Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations, however, data are lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype-phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were 288 with vesicoureteral reflux, 120 with renal hypodysplasia and 90 with unilateral renal agenesis. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children

Mineral Characterization of Soil Type Ranker Formed on Serpentines Occurring in Southern Belgrade Environs Bubanj Potok

The paper addresses the issue of health risk associated with the presence of chrysotile in the soil type ranker formed on massive serpentines occurring in the area of Bubanj Potok, a settlement located in the southern Belgrade environs, Serbia. Characterization of the ranker soil was conducted by scanning electron microscopy, X-ray diffraction, micro-Raman spectroscopy and transmission Fe-57 Mossbauer spectroscopy. Scanning electron microscopy figures showed regular shaped smectite (montmorillonite) particles, aggregates of chlorite, and elongated sheets of serpentines minerals antigorite. X-ray diffraction analysis confirmed the presence of detrital mineral quartz polymorph as well as minor amounts of other mineral species. Micro-Raman spectroscopy identified the presence of dominant minerals, such as montmorillonite, kaolinite, muscovite, gypsum, calcite, albite, amphiboles (hornblende/kaersutite) and orthoclase. Important polymorph silica modifications of quartz, olivine (forsterite), pyroxene (enstatite/ferrosilite, diopside/hedenbergite), and serpentine (antigorite/lizardite/chrysotile) were identified

Quantum interference of electromechanically stabilized emitters in nanophotonic devices

Photon-mediated coupling between distant matter qubits may enable secure communication over long distances, the implementation of distributed quantum computing schemes, and the exploration of new regimes of many-body quantum dynamics. Nanophotonic devices coupled to solid-state quantum emitters represent a promising approach towards realization of these goals, as they combine strong light-matter interaction and high photon collection efficiencies. However, the scalability of these approaches is limited by the frequency mismatch between solid-state emitters and the instability of their optical transitions. Here we present a nano-electromechanical platform for stabilization and tuning of optical transitions of silicon-vacancy (SiV) color centers in diamond nanophotonic devices by dynamically controlling their strain environments. This strain-based tuning scheme has sufficient range and bandwidth to alleviate the spectral mismatch between individual SiV centers. Using strain, we ensure overlap between color center optical transitions and observe an entangled superradiant state by measuring correlations of photons collected from the diamond waveguide. This platform for tuning spectrally stable color centers in nanophotonic waveguides and resonators constitutes an important step towards a scalable quantum network

Whole exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association

Schimke immunoosseous dysplasia: defining skeletal features

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

Brain activity changes associated with treadmill training after stroke.

BACKGROUND AND PURPOSE: The mechanisms underlying motor recovery after stroke are not fully understood. Several studies used functional MRI longitudinally to relate brain activity changes with performance gains of the upper limb after therapy, but research into training-induced recovery of lower limb function has been relatively neglected thus far. METHODS: We investigated functional reorganization after 4 weeks of treadmill training with partial body weight support in 18 chronic patients (mean age, 59.9+/-13.5 years) with mild to moderate paresis (Motricity Index affected leg: 77.7+/-10.5; range, 9 to 99) and gait impairment (Functional Ambulation Category: 4.4+/-0.6; range, 3 to 5) due to a single subcortical ischemic stroke using repeated 3.0-T functional MRI and an ankle-dorsiflexion paradigm. RESULTS: Walking endurance improved after training (2-minute timed walking distance: 121.5+/-39.0 versus pre: 105.1+/-38.1 m; P=0.0001). For active movement of the paretic foot versus rest, greater walking endurance correlated with increased brain activity in the bilateral primary sensorimotor cortices, the cingulate motor areas, and the caudate nuclei bilaterally and in the thalamus of the affected hemisphere. CONCLUSIONS: Despite the strong subcortical contributions to gait control, rehabilitation-associated walking improvements are associated with cortical activation changes. This is similar to findings in upper limb rehabilitation with some differences in the involved cortical areas. We observed bihemispheric activation increases with greater recovery both in cortical and subcortical regions with movement of the paretic foot. However, although the dorsal premotor cortex appears to play an important role in recovery of hand movements, evidence for the involvement of this region in lower extremity recovery was not found