[COVID-19 in children: SARS-CoV-2-related inflammatory multisystem syndrome mimicking Kawasaki disease]. / COVID-19 chez l'enfant : syndrome inflammatoire multi-systémique lié à SARS-CoV-2 mimant un syndrome de Kawasaki.

SARS-CoV-2 pandemics is characterized by a high level of infectivity and a high mortality among adults at risk (older than 65 years, obesity, diabetes, systemic hypertension). Following a common viral pneumonia, a multisystem inflammatory syndrome sometimes occurs, including an Acute Respiratory Distress Syndrome (ARDS) carrying a high mortality. Unlike most common respiratory viruses, children seem less susceptible to SARS-CoV-2 infection and generally develop a mild disease with low mortality. However, clusters of severe shock associated with high levels of cardiac biomarkers and unusual vasoplegia requiring inotropes, vasopressors and volume loading have been recently described. Both clinical symptoms (i.e., high and persistent fever, gastrointestinal disorders, skin rash, conjunctivitis and dry cracked lips) and biological signs (e.g., elevated CRP/PCT, hyperferritinemia) resembled Kawasaki disease. In most instances, intravenous immunoglobin therapy improved the cardiac function and led to full recovery within a few days. However, adjunctive steroid therapy and sometimes biotherapy (e.g., anti-IL-1Ra, anti-IL-6 monoclonal antibodies) were often necessary. Although almost all children fully recovered within a week, some of them developed coronary artery dilation or aneurysm. Thus, a new 'Multisystem Inflammatory Syndrome associated with SARS-CoV-2' has been recently described in children and helps to better understand Kawasaki disease pathophysiology.

Early inhaled nitric oxide at high dose enhances rat lung development after birth.

RATIONAL: Inhaled nitric oxide (NO) is frequently administered to full term and preterm newborns in various clinical settings in order to alleviate pulmonary hypertension whilst improving oxygenation. However, the physiological effect of NO on early postnatal lung development has not yet been clearly described. We therefore investigated whether NO administered by inhalation affects lung development at early postnatal life. METHODS: Pregnant rats were placed in a chamber containing 5 ppm (iNO-5 ppm group) and 20 ppm NO (iNO-20 ppm group), started from the last day of their pregnancy in order to keep rat pups under ambient NO from birth to 7 days postnatal. Control animals were kept at room air and all rat pups were sacrificed at postnatal day 7 and day 14. RESULTS: Lung-to-body weight and wet-to-dry lung weight ratios did not significantly differ among 3 groups at postnatal day 7 and day 14. Vascular volume densities (Vv) in both NO groups (5 and 20 ppm) were higher than controls (P<0.05; P<0.001). Pulmonary vessel number was significantly increased in iNO-20 ppm group. Radial alveolar counts (RAC) and mean linear intercepts (MLI) markedly increased (consistent with increased alveolarization) in iNO-20 ppm group. This was associated with upregulation of VEGF/VEGFR-2, MT1-MMP/MMP2 and HO-1 protein expression in iNO-20 ppm group. CONCLUSIONS: We concluded that inhaled NO at 20 ppm enhanced lung development possibly through increased expression of HO-1, VEGF/VEGFR-2, and MMP2 at early stage of postnatal rat life.

CFTR pharmacological modulators: A great advance in cystic fibrosis management.

Cystic fibrosis is a severe monogenic disease that affects around 7400 patients in France. More than 2100 mutations in the cystic fibrosis conductance transmembrane regulator (CFTR), the gene encoding for an epithelial ion channel that normally transports chloride and bicarbonate, lead to mucus dehydration and impaired bronchial clearance. Systematic neonatal screening in France since 2002 has enabled early diagnosis of cystic fibrosis. Although highly demanding, supportive treatments including daily chest physiotherapy, inhaled aerosol therapy, frequent antibiotic courses, nutritional and pancreatic extracts have improved the prognosis. Median age at death is now beyond 30 years. Ivacaftor was the first CFTR modulator found to both reduce sweat chloride concentration and improve pulmonary function in the rare CFTR gating mutations. Combinations of modulators such as lumacaftor + ivacaftor or tezacaftor + ivacaftor were found to improve pulmonary function both in patients homozygous for the F508del mutation characterized by the lack of CFTR protein and those heterozygous for F508del with minimal CFTR activity. The triple combination of ivacaftor + tezacaftor + elexacaftor was recently shown to significantly improve pulmonary function and quality of life, to normalize sweat chloride concentration, and to reduce the need for antibiotic therapy in patients with at least one F508del mutation (83% in France). These impressive data, however, need to be confirmed in the long term. Nevertheless, it is encouraging to hear treated patients testify about their markedly improved quality of life and to observe that the number of lung transplants for cystic fibrosis decreased dramatically in France after 2020, despite the COVID pandemic, with no increase in deaths without lung transplant.

Impact of implementing French antibiotic guidelines for acute respiratory-tract infections in a paediatric emergency department, 2005-2009.

Acute respiratory tract infections (ARTIs) are the main reason for antibiotic prescription in children. In 2005, the French Drug Agency published guidelines to minimise inappropriate use of antibiotics for ARTI. The purpose of this study was to assess the impact of implementing these guidelines in a paediatric emergency department. We retrospectively analysed data collected prospectively in a French paediatric emergency department from November 2005 (date of guideline implementation) to October 2009. For each child diagnosed with ARTI, we collected age, diagnosis, and prescribed antibiotics. We computed antibiotic prescription rates in the study population. During the study period, 53,055 children were diagnosed with ARTI and 59% of the 22,198 antibiotic prescriptions given at discharge were related to ARTI. The proportion of ARTI patients given antibiotic prescriptions fell from 32.1% during the first year to 21% in year 4 (p<10(-4), Cochran-Armitage test). Amoxicillin-clavulanic acid and amoxicillin accounted for 50% and 34% of antibiotic prescriptions for ARTI, respectively. French antibiotic guidelines led to significant decreases in antibiotic prescription for ARTI in our paediatric emergency department.

Sensitivity and specificity of a rapid influenza diagnostic test in children and clinical utility during influenza A (H1N1) 2009 outbreak.

INTRODUCTION: The influenza A (H1N1) 2009 outbreak caused death and a disruption of public health services. Rapid influenza diagnostic tests (RIDT) could be helpful to ease the triage of patients and prevent an overload of emergency and laboratory facilities. OBJECTIVES: To compare the sensitivity and specificity of the Clearview Exact Influenza A&B test and real-time reverse transcription(RT)-PCR to detect influenza A (H1N1) 2009 in a paediatric emergency department of a paediatric teaching hospital in Paris, France. METHODS: 76 children with an influenza-like illness and either severe symptoms or an underlying medical condition were prospectively recruited between July 2009 and October 2009. RIDT and RT-PCR were simultaneously performed and compared. RESULTS: Among 39 influenza A (H1N1) 2009 RT-PCR-positive children (median age 5 years), 23 Clearview Exact Influenza A&B tests were positive. Sensitivity was 59% (95% CI 42.2 to 74) and specificity was 94.6% (95% CI 80.5 to 99.1). CONCLUSIONS: This study shows a sensitivity of RIDT of 59%, in agreement with other prospective studies, which could be useful in clinical practice for diagnosis influenza A (H1N1) 2009 in children. In outbreaks of a high prevalence, such as the 2009 outbreak, this test can help to prevent an overload of public health services.

Invasive group A streptococcal infection in children: clinical manifestations and molecular characterization in a French pediatric tertiary care center.

Invasive group A streptococcal (GAS) infections have a broad and evolving clinical spectrum, associated with various GAS genotypes and/or virulence factors that are only poorly described in children. We aimed to assess the clinical and molecular characteristics of invasive GAS infections in 28 children admitted from 2000 to 2007 at a large French pediatric tertiary care center. The GAS isolates were characterized molecularly by emm-typing and by the determination of the main virulence factors: speA, speB, speC, smeZ-1, ssa, sic, and silC. The median age of the children was 2.9 years. Osteoarticular infection (OAI) was the main clinical manifestation (n=15/28, 53%). emm-1 predominated (n=10/28), followed by emm-12, 3, and 4. No significant correlation was found between emm type and clinical manifestations, but emm-1 predominated in cases of OAI (n=7/15) and was associated with speA, speB, smeZ-1, and sic virulence factor genes. In this pediatric study, we describe a predominance of OAI associated with emm-1 GAS. Further larger international pediatric studies, including host immunity evaluation, are needed in order to better assess the pathogenesis of GAS infection in children.

Risks of severe hyponatremia in children receiving hypotonic fluids.

Intravenous fluids are frequently used in hospitalized children. Hypotonic fluids have been the standard of care in pediatrics for many years. This might be explained by the empiricism of early recommendations favoring fluids with dextrose, but an insufficient amount of sodium. The risk of hyponatremia (<135mmol/L) might be increased by the occurrence of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in the course of common acute diseases (e.g., bronchiolitis, acute gastroenteritis, encephalitis, meningitis) in children. Severe hyponatremia (<130mmol/L) is often associated with neurologic complications leading to sequelae or even death. Over the last few years, hyponatremia induced by hypotonic fluids has been increasingly reported, and significant progress has been made in the understanding of cerebral edema and osmotic demyelination. Several randomized clinical trials have shown weak but significant evidence that isotonic fluids were superior to hypotonic solutions in preventing hyponatremia. However, clinical practices have not changed much in France, as suggested by the analysis of intravenous fluids ordered from the Assistance Publique-Hôpitaux de Paris (AP-HP) central pharmacy (PCH) in 2017. Therefore, it would be advisable that national guidelines be released under the French Health Authorities regarding the safe infusion of infants and children.

[Clinical signs suggestive of bacterial meningitis in infants]. / Signes évocateurs de méningite chez le nourrisson.

Bacterial meningitis is a medical emergency requiring prompt recognition and evaluation and urgent initiation of appropriate antibacterial therapy. However, early recognition of severe bacterial infection including bacterial meningitis is a challenge in infants. Two clinical forms are basically observed in infants and young children: firstly, clinical meningitis which is characterized by fever, usually greater than 39 degrees C, and poorly specific gastrointestinal signs such as refusal of feeding and/or vomiting; irritability, abnormal crying, bulging fontanel, unusual generalized seizures occurring before six months of age and lasting more than 10 min should draw the clinician's attention and lead him/her to perform a lumbar puncture and initiate antibiotics; secondly, severe sepsis which is characterized by tachycardia, cold and/or mottled limbs and sometimes leg pain which should suggest a meningococcal disease; it is quite urgent to administer rapid fluid loading and antibiotic treatment while postponing lumbar puncture before the septic cascade evolves towards septic shock, extensive hemorrhagic rash, and ischemic limbs. Given the relative frequency of viral self-limiting diseases and rarity of serious bacterial infections, guidelines were published to guide the clinician's decision when dealing with a febrile infant. However, an alternative to these guidelines was recently suggested with a more clinically oriented decision-making attitude appearing as efficient while limiting hospitalizations.

Ventilation-induced pulmonary vasodilatation in lambs with congenital diaphragmatic hernia is modulated by nitric oxide.

Endogenous nitric oxide (NO) mediates pulmonary vasodilatation at birth, but inhaled NO fails to reduce pulmonary vascular resistance (PVR) in newborns with congenital diaphragmatic hernia (CDH). This study was designed to investigate the effects of ventilation, and the nature of its endogenous mediator, in fetal lambs with experimental CDH. Investigations at 138 days of gestation showed that ventilation markedly decreased PVR. Inhibition of NO synthesis reduced ventilation-induced pulmonary vasodilatation in vivo and increased in vitro isometric tension of vascular rings. Ventilation therefore reduces PVR at birth in lambs with CDH, and endogenous NO seems to contribute to this reduction.

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca2+ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (Em) or HPV. However, the Kv channels involved in Em and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1. 5 and Kv2.1 to PASMC electrophysiology and vascular tone. Immunoblotting confirmed the presence of Kv1.1, 1.2, 1.3, 1.5, 1.6, and 2.1, but not Kv1.4, in PASMCs. Intracellular administration of anti-Kv2.1 inhibited whole cell K+ current (IK) and depolarized Em. Anti-Kv2.1 also elevated resting tension and diminished 4-AP-induced vasoconstriction in membrane-permeabilized pulmonary artery rings. Anti-Kv1.5 inhibited IK and selectively reduced the rise in [Ca2+]i and constriction caused by hypoxia and 4-AP. However, anti-Kv1.5 neither caused depolarization nor elevated basal pulmonary artery tone. This study demonstrates that antibodies can be used to dissect the whole cell K+ currents in mammalian cells. We conclude that Kv2. 1 is an important determinant of resting Em in PASMCs from resistance arteries. Both Kv2.1 and Kv1.5 contribute to the initiation of HPV.

Evaluation of frequency of paediatric oral liquid medication dosing errors by caregivers: amoxicillin and josamycin.

OBJECTIVE: To study reconstitution and preparation dosing errors of liquid oral medications given by caregivers to children. METHODS: A prospective observational study was carried out in the departments of general paediatrics and emergency paediatrics at the Robert-Debré Children's University Hospital. An interview with caregivers involved (1) practical reconstitution and preparation of an oral liquid medication from a prescription drawn at random (amoxicillin (Clamoxyl, dosing spoon) or josamycin (Josacine, dose-weight pipette)) and (2) a questionnaire about their use. RESULTS: One hundred caregivers were included. Clamoxyl and Josacine were incorrectly reconstituted in 46% (23/50) and 56% (28/50) of cases, respectively, with a risk of underdosing of Clamoxyl (16/23) and overdosing of Josacine (23/28). Dose preparation with the dosing spoon was incorrect in 56% of cases, and in 10% of cases with the dose-weight pipette. Female sex, native French speaker, and age were significantly associated with correct reconstitution. Male sex and medication were significantly associated with correct preparation. CONCLUSIONS: This study highlights the high incidence of errors made by caregivers in reconstituting and preparing doses of these liquid oral medicines, which are associated with considerable risks of over- and underdosing. Factors associated with these errors have been identified which could help health professionals to optimise their strategy for educating families about the use of liquid oral medications and the need to check that they understand these instructions.

[Suicide attempts in children under 12 years of age]. / Tentatives de suicide chez les enfants de moins de 12 ans.

Suicide attempts (SA) in children are often considered rare and poorly studied. The aim of this study was to explore the clinical characteristics of SA in children under 12 years of age. A retrospective assessment was conducted in 30 consecutive SAs reported in children under 12 years of age admitted to the emergency department at the Robert-Debré University Hospital (Paris, France) from 2007 to 2010 and the Regional University Hospital (Besançon, France) from 2000 to 2008. All suicide attempters were directly assessed at the somatic and psychiatric level. Patients were 8-11 years old (mean, 10.2±0.8). The sex ratio was 0.9 boys for 1 girl. The leading SA methods were poisoning by medication (53.3%), hanging or strangulation (23.3%), jumping from a height (16.7%), poisoning by chemicals (3.3%), and lesions inflicted by sharp objects (3.3%). In addition, SAs were characterized by high lethality (43.7%) contrasting with their low to moderate suicidal intentionality (43.8% and 56.2%, respectively). In conclusion, we reported that SA in children differs from those of adolescents by their greater lethality related to the methods used, but contrasting with the low intentionality mentioned by these patients.

Feasibility of a reduction protocol in the emergency department for diaphyseal forearm fractures in children.

INTRODUCTION: Diaphyseal forearm fractures are very common pediatric traumas. At present, distal radius metaphyseal fractures are often successfully treated with closed reduction by emergency physicians. However, the management of diaphyseal fractures remains controversial. The purpose of this study was to analyze the results of diaphyseal forearm fractures in the emergency department (ED) in children. MATERIALS AND METHODS: In a prospective 2-year-study, all closed diaphyseal forearm fractures in patients under 15, with an angle of >15° and treated by closed reduction in the ED were included. Fractures with overlapping fragments were excluded. Reduction was performed by an emergency physician, with a standardized analgesic protocol (painkillers and nitrous oxide). Clinical tolerance was checked within the first 24hours, and the radiographic stability of reduction was assessed at days 8 and 15. Initial and final follow-up radiographs were analyzed. Elbow and wrist range of motion was assessed at the final follow-up. RESULTS: Sixty patients (41 boys and 19 girls) were included. Mean age was 5.2 years old (±3). At initial evaluation, the maximum angle was 30° (±11.3). After reduction, the maximum angle was significantly reduced (30° vs. 5°, P<0.001). Mean immobilization in a cast was 11.7 weeks (±2). There were no cast related complications in any of these children. There was no surgery for secondary displacement. Full range of motion was obtained in all patients at the final follow-up. DISCUSSION: The outcome of conservative treatment of closed diaphyseal forearm fractures, without overlapping fragments was excellent. However, reduction is usually performed in the operating room by orthopedic surgeons under general anesthesia and requires hospitalization, which is very expensive. The results of this study show that high quality care may be obtained in the ED by a trained and experienced team. These results are similar to those for distal metaphyseal fractures, which could extend the indications for reduction in the ED. LEVEL OF EVIDENCE: Level IV. Retrospective study.

Sequence of the murine alpha-lactalbumin-encoding cDNA: interspecies comparison of the coding frame and deduced pre-protein.

The structure of the mouse alpha-lactalbumin-encoding mRNA was deduced from sequence analysis of eight cDNA clones. The almost full-length mRNA of 732 nucleotides [poly(A) tail excluded] and the deduced pre-protein share 85% and 86% homology with their rat counterpart, respectively. Interspecies comparison of the pre-protein showed the occurrence of an extra amino acid (aa) in the signal peptide and of two mutations affecting two reported invariant aa residues at positions 44 and 107, which weakens the assumption that both aa residues might play a significant structural and/or functional role.

Complete sequence of the ovine beta-casein-encoding gene and interspecies comparison.

The 9149-bp transcription unit encoding ovine beta-casein (Cas) and 4636 bp of 5' flanking region were completely sequenced. The gene is composed of nine exons and its overall organization is similar to that of its counterparts from other species. Intron 4, the largest, shares three similar stretches (sizes ranging from 0.1 to 0.3 kb) with the region upstream from the transcription unit. These common sequences are part of short interspersed nuclear elements (SINE) specific to Bovidae (Bov). Intron 4 contains two 274-bp Bov-A2 SINE in opposite orientation, as well as a full-length 569-bp Bov-B SINE. This latter SINE, also present in caprine intron 4, is missing in cattle. This suggests that the amplification of Bov-SINE has continued after the divergence of cattle from sheep and goats, assuming that the presently known sequences are representative of these species.

Bovine alpha s2-casein D is generated by exon VIII skipping.

Bovine alpha s2-casein D (CasD) differs from the common type A by the deletion of a stretch of 9 amino acids (aa) starting at a position not precisely known, either at aa 50, 51, or 52. The sequence of cloned PCR-amplified genomic DNA from three homozygous cows, two unrelated females carrying the CasD allele and one carrying the CasA allele, did not reveal any deletion and showed two identical nucleotide (nt) substitutions in the 1.7-kb region of both CasD alleles encompassing codons 43-75 in the cDNA encoding alpha s2-CasA. This strongly suggests that the deleted bovine alpha s2-CasD arises from skipping the 27-nt exon, now identified as exon VIII, which encodes aa 51-59 of alpha s2-CasA. The G-->T transversion (allele A-->D) affecting the last nt of exon VIII, i.e., the 5' consensus splicing site, might be responsible for the altered splicing of the primary transcript of alpha s2-CasD.

Sequence of the goat alpha-lactalbumin-encoding gene: comparison with the bovine gene and evidence of related sequences in the goat genome.

The isolation and characterization of a genomic clone encoding goat alpha-lactalbumin (alpha LA) are described, and its sequence was aligned with that of its bovine counterpart. The 5'-flanking regions are highly homologous, but two small insertions were found in the goat sequence. One of these insertions fills the gap found in the so-called 'milk-box' consensus sequence of the bovine gene. Southern analysis indicates the presence of several alpha LA-related sequences in the goat genome, as previously observed in cow and sheep, which suggests that the relevant duplication event(s) occurred before divergence of these ruminant species.

The bovine and ovine genomes contain multiple sequences homologous to the alpha-lactalbumin-encoding gene.

Bovine and ovine (pseudo)genes homologous to the alpha-lactalbumin-encoding gene are described. In both cases, sequence analysis reveals homology extending downstream from exon 2. Southern analysis indicates the presence of a family of alpha-lactalbumin-related sequences in the bovine genome.

Developmental regulation of murine integrin beta 1 subunit- and Hsc73-encoding genes in mammary gland: sequence of a new mouse Hsc73 cDNA.

A partial integrin beta 1 subunit-encoding cDNA (Itg beta 1) and a new heat-shock protein 70-like-encoding cDNA (Hsc73) homologous to rat Hsc73 were cloned by differential display and RT-PCR from mouse mammary gland. Their developmental regulation during pregnancy, lactation and involution is reported. The Itg beta 1 mRNA content was stable in the first half of gestation, decreased to a minimum during lactation and increased markedly in early involution. Hsc73 gene expression was high in the first half of gestation and decreased to a minimum during lactation. The possible significance of the two observed patterns of expression is discussed.