The "MINOTOR" H2020 project for ECR thruster development

Electric propulsion has been identified by European actors as a strategic technology for improving competitiveness in different space areas such as in-space operations and transportation. The European Commission has set up the "In-space Electrical Propulsion and Station-Keeping" Strategic Research Cluster (SRC) in the "Horizon 2020" funding framework with the goal of enabling major advances in Electric Propulsion for in-space operations and transportation. In this framework, the MINOTOR project was funded to mature a potentially disruptive cathodeless electric propulsion technology, the Electron Cyclotron Resonance (ECR) thruster. In recent years, the consortium leader ONERA has built up a large experience on ECR technology for electric propulsion, and the MINOTOR project will bring the expertise from three industrial partners (TMI, TAS-B and SAFRAN) and two university partners (UC3M and JLU) to take the next step.This work was made in the framework of project MINOTOR that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 730028

Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

<p>Abstract</p> <p>Background</p> <p>In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.</p> <p>Methods</p> <p>COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis.</p> <p>Results</p> <p>Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of <it>POLG </it>were subsequently found in both the 2nd and 3rd patients.</p> <p>Conclusion</p> <p>Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent than observed until now. A novel pathogenic mutation in <it>POLG </it>is reported.</p> <p>Tentative explanations for the mitochondrial mosaics are, in one patient, unequal partition of mutated mitochondria during mitoses, and in two others, an interaction between products of several genes required for mtDNA maintenance.</p

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1.Purpose WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.Estonian Research CouncilNational Natural Science Foundation of ChinaRoyal SocietySouth Carolina Department of Disabilities and Special Needs (SCDDSN)National Institute of Neurological Disorders and Stroke (NINDS

adaptation in neonatalogy of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit.

BACKGROUND: The bactericidal efficacy of aminoglycosides is directly related to peak serum concentration (Cmax), particularly the first one. Transitory high concentrations of aminoglycosides do not result in such a high drug uptake by renal and cochlear tissues because of the saturation of cell binding sites. These observations have led to the concept that less frequent administration of relatively larger doses of aminoglycosides would be of interest in treating infectious diseases. OBJECTIVE: Prospective evaluation of a dosing chart of amikacin (Ak) in high-risk neonates suspected of infection within the first 2 days of life. This dosing chart was based on a previous pharmacokinetic population study published elsewhere, treated accordingly to the new once-daily concept of aminoglycoside administration. STUDY DESIGN: One hundred and seventy-seven neonates (69 females and 108 males; mean gestational age (GA +/-SD: 33.6 +/- 4.1 weeks (W) received Ak regimen dosage according to the following dosing chart: Group (Gr) 1a GA /= 37 W: 15.5 mg/kg/24 h. In case of asphyxia, hypoxic episode and intercourse treatment with indomethacin, the interval was systemically increased by 6 h whatever the GA groups. The mean duration time of Ak treatment (+/- 1 SD) was 5.00 +/- 2.01 days (range 2-13). Ak serum concentrations 1 h after completion of 30 min infusion (C1h), and successive Ak serum concentrations just before next administration depending on the difference of interval between each group (so defined minimum serum concentration (Cmin)), were determined in each neonate. Creatininemia during the fist postnatal weeks was used as an index of glomerular filtration rate; brainstem auditory evoked potentials (BEAPs) were used in 139 babies when reaching a postconceptional age of >/= 36 weeks to assess possible ototoxicity, and were compared to values from a group of term and a group of preterm babies, previously defined as our reference control groups. RESULTS: At day 1 of treatment, there was no correlation between the Ak C1hS and the GA at birth (mean 27.8 +/- 5.21 microgram/ml (+/- 1 SD); median 28; r = -0.003; range 10-40). In the same way, there was no correlation between the first Ak CminS and the GA at birth (mean 3.7 +/- 2.0 microgram/ml (+/- 1 SD); median 3.0; r = -0.33; range 0-10). The lack of correlation between these first observed C1hS and CminS and the GA at birth suggests the validity of our previous established dose regimen recommendations. Analyzing the data between groups, the mean value +/- 1 SD of Ak C1hS at day 1 of treatment was not significantly different (p > 0.05). Concerning the first Ak CminS, a significant difference (p 0.05) between the treated groups (preterm group and term group) and the corresponding control groups. While the primary aim of the study was not to test the bactericidal efficacy of this new regimen, the recovery was excellent in 37 babies with proven or highly suspected infectious disease, except in 1 of them who died from septic shock (group B Streptococcus). After 5 years of using this kind of Ak administration in the unit, minimal inhibitory concentration profiles tested in 43 successive bacterial strains collected from inborn patients remained adequate. (ABSTRACT TRUNCATED

Once-a-day administration of amikacin in neonates: Assessment of nephrotoxicity and ototoxicity

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age greater than or equal to 34 weeks; postnatal age less than or equal to 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta(2)-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of greater than or equal to 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages

Efficacy of high dose steroid therapy in children with severe acute transverse myelitis

No effective treatment has been demonstrated for patients with acute transverse myelopathy. In a multicentre controlled study, 12 children with severe acute transverse myelopathy were treated with intravenous methylprednisolone (IVMP) and compared with a historical group of 17 patients. The treatment had a significant effect on the proportion of patients walking independently at I month and on the proportion with full recovery at I year, with no differences in the frequency of complications between the two groups