Genuine humanin vitromodels that reproduce valvular (patho)biology are thus needed. We here developed a human pluripotent stem cell-derived model fit to decode the early steps of human valvulogenesis and to recapitulate valve disease traits in a dish.Using cellular based, single cell omics-informed andin vivo-validated approaches, we derived a population of pre-valvular endocardial cells from a pluripotent stem cell source. These human prevalvular cells (HPVCs) expressed gene patterns conforming to the atrio-ventricular canal (AVC) endocardium signature originally established in E9.0 mouse embryos. In fact, HPVC treated with BMP2, cultured onto mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, underwent endothelial-to-mesenchymal transition and expressed markers of valve interstitial cells of different valvular layers demonstrating tissue functionality. HPVCs also differentiated into tendinous/chondrogenic cells in line with the valvular repertoire. Extending this valvulogenic model to patient specific iPS cells, we recapitulated features of mitral valve prolapse and uncovered that dysregulation of the SHH pathway is likely to be at the origin of the disease thus providing a putative therapeutic target.Human pluripotent stem cells recapitulate early valvulogenesis and provide a powerful model to systematically decipher the origin and lineage contribution of different valvular cell types in humans as well as to study valve diseases in a dish.

International audience; Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here, we show in mouse that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of Krox20-expressing neural crest cells shows a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of Krox20 function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest Krox20-deficient embryos. Genetic lineage tracing in Krox20(-/-) mutant mice shows that endothelial-derived cells are normal, whereas neural crest-derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of Krox20-expressing cells is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings demonstrate a crucial role for Krox20 in arterial valve development and reveal that an excess of neural crest cells may be associated with bicuspid aortic valve.

International audience; 6p25 deletion is a rare but well-known entity. The main clinical features include an abnormal facial appearance, developmental delay, and ocular anomalies. Cardiac anomalies are frequently seen but remain poorly delineated. We describe a 4-year-old girl with 6p25.3 deletion, which includes the FOXC1 gene, typical dysmorphic features associated with developmental delay and oculo-motor anomalies. Aortic valve dysplasia was diagnosed early in life. The cardiac lesion progressed very rapidly between the age of 3 and 4 years requiring aortic valve replacement. Genomic analysis of blood and excised valve tissue showed down-regulation of FOXC1 but also FOXC2 expression in the diseased aortic valve. This allows us to speculate on the potential role of FOXC1 in aortic valve anomalies.

Background The physiopathology of bicuspid aortic valve (BAV) degeneration remains unknown. Altered hemodynamic environment could favor valve degeneration. Aim (1) To compare clinical and echocardiographic data of normally functioning and dysfunctional BAV; and (2) to correlate BAV phenotype to valve function. Methods Consecutive patients with normally functioning (NF-BAV) or dysfunctional BAV (D-BAV) were prospectively included. Sievers’ classification was used to compare BAV regarding valve function. Results A total of 223 patients with BAV were prospectively included. Mean age was 52.9 ± 16.5 years with a male predominance (n = 168, 75.3%). Twenty-four patients had NF-BAV and 199 patients had D-BAV. One hundred and seventy-eight patients (82.4%) had a Sievers’ type 1 BAV, mainly with an intercoronary leaflet fusion (n = 155, 87.1%). BAV aortopathy was found in 86 patients (38.5%). By multivariable analysis, age > 50 years (5.5 [2.2–17.4], P = 0.0006), male gender (3.4 [1.2–9.3], P = 0.01) and the presence of a raphe (3.6 [1.2–9.9], P = 0.01) were significantly associated with BAV dysfunction. Among D-BAV, 68 patients (34%) had AS and 91 patients (45%) had AR. Multivariate analysis revealed that a higher age (1.9 [1.85–1.94], P Fig. 1 ). Conclusions Commissural fusion of aortic cusps is associated with BAV dysfunction. By altering aortic blood flow and stiffening fused leaflet, the raphe could accelerate valve degeneration. These results suggested the emerging role of mechanobiology in BAV degeneration.

International audience; Background. - The mechanism involved in the onset of aortic valve (AoV) disease remains unclear despite its poor prognosis and frequency. Recently, we reported that Krox20 (EGR2 in humans) is involved in AoV development and dysfunction. Aim. - Analyze Krox20 heterozygous mice (Krox20(+/-)) to discover whether incomplete expression of Krox20 can cause valvular diseases. Methods. - Transcriptional levels of Col1a2/COL1A2 and Krox20/EGR2 in AoVs from Krox20(+/-) mice and human patients operated on for severe aortic regurgitation were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Human control valves were obtained from three transplanted patients without AoV disease. Twenty-one heterozygous Krox20(+/-) mice were compared with 35 controls at different ages. Three independent measurements of valve thickness were performed on magnified tissue sections using Image J software. In vivo valve structure and function were evaluated using the high-frequency Vevo (R) 2100 echocardiogram. Results. - qRT-PCR analysis using AoVs from patients with severe aortic regurgitation showed a decrease in EGR2 expression associated with significant downregulation of COL1A2 expression (P < 0.05). Similar results were observed in the AoVs of Krox20(+/-) mice. Anatomical examination revealed that incomplete invalidation of Krox20 caused significant thickening of the aortic leaflet compared with controls (145 +/- 22 vs. 75 +/- 24 mu m; P=0.01). Within the mutant group, this thickening worsened significantly over time (Krox20(+/-) mice aged >7 vs. < 7 months: 136 +/- 48 vs. 102 +/- 41 mu m; P

International audience; DiGeorge syndrome (DGS) is a congenital disease causing cardiac outflow tract anomalies, craniofacial dysmorphogenesis, thymus hypoplasia, and mental disorders. It results from defective development of neural crest cells (NCs) that colonize the pharyngeal arches and contribute to lower jaw, neck and heart tissues. Although TBX1 has been identified as the main gene accounting for the defects observed in human patients and mouse models, the molecular mechanisms underlying DGS etiology are poorly identified. The recent demonstrations that the SDF1/CXCR4 axis is implicated in NC chemotactic guidance and impaired in cortical interneurons of mouse DGS models prompted us to search for genetic interactions between Tbx1, Sdf1 (Cxcl12) and Cxcr4 in pharyngeal NCs and to investigate the effect of altering CXCR4 signaling on the ontogeny of their derivatives, which are affected in DGS. Here, we provide evidence that Cxcr4 and Sdf1 are genetically downstream of Tbx1 during pharyngeal NC development and that reduction of CXCR4 signaling causes misrouting of pharyngeal NCs in chick and dramatic morphological alterations in the mandibular skeleton, thymus and cranial sensory ganglia. Our results therefore support the possibility of a pivotal role for the SDF1/CXCR4 axis in DGS etiology.

International audience; AIMS: Heart valve maturation is achieved by the organization of extracellular matrix (ECM) and the distribution of valvular interstitial cells. However, the factors that regulate matrix components required for valvular structure and function are unknown. Based on the discovery of its specific expression in cardiac valves, we aimed to uncover the role of Krox20 (Egr-2) during valve development and disease. METHODS AND RESULTS: Using series of mouse genetic tools, we demonstrated that loss of function of Krox20 caused significant hyperplasia of the semilunar valves, while atrioventricular valves appeared normal. This defect was associated with an increase in valvular interstitial cell number and ECM volume. Echo Doppler analysis revealed that adult mutant mice had aortic insufficiency. Defective aortic valves (AoVs) in Krox20(-/-) mice had features of human AoV disease, including excess of proteoglycan deposition and reduction of collagen fibres. Furthermore, examination of diseased human AoVs revealed decreased expression of KROX20. To identify downstream targets of Krox20, we examined expression of fibrillar collagens in the AoV leaflets at different stages in the mouse. We found significant down-regulation of Col1a1, Col1a2, and Col3a1 in the semilunar valves of Krox20 mutant mice. Utilizing in vitro and in vivo experiments, we demonstrated that Col1a1 and Col3a1 are direct targets of Krox20 activation in interstitial cells of the AoV. CONCLUSION: This study identifies a previously unknown function of Krox20 during heart valve development. These results indicate that Krox20-mediated activation of fibrillar Col1a1 and Col3a1 genes is crucial to avoid postnatal degeneration of the AoV leaflets.