Oral alendronate (5 or 10 mg daily) for 2 years in children with osteogenesis imperfecta was well-tolerated, significantly increased spine bone mineral density, and decreased bone turnover.
Context:
...Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited.
Objective:
The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI.
Design and Participants:
We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4–19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater.
Main Outcome Measures:
Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured.
Results:
ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from −4.6 to −3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from −4.6 to −4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups.
Conclusions:
Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.
The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart ...defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far.
By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein.
The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of ...OI, there have been no large‐scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross‐sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen‐related OI. Analysis of such well‐collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis‐driven research, especially in the context of ‘phenotypic expansion’ driven by next‐generation sequencing.
Long term planning of urban water infrastructure requires acknowledgement that transitions in the water system are driven by changes in the urban environment, as well as societal dynamics. Inherent ...to the complexity of these underlying processes is that the dynamics of a system's evolution cannot be explained by linear cause-effect relationships and cannot be predicted under narrow sets of assumptions. Planning therefore needs to consider the functional behaviour and performance of integrated flexible infrastructure systems under a wide range of future conditions. This paper presents the first step towards a new generation of integrated planning tools that take such an exploratory planning approach. The spatially explicit model, denoted DAnCE4Water, integrates urban development patterns, water infrastructure changes and the dynamics of socio-institutional changes. While the individual components of the DAnCE4Water model (i.e. modules for simulation of urban development, societal dynamics and evolution/performance of water infrastructure) have been developed elsewhere, this paper presents their integration into a single model. We explain the modelling framework of DAnCE4Water, its potential utility and its software implementation. The integrated model is validated for the case study of an urban catchment located in Melbourne, Australia.
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•Long term planning of urban water infrastructure needs to account for transitions.•DAnCe4Water links urban and societal dynamics with infrastructure evolution.•The complexity of the system requires an exploratory planning approach.•The model was able to predict transition towards decentralized drainage solutions.
Arabidopsis 14-3-3 proteins are a family of conserved proteins that interact with numerous partner proteins in a phospho-specific manner, and can affect the target proteins in a number of ways; e.g. ...modification of enzymatic activity. We isolated T-DNA insertion lines in six 14-3-3 genes within the non-epsilon group that phylogenetically group in three closely related gene pairs. In total, 6 single, 3 double, 12 triple, and 3 quadruple mutants were generated. The mutants were phenotyped for primary root growth on control plates: single and double mutants were indistinguishable from WT, whereas six triples and all quadruples showed a shorter primary root. In addition, length of the first epidermal cell with a visible root hair bulge (LEH) was used to determine primary root elongation on medium containing mannitol and 1-aminocyclopropane-1-carboxylic acid (ACC). This analysis showed clear differences depending on the stress and 14-3-3 gene combinations. Next to the phenotypic growth analyses, a 14-3-3 pull-down assay on roots treated with and without mannitol showed that mannitol stress strongly affects the 14-3-3 interactome. In conclusion, we show gene specificity and functional redundancy among 14-3-3 proteins in primary root elongation under control and under abiotic stress conditions and changes in the 14-3-3 interactome during the onset of stress adaptation.
Our research shows that there is isoform specificity and redundancy among 6 out of 13 14-3-3 members in root growth under control and abiotic stress conditions.
The Cluster mission offers an excellent opportunity to investigate the evolution of the plasma population in a large part of the inner magnetosphere, explored near its orbit's perigee, over a ...complete solar cycle. The WHISPER sounder, on board each satellite of the mission, is particularly suitable to study the electron density in this region, between 0.2 and 80 cm super(-3). Compiling WHISPER observations during 1339 perigee passes distributed over more than three years of the Cluster mission, we present first results of a statistical analysis dedicated to the study of the electron density morphology and dynamics along and across magnetic field lines between L = 2 and L = 10. In this study, we examine a specific topic: the refilling of the plasmasphere and trough regions during extended periods of quiet magnetic conditions. To do so, we survey the evolution of the ap index during the days preceding each perigee crossing and sort out electron density profiles along the orbit according to three classes, namely after respectively less than 2 days, between 2 and 4 days, and more than 4 days of quiet magnetic conditions (ap less than or equal to 15 nT) following an active episode (ap > 15 nT). This leads to three independent data subsets. Comparisons between density distributions in the 3-D plasmasphere and trough regions at the three stages of quiet magnetosphere provide novel views about the distribution of matter inside the inner magnetosphere during several days of low activity. Clear signatures of a refilling process inside an expended plasmasphere in formation are noted. A plasmapause-like boundary, at L ~ 6 for all MLT sectors, is formed after 3 to 4 days and expends somewhat further after that. In the outer part of the plasmasphere (L ~ 8), latitudinal profiles of median density values vary essentially according to the MLT sector considered rather than according to the refilling duration. The shape of these density profiles indicates that magnetic flux tubes are not fully replenished after 6 days of quiet conditions. In addition, the outer plasmasphere in the night and dawn sectors (22:00 to 10:00 MLT range) maintains an overall clear deficit of ionospheric population, when compared to the situation in the noon and dusk sectors (10:00 to 22:00 MLT range).
The Cluster multi-point mission offers a unique collection of non-thermal continuum (NTC) radio waves observed in the 2–80 kHz frequency range over almost 15 years, from various view points over the ...radiating plasmasphere. Here we present rather infrequent case events, such as when primary electrostatic sources of such waves are embedded within the plasmapause boundary far from the magnetic equatorial plane. The spectral signature of the emitted electromagnetic waves is structured as a series of wide harmonic bands within the range covered by the step in plasma frequency encountered at the boundary. Developing the concept that the frequency distance df between harmonic bands measures the magnetic field magnitude B at the source (df = Fce, electron gyrofrequency), we analyse three selected events. The first one (studied in Grimald et al., 2008) presents electric field signatures observed by a Cluster constellation of small size (~ 200 to 1000 km spacecraft separation) placed in the vicinity of sources. The electric field frequency spectra display frequency peaks placed at frequencies fs = n df (n being an integer), with df of the order of Fce values encountered at the plasmapause by the spacecraft. The second event, taken from the Cluster tilt campaign, leads to a 3-D view of NTC waves ray path orientations and to a localization of a global source region at several Earth radii (RE) from Cluster (Décréau et al., 2013). The measured spectra present successive peaks placed at fs ~ (n+ 1/2) df. Next, considering if both situations might be two facets of the same phenomenon, we analyze a third event. The Cluster fleet, configured into a constellation of large size (~ 8000 to 25 000 km spacecraft separation), allows us to observe wide-banded NTC waves at different distances from their sources. Two new findings can be derived from our analysis. First, we point out that a large portion of the plasmasphere boundary layer, covering a large range of magnetic latitudes, is radiating radio waves. The radio waves are issued from multiple sources of small size, each related to a given fs series and radiating inside a beam of narrow cone angle, referred to as a beamlet. The beamlets illuminate different satellites simultaneously, at different characteristic fs values, according to the latitude at which the satellite is placed. Second, when an observing satellite moves away from its assumed source region (the plasmapause surface), it is illuminated by several beamlets, issued from nearby sources with characteristic fs values close to each other. The addition of radio waves blurs the spectra of the overall received electric field. It can move the signal peaks such that their position fs satisfiesfs = (n+α) df, with 0 < α < 1. These findings open new perspectives for the interpretation of NTC events displaying harmonic signatures.
We report on a search for weakly interacting massive particles (WIMPs) using 278.8 days of data collected with the XENON1T experiment at LNGS. XENON1T utilizes a liquid xenon time projection chamber ...with a fiducial mass of (1.30±0.01) ton, resulting in a 1.0 ton yr exposure. The energy region of interest, 1.4,10.6 keV_{ee} (4.9,40.9 keV_{nr}), exhibits an ultralow electron recoil background rate of 82_{-3}^{+5}(syst)±3(stat) events/(ton yr keV_{ee}). No significant excess over background is found, and a profile likelihood analysis parametrized in spatial and energy dimensions excludes new parameter space for the WIMP-nucleon spin-independent elastic scatter cross section for WIMP masses above 6 GeV/c^{2}, with a minimum of 4.1×10^{-47} cm^{2} at 30 GeV/c^{2} and a 90% confidence level.
We report the first dark matter search results from XENON1T, a ∼2000-kg-target-mass dual-phase (liquid-gas) xenon time projection chamber in operation at the Laboratori Nazionali del Gran Sasso in ...Italy and the first ton-scale detector of this kind. The blinded search used 34.2 live days of data acquired between November 2016 and January 2017. Inside the (1042±12)-kg fiducial mass and in the 5,40 keV_{nr} energy range of interest for weakly interacting massive particle (WIMP) dark matter searches, the electronic recoil background was (1.93±0.25)×10^{-4} events/(kg×day×keV_{ee}), the lowest ever achieved in such a dark matter detector. A profile likelihood analysis shows that the data are consistent with the background-only hypothesis. We derive the most stringent exclusion limits on the spin-independent WIMP-nucleon interaction cross section for WIMP masses above 10 GeV/c^{2}, with a minimum of 7.7×10^{-47} cm^{2} for 35-GeV/c^{2} WIMPs at 90% C.L.
Indium antimonide (InSb) nanowires are used as building blocks for quantum devices because of their unique properties, that is, strong spin‐orbit interaction and large Landé g‐factor. Integrating ...InSb nanowires with other materials could potentially unfold novel devices with distinctive functionality. A prominent example is the combination of InSb nanowires with superconductors for the emerging topological particles research. Here, the combination of the II–VI cadmium telluride (CdTe) with the III–V InSb in the form of core–shell (InSb–CdTe) nanowires is investigated and potential applications based on the electronic structure of the InSb–CdTe interface and the epitaxy of CdTe on the InSb nanowires are explored. The electronic structure of the InSb–CdTe interface using density functional theory is determined and a type‐I band alignment is extracted with a small conduction band offset ( ⩽0.3 eV). These results indicate the potential application of these shells for surface passivation or as tunnel barriers in combination with superconductors. In terms of structural quality, it is demonstrated that the lattice‐matched CdTe can be grown epitaxially on the InSb nanowires without interfacial strain or defects. These shells do not introduce disorder to the InSb nanowires as indicated by the comparable field‐effect mobility measured for both uncapped and CdTe‐capped nanowires.
Combining indium antimonide (InSb) nanowires with materials of dissimilar properties, has enabled the engineering of exotic materials, such as topological superconductors. This work explores potential applications of the material combination of InSb with cadmium telluride in the form of core–shell nanowire heterostructures. These heterostructures are studied in terms of growth, epitaxy, electronic structure of their interface, and electric transport properties.
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