SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients.

BACKGROUND: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density. RESULTS: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%). CONCLUSION: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS).

Severe Thoracic and Spinal Bone Abnormalities in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors. Classical skeletal abnormalities encompass sphenoid wing dysplasia, congenital bowing of the long bones and vertebral osteopathy associated with non-dystrophic or dystrophic scoliosis found in about 10% of NF1 patients. We report a 17-year-old boy affected by NF1 with extreme severe spinal and thoracic malformations affecting bone and lung tissues, including hypoplasia of the right lung, unilateral costal agenesis and severe dystrophic scoliosis characterized by association of hemivertebra, fusion of adjacent vertebral bodies and defective pedicles. At birth, he presented an acute respiratory distress requiring invasive ventilator support. The diagnosis of NF1 was confirmed at age 5 by the identification of a de novo heterozygous mutation c.4537C > T, p.Arg1513* in NF1. Trio-based Whole Exome Sequencing (WES) was performed to exclude coexistence of a second hit but no clearly other pathogenic variant has been identified. Until now, only one similar NF1 patient suffering from the same association of severe scoliosis and chest deformity leading to respiratory insufficiency was described. The severe prenatal NF1-related scoliosis could explain the lung abnormal development by absence of mechanical constraints. Severe Thoracic and Spinal Bone Abnormalities may be part of the NF1 bone phenotype and should be taken into account to allow adequate genetic counseling.

Characterizing export of land-based microplastics to the estuary - Part I: Application of integrated geospatial microplastic transport models to assess tire and road wear particles in the Seine watershed.

Human and ecological exposure to micro- and nanoplastic materials (abbreviated as MP, < 5 mm) occurs in both aquatic and terrestrial environments. Recent reviews prioritize the need for assessments linking spatially distributed MP releases with terrestrial and freshwater transport processes, thereby providing a better understanding of the factors affecting MP distribution to the sea. Tire and road wear particles (TRWP) have an estimated generation rate of 1 kg tread inhabitant-1 year-1 in Europe, but the fate of this MP source in watersheds has not been systematically assessed. An integrated temporally and geospatially resolved watershed-scale MP modeling methodology was applied to TRWP fate and transport in the Seine (France) watershed. The mass balance considers TRWP generation and terrestrial transport to soil, air, and roadways, as well as freshwater transport processes including particle heteroaggregation, degradation and sedimentation within subcatchments. The per capita TRWP mass release estimate in the Seine watershed was 1.8 kg inhabitant-1 yr-1. The model estimates indicated that 18% of this release was transported to freshwater and 2% was exported to the estuary, which demonstrated the potential for appreciable capture, degradation, and retention of TRWP prior to export. The modeled pseudo-steady state sediment concentrations were consistent with measurements from the Seine watershed supporting the plausibility of the predicted trapping efficiency of approximately 90%. The approach supported the efficient completion of local and global sensitivity analyses presented in Part II of this study, and can be adapted to the assessment of other MPs.

Characterizing export of land-based microplastics to the estuary - Part II: Sensitivity analysis of an integrated geospatial microplastic transport modeling assessment of tire and road wear particles.

Integrated models addressing microplastic (MP) generation, terrestrial distribution, and freshwater transport are useful tools characterizing the export of MP to marine waters. In Part I of this study, a baseline watershed-scale MP mass balance model was developed for tire and road wear particles (TRWP) in the Seine watershed. In Part II, uncertainty and sensitivity analysis (SA) methods were used to identify the parameters that determine the transport of these particles to the estuary. Local differential, local range and global first-order variance-based SA identified similar key parameters. The global SA (1000 Monte Carlo simulations) indicated that most of the variance in TRWP exported to the estuary can be apportioned to TRWP diameter (76%), TRWP density (5.6%), the fraction of TRWP directed to combined sewers with treatment (3.9%), and the fraction of TRWP distributed to runoff (versus roadside soil; 2.2%). The export fraction was relatively insensitive to heteroaggregation processes and the rainfall intensity threshold for road surface washoff. The fraction of TRWP exported to estuary in the probabilistic assessment was centered on the baseline estimate of 2%. This fraction ranged from 1.4 to 4.9% (central tendency defined as 25th to 75th percentile) and 0.97% to 13% (plausible upper bound defined as 10th to 90th percentiles). This study emphasizes the importance of in situ characterization of TRWP diameter and density, and confirms the baseline mass balance presented in Part I, which indicated an appreciable potential for capture of TRWP in freshwater sediment.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

96 perfusable blood vessels to study vascular permeability in vitro.

Current in vitro models to test the barrier function of vasculature are based on flat, two-dimensional monolayers. These monolayers do not have the tubular morphology of vasculature found in vivo and lack important environmental cues from the cellular microenvironment, such as interaction with an extracellular matrix (ECM) and exposure to flow. To increase the physiological relevance of in vitro models of the vasculature, it is crucial to implement these cues and better mimic the native three-dimensional vascular architecture. We established a robust, high-throughput method to culture endothelial cells as 96 three-dimensional and perfusable microvessels and developed a quantitative, real-time permeability assay to assess their barrier function. Culture conditions were optimized for microvessel formation in 7 days and were viable for over 60 days. The microvessels exhibited a permeability to 20 kDa dextran but not to 150 kDa dextran, which mimics the functionality of vasculature in vivo. Also, a dose-dependent effect of VEGF, TNFα and several cytokines confirmed a physiologically relevant response. The throughput and robustness of this method and assay will allow end-users in vascular biology to make the transition from two-dimensional to three-dimensional culture methods to study vasculature.

Model-predicted occurrence of multiple pharmaceuticals in Swedish surface waters and their flushing to the Baltic Sea.

An exposure assessment for multiple pharmaceuticals in Swedish surface waters was made using the STREAM-EU model. Results indicate that Metformin (27 ton/y), Paracetamol (6.9 ton/y) and Ibuprofen (2.33 ton/y) were the drugs with higher amounts reaching the Baltic Sea in 2011. 35 of the studied substances had more than 1 kg/y of predicted flush to the sea. Exposure potential given by the ratio amount of the drug exported to the sea/amount emitted to the environment was higher than 50% for 7 drugs (Piperacillin, Lorazepam, Metformin, Hydroxycarbamide, Hydrochlorothiazide, Furosemide and Cetirizine), implying that a high proportion of them will reach the sea, and below 10% for 27 drugs, implying high catchment attenuation. Exposure potentials were found to be dependent of persistency and hydrophobicity of the drugs. Chemicals with Log D > 2 had exposure potentials <10% regardless of their persistence. Chemicals with Log D  <  -2 had exposure potentials >35% with higher ratios typically achieved for longer half-lives. For Stockholm urban area, 17 of the 54 pharmaceuticals studied had calculated concentrations higher than 10 ng/L. Model agreement with monitored values had an r2 = 0.62 for predicted concentrations and an r2 = 0.95 for predicted disposed amounts to sea.

CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

Evaluation of human pharmaceutical emissions and concentrations in Swedish river basins.

An emissions inventory for top consumed human pharmaceuticals in Sweden was done based on national consumption data, human metabolic rates and wastewater treatment removal rates. Concentrations of pharmaceuticals in surface waters in Swedish river basins were predicted using estimated emissions from the inventory and river discharges. Our findings indicate that the top ten emitted pharmaceuticals in our study set of 54 substances are all emitted in amounts above 0.5ton/y to both surface waters and soils. The highest emissions to water were in decreasing order for Metformin, Furosemide, Gabapentin, Atenolol and Tramadol. Predicted emissions to soils calculated with the knowledge that in Sweden sludge is mostly disposed to soil, point to the highest emissions among the studied drugs coming from, in decreasing order, Metformin, Paracetamol, Ibuprofen, Gabapentin and Atenolol. Surface water concentrations in Sweden's largest rivers, all located in low density population zones, were found to be below 10ng/L for all substances studied. In contrast, concentrations in surface waters in Stockholm's metropolitan area, the most populous in Sweden, surpassed 100ng/L for four substances: Atenolol, Metformin, Furosemide and Gabapentin.

Europe-wide estuarine export and surface water concentrations of PFOS and PFOA.

The STREAM-EU model was used to predict the water concentrations, estuarine export and retention of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in the eleven most populated European river catchments to provide a European-wide perspective on the contamination by these substances. Emissions of PFOS and PFOA to those catchments were calculated based on population, wealth and wastewater treatment plant (WWTP) coverage and efficiency using a previously published method and used as model input. Our estimated emissions showed the lowest values for the Thames catchment (PFOS: 0.4 ton/y; PFOA: 0.2 ton/y) and the highest values for the Rhine for PFOS (1.6 ton/y) and for the Dnieper for PFOA (1.7 ton/y). The model predicted concentrations agreed reasonable well with the existing range of measurements, apart from for PFOA in the River Po, where there is a known historical industrial contamination, and PFOS in the Rhone River, where results were much higher than the few measurements available. It was concerning that the model predicted that the surface water EQS for PFOS (0.65 ng/L) was exceeded by a wide margin in all the eleven studied European river catchments. The total calculated riverine export to the seas from the eleven catchments was 4.5 ton/y of PFOS and 3.7 ton/y of PFOA with highest exported quantities from the Rhine (PFOS: 1.0 ton/y; PFOA: 1.0 ton/y) and Danube estuaries (PFOS: 0.9 ton/y; PFOA: 0.7 ton/y). For the seas where the rivers discharge, riverine discharge of PFOS was estimated to be 2.5-30 times more important as an input than atmospheric deposition, whereas for PFOA the opposite was true (atmospheric deposition was 2-10 times more important) except for very small seas.

A large-scale model for simulating the fate & transport of organic contaminants in river basins.

We present STREAM-EU (Spatially and Temporally Resolved Exposure Assessment Model for EUropean basins), a novel dynamic mass balance model for predicting the environmental fate of organic contaminants in river basins. STREAM-EU goes beyond the current state-of-the-science in that it can simulate spatially and temporally-resolved contaminant concentrations in all relevant environmental media (surface water, groundwater, snow, soil and sediments) at the river basin scale. The model can currently be applied to multiple organic contaminants in any river basin in Europe, but the model framework is adaptable to any river basin in any continent. We simulate the environmental fate of perfluoroctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in the Danube River basin and compare model predictions to recent monitoring data. The model predicts PFOS and PFOA concentrations that agree well with measured concentrations for large stretches of the river. Disagreements between the model predictions and measurements in some river sections are shown to be useful indicators of unknown contamination sources to the river basin.

Short-term foraging costs and long-term fueling rates in central-place foraging swans revealed by giving-up exploitation times.

Foragers tend to exploit patches to a lesser extent farther away from their central place. This has been interpreted as a response to increased risk of predation or increased metabolic costs of prey delivery. Here we show that migratory Bewick's swans (Cygnus columbianus bewickii), though not incurring greater predation risks farther out or delivering food to a central place, also feed for shorter periods at patches farther away from their roost. Predictions from an energy budget model suggest that increasing metabolic travel costs per se are responsible. Establishing the relation between intake rate and exploitation time enabled us to express giving-up exploitation times as quitting harvest rates (QHRs). This revealed that net QHRs were not different from observed long-term net intake rates, a sign that the birds were maximizing their long-term net intake rate. This study is unique because giving-up decisions were measured at the individual level, metabolic and predation costs were assessed simultaneously, the relation with harvest rate was made explicit, and finally, short-term giving-up decisions were related to long-term net intake rates. We discuss and conceptualize the implications of metabolic traveling costs for carrying-capacity predictions by bridging the gap between optimal-foraging theory and optimal-migration theory.

[A literature review of equine piroplasmosis after an episode of acute babesiosis in a Dutch Standardbred foal after a stay in Normandy]. / Een literatuuroverzicht van equine piroplasmose naar aanleiding van acute babesiose bij een Nederlands draverveulen na verblijfin Normandië.

Piroplasmosis, a disease endemic to most tropical and subtropical areas, appears to be spreading to more temperate zones. This article gives a review of equine piroplasmosis and describes an acute case of infection with Babesia caballi in a Dutch Standard bred foal after a short stay at a stud in Normandy (France). A 3-month-old stallion foal was presented with lethargy, fever of 41 degrees C, and pale mucosal membranes. Haematology revealed a low packed cell volume (14 l/l) leucytosis (25 G/l) and a high blood urea nitrogen concentration (20.1mmol/l). Infection with B. caballi was diagnosed on the basis of Giemsa staining blood smears and was confirmed by polymerase chain reaction in combination with RLB. Treatment with imidocarb dipropionate and a blood transfusion resolved the haemolytic crisis.

Changes of the nutrient loads of the Danube since the late eighties: An analysis based on long term changes along the whole Danube River and its main tributaries.

The Danube nutrient loads are affected by human impacts mainly from agriculture and wastewater discharges. Knowledge about the Danube nutrient loads and the changes of these loads over time is essential for understanding the changes within the ecosystem of the Black Sea, induced by these loads. The paper shows the long term changes of the nutrient load along the Danube estimated by measurements from different countries and institutions. The results show large differences between Dissolved Inorganic Nitrogen (DIN) and Total Phosphorus (TP). For TP, the Danube River loads show a strong decrease since 1988-1992, especially in the Middle and Lower basin. This change is probably partly connected to the dramatic economic changes in the Middle and Eastern European countries following the collapse of the communist system. The DIN load does not show a decreasing trend in the last decade. The data indicate that there may be a decreasing trend in the anthropogenic emissions, but that such a trend is counteracted by a significantly increasing trend of the Danube discharge in the last decade. The accuracy of the available data is analysed in the paper as well.

Nutrient fluxes from the Danube Basin to the Black Sea.

This paper deals with the state of the art of quantification of sources, pathways and sinks of nutrients in the Danube Basin and their transport from the catchment to the Black Sea. It shows main results of emission estimates to surface waters and the Danube Water Quality Model approach to link these emissions estimates to measured water monitoring data. The current paper provides a quantitative synthesis of available knowledge regarding the fate of nutrients in the Danube Basin. Even though many knowledge gaps existed, our understanding of the system has increased. As such, the paper provides a vehicle to carry the discussion one step beyond just complaining about how much we do not know yet.

The difficulty of height prediction in Weaver syndrome.

Accelerated growth and advanced bone age are consistent findings in Weaver-Smith syndrome (WSS). According to the rather scant reports in the literature, persons afflicted with WSS appear to achieve supranormal heights despite a significant bone age advancement in their growth period. The literature does not state clearly whether there is a discrepancy between bone age advancement and the time of onset of puberty in WSS. We report a girl with Weaver syndrome whose final height predictions were within normal limits according to the standard prediction models, who had to be eventually treated with high doses of estrogen in order to keep her final height within reasonable limits. We conclude that the pattern of growth and maturation in children with WSS may form an exception to the general rule that tall children with an advanced bone age mature early and thus attain a normal final height. A careful evaluation of growth data of other children with WSS is necessary to clarify this issue.

[Perinatal pertussis: from mother to child]. / Perinatale pertussis: van moeder naar kind.

Two infants, a girl, aged four weeks, and a boy, aged three weeks, came to our attention with poor feeding and weight loss. Later the typical cough of pertussis appeared. Serological testing confirmed that both patients' mothers had recently had pertussis. One mother suffered from severe and typical coughing periods even throughout labour. Despite the vaccination program in the Netherlands, each year new-born infants with pertussis require hospitalisation. Pertussis during the neonatal period is seldom described. Adults can suffer from pertussis, even when they have been vaccinated in childhood. They then become contagious for unvaccinated infants. Pertussis during the neonatal period is an insidious disease with sometimes severe complications. If pertussis is suspected in mothers with new-born infants or pregnant women towards the end of the pregnancy, they should be treated with antibiotics to prevent pertussis in the new-born infant.

Distribution of beta-endorphin-like-immunoreactive structures in the chicken and quail brain as demonstrated with a new homologous antibody directed against a synthetic peptide.

A polyclonal rabbit antibody was raised against a synthetic peptide fragment located at the C-terminal end of turkey beta-endorphin (beta-END) and used to analyze the distribution of beta-END-immunoreactive-like structures in the quail and chicken brain. Three major groups of immunopositive cells were detected in the preoptic area-hypothalamus complex. A thin layer of immunopositive cells was parallel and adjacent to the ventral edge of the brain in the preoptic and anterior hypothalamic region, a more numerous group of immunoreactive perikarya was located along the walls of the third ventricle in these same regions, and, finally, a few scattered cells were found in a more lateral position on both the internal and external sides of the tip of the fasciculus prosencephali lateralis. The periventricular cell population extended in the caudal direction until the posterior hypothalamus. Labelled fibers were always associated with these immunoreactive perikarya, and they were also found in the adjacent hypothalamic regions. A dense innervation of the median eminence was also detected. These data are compared with previous studies in mammals and birds that had identified more restricted populations of immunoreactive cells and the possible sources of the observed discrepancy are discussed. The functional significance of the present data is also briefly analyzed.

Immunocytochemical localization of L-dopa and dopamine in the brain of the chicken (Gallus domesticus).

A light microscopic immunocytochemical study, with antisera against dihydroxyphenylalanine (L-DOPA) and dopamine (DA), revealed the dopaergic and dopaminergic systems in the brain of the chicken (Gallus domesticus). L-DOPA- and DA-immunoreactive (ir) elements are similarly distributed throughout the entire brain. Virtually all regions of the brain contained a dense innervation by L-DOPA- and DA-immunopositive varicose fibers. The neuronal cell bodies immunoreactive for the two monoamines were confined to more restricted regions, the hypothalamus, the midbrain and the brainstem. In the hypothalamus, DA- and L-DOPA-ir neurons were subdivided into a medial periventricular and a lateral group. The medial group starts at the level of the anterior commissure, in the ventral part of the nucleus periventricularis hypothalami, and continues in a more dorsal periventricular position caudally into the dorsal tuberal hypothalamic region. Densely labeled cerebrospinal fluid contacting cells can be observed in the paraventricular organ. The lateral group consists of immunopositive neurons loosely arranged in the lateral hypothalamic area and in the nucleus mamillaris lateralis. Most of the dopaminergic cell groups, identified in the hypothalamus of mammals, could be observed in the chicken, with the exception of the tuberoinfundibular group. The majority of L-DOPA- and DA-ir perikarya is, however, situated in the mesencephalic tegmentum, in the area ventralis of Tsai and in the nucleus tegmenti pedunculo-pontinus, pars compacta, the avian homologues of, respectively, the ventral tegmental area and the substantia nigra of mammals. In the pons, dense groups of cells are found in the locus coeruleus and in the nucleus subcoeruleus ventralis and dorsalis. A few labeled cells appear in and around the nucleus olivaris superior in the most caudal part of the metencephalic tegmentum. In the medulla oblongata, L-DOPA- and DA-ir cells can be seen at the level of the nucleus of the solitary tract and in a ventrolateral complex. A comparison with tyrosine hydroxylase (TH) immunocytochemistry revealed TH-immunopositive neurons greatly outnumbering the cells exhibiting DA and L-DOPA immunoreactivity. These results are discussed in relation to catecholaminergic systems previously reported in avian species and in the mammalian brain.