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The myogenic regulatory factors, Mrf4 and Myf5, play a key role in skeletal muscle formation. An enhancer trap approach, devised to isolate positive-acting elements from a 200-kb YAC covering the mouse Mrf4-Myf5 locus in a C2 myoblast assay, yielded an enhancer, A17, which mapped at -8 kb 5' of Mrf4 and -17 kb 5' of Myf5. An E-box bound by complexes containing the USF transcription factor is critical for enhancer activity. In transgenic mice, A17 gave two distinct and mutually exclusive expression profiles before birth, which correspond to two phases of Mrf4 transcription. Linked to the Tk or Mrf4 minimal promoters, the nlacZ reporter was expressed either in embryonic myotomes, or later in fetal muscle, with the majority of Mrf4 lines showing embryonic expression. When linked to the Myf5 minimal promoter, only fetal muscle expression was detected. These observations identify A17 as a sequence that targets sites of myogenesis in vivo and raise questions about the mutually exclusive modes of expression and possible promoter/enhancer interactions at the Mrf4-Myf5 locus. Keywords: Enhancer; Mrf4; Myf5; myogenesis; Myogenic regulatory factors

Mice without hepatocyte nuclear factor 1 (HNF1) die during weaning after a progressive wasting syndrome and enlarged kidneys. The transcription rate of genes such as albumin and alpha-1-antitrypsin is decreased while the gene coding for phenylalanine hydroxylase is totally inactivated, causing phenylketonuria. These mice also have Fanconi syndrome because of the malfunction of the renal proximal tube.

Transgenic experiments were carried out to determine the role of the cardiac actin gene in muscle development in the mouse. High-level expression of the cardiac actin gene in the skeletal muscle of transgenic mice involved distal and proximal enhancer sequences and the proximal promoter sequences. It also generated an nlacZ reporter gene. It is suggested that expression of the cardiac actin gene requires a cardiac enhancer located in between the proximal enhancer and proximal promoter regions.

It is well established that a number of birth defects are associated with improper formation of the respiratory tract. Important progress has been made in the identification of components of the regulatory networks controlling lung morphogenesis. They comprise a variety of soluble factors, receptors, transcription factors, and miRNAs. However, the underlying molecular mechanisms remain unsolved and fundamental questions, such as those related to lung branching are still unanswered. Congenital cystic lung diseases consist of a heterogeneous group of rare lung diseases mainly detected prenatally and characterized by airway dilatation. Despite their apparent phenotypic heterogeneity, these malformations are proposed to be related to a common malformation sequence occurring during lung branching morphogenesis. [ABSTRACT FROM AUTHOR]

Summary: Intrathoracic congenital malformations may be associated with long-term pulmonary morbidity. This certainly is the case for congenital diaphragmatic hernia, esophageal atresia and cardiac and aortic arch abnormalities. These conditions have variable degrees of impaired development of both the airways and lung vasculature, with a postnatal impact on lung function and bronchial reactivity. Pulmonary complications are themselves frequently associated to non-pulmonary morbidities, including gastrointestinal and orthopaedic complications. These are best recognized in a structured multidisciplinary follow-up clinic so that they can be actively managed. [Copyright &y& Elsevier]

Alagille syndrome (AGS; Online Mendelian Inheritance in Man no. 118450) is a multisystem autosomal dominant disorder with highly variable expression characterized by chronic cholestasis caused by a paucity of interlobular bile ducts, skeletal abnormalities, peculiar facies, ocular abnormalities, and cardiovascular disorders. AGS is diagnosed almost exclusively in children in the setting of predominant liver manifestations or, more rarely, in their adult relatives. We report 2 patients in whom AGS was diagnosed in adulthood during the workup of renal disease in the absence of a well-defined familial history. Renal disease caused by AGS probably is underdiagnosed in adult patients.Copyright © 2007 by National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Syndromes with smooth muscle dysmotility are uncommon, and may be related either to smooth muscle myopathy, or to neuropathy. In most instances, neuropathic visceral dysmotility is an isolated finding leading to chronic intestinal pseudo-obstruction syndrome (CIPO). We report here on two sibs, born to consanguineous parents, with neuropathic visceral dysmotility and CNS anomalies. They share facial dysmorphia, neurogenic megacystis, intracerebral calcifications, and developmental delay. The elder one, a girl, has microcephaly and multicystic kidneys, and her brother has a more extensive neuropathic visceral disorder leading clinically to CIPO. CIPO associated with megacystis is relatively frequent but is rarely associated with mental retardation. The cases reported in the literature are different from those described here, clinically and histologically. A recessively inherited form of CIPO associated with widespread intra-cerebral calcifications, malabsorption is known as Cockel syndrome. Severity of Cockel syndrome, absence of urinary tract involvement and neuropathologic discrepancies allow distinction with the disorder reported here. In conclusion, the two siblings described here have facial dysmorphia, vesical and (in one of them) intestinal neurogenic dysmotility, intracerebral calcifications and developmental delay that could represent a specific, recessively inherited form of CIPO. [Copyright &y& Elsevier]

Missense mutations in the WNK4 gene lead to the development of familial hyperkalemic hypertension, a rare form of human hypertension. It was shown in vitro that WNK4 regulates the surface expression and activity of a number of ion channels and transporters. The in vivo analysis of wild-type and mutant WNK4 overexpression in transgenic mice models demonstrated that this serine-threonine kinase controls ion handling in the kidney mainly, and probably exclusively, through the regulation of the Na-Cl contransporter NCC activity. [Copyright &y& Elsevier]

Summary: The need to systematically remove congenital cystic lung lesions is based on three main arguments. First, cystic malformations are often considered as congenital cystic adenomatoid malformations (CCAM), while other less favorable diagnoses are possible, such as pleuropulmonary blastoma. Only postsurgical pathological analysis allows diagnosis. Second, there are clinical and biological arguments for considering macrocystic lesions as likely to degenerate. The only prevention is surgical removal. Finally, there is no recommendation on how to follow these children, in the absence of removal, causing unnecessary family stress. This seems unjustified, compared to a feasibility of thoracoscopic removal in most cases. [Copyright &y& Elsevier]

Résumé Les jeux vidéo ont été beaucoup étudiés pour leurs risques en pédiatrie. Cependant, associés à une intention sérieuse, ils peuvent représenter des outils efficaces et ne doivent pas être négligés par la communauté pédiatrique. En matière de santé publique, les jeux vidéo sérieux sont un moyen de réduire les consommations de drogue ou les comportements sexuels à risque chez les adolescents. Au sein des établissements scolaires, ils peuvent permettre de changer le regard d’une classe sur la maladie de l’un de ses élèves ou être utilisés pour former aux premiers secours. Ils trouvent également leur utilité auprès des patients, que ce soit pour distraire l’enfant pendant un soin anxiogène ou douloureux, renforcer la compliance aux traitements ou participer à une rééducation. Enfin les jeux vidéo sérieux à destination des professionnels de santé de la petite enfance sont amenés à se développer rapidement avec l’apparition de simulations virtuelles permettant de s’entraîner à prendre en charge des situations urgentes ou graves sans aucun risque pour le patient. Cette revue présente pour chacun de ces domaines d’application le rationnel ayant conduit à choisir les jeux vidéo comme outil, suivi d’exemples concrets et des résultats de leurs évaluations scientifiques. Playing video games has been associated with several negative effects in children. However, serious games, which are video games designed for a primary purpose other than pure entertainment, should not be neglected by pediatricians. In the field of public health, some serious games are a means to decrease drug consumption and improve sexual health behavior in adolescents. In schools, serious games can be used to change students’ perception of the disease of one of their classmates, or to train students on basic life support. Serious games are also used with patients: they can distract them from a painful procedure, increase their compliance to treatments, or participate in their rehabilitation. Finally, serious games allow healthcare professionals to train on the management of various medical situations without risk. For every field of application, this review presents the rationale of the use of video games, followed by concrete examples of video games and the results of their scientific evaluation. [ABSTRACT FROM AUTHOR]

Mutations at the WNK1 gene cause Gordon syndrome, a rare inherited form of arterial hypertension. The gene encodes a short kidney-specific isoform and a complete long isoform, L-WNK1, expressed ubiquitously and notably within the vascular system. Objective: The aim of our study was to investigate the vascular role of L-WNK1 in mice. Method: We used mice bearing a constitutive homozygous inactivation of L-WNK1 (L-WNK1-/-) which die in utero before day 13 of gestation as well as adult healthy heterozygous (L-WNK1+/-) and wild-type (L-WNK1+/+) littermates. We isolated vessels from L-WNK1+/- and L-WNK1+/+ to perform in vitro pharmacological studies in a wire-myograph system and an arteriograph system. Results: We first showed that L-WNK1-/- embryos present growth retardation and severe oedema. An abnormal vascular remodeling was observed at day 10.5 within the primary vascular network of L-WNK1-/- embryos as well as in the yolk sac, suggesting an important role of L-WNK1 in cardiovascular development. We next showed that vascular diameters of pressurized arteries as well as arterial blood flow velocities measured by echo-Doppler were comparable between L-WNK1+/- and L-WNK1+/+ mice. Endothelium-dependent dilatations induced either by acetylcholine or by flow were also comparable between both groups of mice. In contrast, phenylephrine-induced vasoconstrictions were significantly reduced in L-WNK1+/- mice compared to L-WNK1+/+ mice in thoracic aorta as well as in mesenteric arteries (27.45 % (P=0.04) and 39.6 % (P=0.0015) decrease at maximal concentration, respectively) whereas potassium chloride contractions remained comparable. Furthermore, myogenic tone in L-WNK1+/- mesenteric arteries was also significantly blunted when compared to L-WNK1+/+ mice (P<0.0001). Conclusions: Our results evidenced for the first time a vascular role for L-WNK1 in pressure- and agonist- induced contractions. [Copyright &y& Elsevier]

Admission to hospital with bronchiolitis may adversely affect breastfeeding. Correct advice and support have been pointed out as a determining factor. We conducted a telephone survey to evaluate a set of actions to promote breastfeeding during hospitalization for acute bronchiolitis. Population: All patients 6 months of age or younger hospitalized with acute bronchiolitis and receiving at least partial breastfeeding were eligible for the study. Patients discharged home whose parents accepted to be contacted by phone were also included. We established a set of actions to promote breastfeeding (posters, flyers, staff training, and equipment) in all pediatric wards attending to these patients. This was a cross-sectional study conducted during two epidemic seasons of bronchiolitis in a tertiary care hospital. Data on continued breastfeeding at 3 months (0.5–6; median, range) postdischarge were collected by telephone and compared with the same set of data collected from patients with bronchiolitis in the same setting the year before the intervention. We conducted a telephone survey to evaluate whether some actions regarding breastfeeding might diminish the risk of unwanted weaning during hospitalization for bronchiolitis. The primary outcome was the proportion of stopped or reduced breastfeeding at discharge. Secondary objectives were to evaluate whether there were factors associated with breastfeeding modification. The results of the evaluation before intervention (phase 1) are published by Heilbronner et al. In Phase 1 of our study, 84 patients were included and 43 mothers (51%) reported that breastfeeding was modified by hospitalization of their child: 20.4% stopped, 14% switched to partial breastfeeding, and 16.6% reduced breastfeeding. These mothers stated that causes of breastfeeding disturbances were lack of support and advice (63%), followed by severity of the child's respiratory disease (32%), logistical hospital difficulties (30%), and personal organizational issues (9.3%). The intervention took place in September. After the intervention, 50 patients could be included in the study between October 1and December 31, 2016. Among them, 40 (80%) mothers kept breastfeeding as before, four (8%) stopped, four (8%) switched to partial breastfeeding, and two (4%) reduced breastfeeding without stopping. Bronchiolitis was more severe among patients with altered breastfeeding in terms of ventilatory support. Bronchiolitis is a high-risk event for breastfeeding disruption but interventions to promote breastfeeding might help to prevent the risk of unwanted weaning. More severe bronchiolitis probably poses the highest risk of weaning and the need for supplementary nutrition. [ABSTRACT FROM AUTHOR]

Among the rare genetic causes of pulmonary alveolar proteinosis (PAP), some have been evidenced to be linked to methionyl-tRNA synthetase (MARS) mutation. Lung transplantation (LTx) can be offer in case of secondary PAP, but it is admitted that underlying genetic PAP should be ruled out to prevent the recurrence of the disease. Nevertheless, recent investigations have evidenced the defective methionyl-tRNA synthetase (MetRS) activity in MARS-related PAP, and further, its correction with methionine supplementation. Because of significant clinical and imaging pulmonary improvement under methionine supplementation in non-transplanted affected patients, LTx was proposed to 2 patients with life-threatening end-stage MARS-related PAP, associated to an anticipated methionine supplementation following LTx. CASE 1 A 21 years old female underwent a bilateral-LTx in July 2019 for an end-stage PAP. A bridge to Tx had to be performed with ECMO. CASE 2 A 32 years old female underwent a bilateral-LTx in June 2021 for an end-stage PAP associated lung fibrosis, despite methionine supplementation started in December 2019. For both: (i) Diagnosis of a biallelic missense mutation in MARS was performed previously; (ii) Post-operative course was uneventful, with satisfactory graft function at 1095 POD and 455 POD, respectively; (ii) Methionine supplementation was administered each day post-LTx without side effects, (iii) At last follow-up, no PAP recurrence was observed in CT-scan (Figure), and patients had stable lung function. Our 2 LTx cases suggest the feasibility of LTx in MARS-related PAP under methionine supplementation. It suggests that the correction of MetRS activity under methionine supplementation allows functioning alveolar macrophage (AM) in a scenario of replacement of AM from donor by recipient origin. Nevertheless, other scenarios involving inflammatory or cholesterol homeostasis pathways cannot be ruled out. [ABSTRACT FROM AUTHOR]

Résumé Le poumon est la cible de complications aiguës et chroniques dans la drépanocytose. L’hypoxie chronique est fréquente, elle joue un rôle dans certaines de ces complications et peut être délétère à long terme. Sa prise en charge repose davantage sur le programme transfusionnel que l’oxygénothérapie. Le syndrome thoracique aigu (STA) peut être d’installation très rapide et demeure la principale cause de décès prématuré. Principalement secondaire à une infection ou une crise vaso-occlusive (CVO), sa prévention et son traitement sont essentiels et ont fait l’objet de nouvelles recommandations. L’asthme n’est pas plus fréquent chez les enfants drépanocytaires mais pourrait être associé à la survenue de CVO, de STA, voire de décès précoces. Sa prise en charge n’est pas spécifique mais l’utilisation des corticoïdes systémiques doit être prudente car elle n’est pas dénuée de risques. L’hypertension pulmonaire chez l’enfant drépanocytaire est probablement source de comorbidité mais pas de mortalité contrairement à ce qui est constaté chez l’adulte. Son dépistage est systématique mais sa prise en charge n’est pas établie. Concernant les fonctions respiratoires, si la prévalence du syndrome obstructif est faible, celle du syndrome restrictif augmente avec l’âge, témoignant d’un déclin rapide et précoce des volumes pulmonaires. L’endurance des enfants drépanocytaires est plus faible mais ne contre-indique pas la pratique mesurée du sport. Les troubles du sommeil, dont le syndrome d’apnée obstructive du sommeil, sont plus fréquents. Ils nécessitent un dépistage régulier car ils peuvent être source de troubles neurologiques significativement diminués par leur prise en charge. Cette importante morbi-mortalité justifie une surveillance respiratoire attentive chez ces enfants. Summary Acute and chronic pulmonary complications are frequent in sickle cell disease (SCD), with different spectrum and characteristics in children and adults. Chronic hypoxia is frequent and plays a role in several respiratory complications in SCD. Furthermore, hypoxia has been associated with a higher risk of cerebral ischemia. Despite differing oxygen affinity between hemoglobin A and S, standard pulse oximetry was shown to be accurate in diagnosing hypoxia in SCD patients. Whereas acute hypoxia management is similar to non-SCD patients, chronic hypoxia treatment is mainly based on a transfusion program rather than long-term oxygen therapy. Acute chest syndrome (ACS) is the foremost reason for admission to the intensive care unit and the leading cause of premature death. Guidelines on its management have recently been published. Asthma appears to be a different comorbidity and may increase the risk of vaso-occlusive crisis, ACS, and early death. Its management is not specific in SCD, but systemic steroids must be used carefully. Pulmonary hypertension (PH) is a major risk factor of death in adult patients. In children, no association between PH and death has been shown. Elevated tricuspid regurgitant velocity was associated with lower performance on the 6-min walk test (6MWT) but its long-term consequences are still unknown. These differences could be due to different pathophysiology mechanisms. Systematic screening is recommended in children. Regarding lung functions, although obstructive syndrome appears to be rare, restrictive pattern prevalence increases with age in SCD patients. Adaptation to physical exercise is altered in SCD children: they have a lower walking distance at the 6MWT than controls and can experience desaturation during effort, but muscular blood flow regulation maintains normal muscular strength. Sleeping disorders are frequent in SCD children, notably Obstructive sleep apnea syndrome (OSAS). Because of the neurological burden of nocturnal hypoxia, OSAS care is primordial and mainly based on adenotonsillectomy, which has been shown to reduce ischemic events. The high morbidity and mortality related to pulmonary impairments in SCD require a careful pulmonary assessment and follow-up. Mainly based on clinical examination, follow-up aims to the diagnosis of SCD-related respiratory complications early in these children. [ABSTRACT FROM AUTHOR]

Objective Proprotein convertase subtilisin/kexin type 9 (PCSK9) is highly expressed in the kidney, where its function remains unclear. In vitro data suggested that PCSK9 could impair the trafficking of the epithelial Na channel (ENaC). Here, we aimed at determining the consequences of PCSK9-deficiency on blood pressure, sodium balance and ENaC function in vivo in mice. Methods Blood pressure was measured using non-invasive tail-cuff system or radiotelemetry under basal conditions in male and female PCSK9 +/+ and PCSK9 −/− mice, as well as in models of hypertension: l -NAME (2 mg/kg/day), angiotensin II (1 mg/kg/day) and deoxycorticosterone acetate (DOCA)-salt in male mice only. Plasma and urine electrolytes (Na + , K + , Cl − ) were collected under basal conditions, after DOCA-salt and amiloride treatment. Renal expression of ENaC subunits was assessed by western blotting. Results PCSK9-deficiency did not alter both basal blood pressure and its increase in salt-insensitive ( l -NAME) and salt-sensitive (Ang-II and DOCA-salt) hypertension models. Plasma PCSK9 concentrations were increased by 2.8 fold in DOCA-salt-induced hypertension. The relative expression of the cleaved, active, 30-kDa αENaC subunit was significantly increased by 32% in kidneys of PCSK9 −/− mice under basal, but not under high-Na + diet or DOCA-salt conditions. Amiloride increased urinary Na + excretion to similar level in both genotypes, indicating that ENaC activity was not affected by PCSK9-deficiency. Conclusions Despite an increase of cleaved αENaC under basal condition, PCSK9 −/− mice display normal sodium balance and blood pressure regulation. Altogether, these data are reassuring regarding the development of PCSK9 inhibitors in hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Ichthyosis is a heterogeneous group of skin disorders characterized by abnormal epidermal scaling. Occasionally, extracutaneous features are associated. A novel autosomal recessive ichthyosis syndrome is described here with scalp hypotrichosis, scarring alopecia, sclerosing cholangitis, and leukocyte vacuolization in two inbred kindreds of Moroccan origin. We also report the mapping of the diseased gene to a 21.2 cM interval of chromosome 3q27–q28. Homo zygosity for polymorphic markers has enabled us to reduce the genetic interval to a 16.2 cM region. Furthermore, comparison of mutant chromosomes in the two families has suggested a common ancestral mutant haplotype. This linkage disequilibrium has reduced the genetic interval encompassing the diseased gene to less than 9.5 cM maximum. Further study of additional families from the same geographic area will hopefully reduce the genetic interval as well as help in the cloning of the gene involved in this rare disorder. [ABSTRACT FROM AUTHOR]

Aminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1. We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms. The first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature. All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia. Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations. Patients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies. [ABSTRACT FROM AUTHOR]

Objectifs Déterminer si une prophylaxie par palivizumab permettait de réduire le taux d’hospitalisation pour bronchiolite à virus respiratoire syncitial (VRS) chez les enfants de moins de 2 ans traités par corticothérapie systémique dans le cadre d’une pneumopathie interstitielle sévère. Matériels et méthodes Étude rétrospective nationale à partir de la base de données Respirare , chez les enfants nés entre le 1/1/2007 et le 1/1/2014. Les données étaient collectées à partir des dossiers médicaux et des carnets de santé. Résultats principaux Vingt-quatre enfants ont été inclus et évalués sur 2 saisons épidémiques, représentant 36 enfants–saisons. Le taux d’hospitalisation pour bronchiolite à VRS, 305 pour 1000 enfants–saisons, était très supérieur à celui de la population générale. Il n’existait pas de différence quant aux taux d’hospitalisation pour bronchiolite à VRS entre les enfants traités par palivizumab et les enfants non traités (respectivement 7/18 versus 4/18, p 0,47). Conclusions Les enfants suivis pour pneumopathie interstitielle et traités par corticothérapie systémique sont sujets à des bronchiolites à VRS plus fréquentes et plus graves, dont la prévention par le palivizumab reste à démontrer. [ABSTRACT FROM AUTHOR]