OCT represents a promising tool for evaluating the PA wall in children with CHD.

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17−/− mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

SummaryTissue Doppler velocity during early diastole (e') is one of the most feasible and reproducible echocardiographic assessments to reflect active relaxation of the left ventricle. Although several reports have described the mechanisms of temporal diastolic dysfunction in the early neonatal period, factors influencing diastolic function have not been determined. The purpose of this study was to elucidate factors significantly influencing e' in the early neonatal period.A total of 179 consecutive normal neonates underwent echocardiographic studies performed at 0 days and 5-10 days after birth. The statistical relationships between e' and age, body weight, mean blood pressure, heart rate, shortening fraction of the left ventricle, peak systolic motion velocity (s'), early diastolic transmitral flow velocity over annulus velocity, Tei index, and diastolic wall strain (DWS) were analyzed.Between the 0 days and 5-10-days-after birth groups, significant differences were shown in mean blood pressure, shortening fraction of left ventricle, e', and Tei index. Age, body weight, mean blood pressure, s', and DWS showed significant correlations with e'. In multivariate regression analysis within these parameters, s' (β = 0.6119, P < 0.0001) and DWS (β = 0.1216, P = 0.0321) showed positive correlations with e'.Longitudinal systolic motion velocity and ventricular wall stiffness of the left ventricle influence diastolic relaxation in normal neonates. Age, body weight, and circumferential systolic function are not significant factors.(Int Heart J 2018; 59: 149-153) Key words: Diastolic wall strain, Diastolic function, Myocardial stiffness T issue Doppler velocity during early diastole (e') is one of the echocardiographic parameters reflecting ventricular relaxation. This feasible and noninvasive assessment can evaluate direct myocardial diastolic function reproducibly. Neonates are known to show temporary diastolic dysfunction soon after birth, but the mechanisms underlying this dysfunction are not clearly identified. In a previous study, the effects of afterload and right ventricular pressure overload due to physiological pulmonary hypertension, maturation, and the number of myocytes was inferred as one factor related to the diastolic function of neonates in the early period.1-4) Including such factors, significant hemodynamic changes occur during the transition from the fetal to the neonatal environment, and these changes could be presented as characteristic in the neonatal period. Besides these hemodynamic and pathological factors, individual background characteristics such as age, body weight at birth, and systolic function should be considered to have potential relationships with diastolic function. The relationships among these various factors are being considered, but the mechanisms underlying the development and maturation of diastolic function in normal neonates have yet to be clarified. The purpose of this study was thus to investigate the factors influencing e', the representative parameter for ventricular relaxa...

Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

Background Hypoxia and low pulmonary arterial (PA) blood flow stimulate the development of systemic-to-pulmonary collateral blood vessels, which can be an adverse factor when performing the Fontan operation. The aim of this study was to use optical coherence tomography (OCT) to elucidate the morphological changes in PA vasculature after creation of a bidirectional cavopulmonary connection (BCPC) in children. Methods This prospective study evaluated PA wall thickness and development of PA vasa vasorum (VV) in the distal PA of eight patients (BCPC group, 1.3 ± 0.3 years) and 20 age-matched children with normal pulmonary artery hemodynamics and morphology (Control group, 1.4 ± 0.3 years). VV development was defined by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images. Results There was no significant difference in PA wall thickness between the BCPC and control groups (0.12 ± 0.03 mm vs. 0.12 ± 0.02 mm, respectively). The VV area ratio was significantly greater in the BCPC group than in the Control group (14.5 ± 3.5% vs. 5.3 ± 1.6%, respectively; p<0.0001). Conclusion OCT is a promising new tool for evaluating PA pathology, including the development of VV in patients after BCPC.