Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective.

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Performance of diagnostic ultrasound to identify causes of hydramnios.

INTRODUCTION: We aimed to assess the diagnostic yield of ultrasonography in the identification of the etiology of hydramnios, and the added value of MRI or amniocentesis. METHODS: We conducted a single-center retrospective study including pregnancies with confirmed hydramnios (defined as deepest pocket ≥8 cm) between January 2013 and May 2017. Twin pregnancies, secondary hydramnios discovered after the diagnosis of a causal pathology, and pregnancies of unknown outcome were excluded. All pregnancies underwent a targeted scan, and selected cases underwent MRI or amniocentesis. RESULTS: A total of 158 patients with confirmed hydramnios were included. Hydramnios was associated with a fetal pathology in 37 cases (23.4%), with diabetes in 39 (24.6%), isolated macrosomia in 16 (10.1%), and considered idiopathic in 66 (41.7%). Ultrasonography established a diagnosis of the underlying pathology in 73% of cases. Amniocentesis was done in 31 cases (20%) and it allowed diagnosis of chromosome anomalies, esophageal atresia, myotonic dystrophy congenital type, Prader-Willi syndrome, and Bartter syndrome. MRI was done in 15 cases (10%) and it allowed one additional diagnosis of esophageal atresia. The diagnostic yields of MRI and amniocentesis were 91.7% and 95.2%, respectively. There were five false positive diagnoses at ultrasonography, and one false positive diagnosis at MRI. CONCLUSION: Hydramnios can be associated with a wide variety of underlying pathologies. Diagnostic ultrasound can attain a diagnosis in the majority of cases. Amniocentesis offers a valuable complementary assessment.

Population-specific dynamics and selection patterns of transposable element insertions in European natural populations.

Transposable elements (TEs) are ubiquitous sequences in genomes of virtually all species. While TEs have been investigated for several decades, only recently we have the opportunity to study their genome-wide population dynamics. Most of the studies so far have been restricted either to the analysis of the insertions annotated in the reference genome or to the analysis of a limited number of populations. Taking advantage of the European Drosophila population genomics consortium (DrosEU) sequencing data set, we have identified and measured the dynamics of TEs in a large sample of European Drosophila melanogaster natural populations. We showed that the mobilome landscape is population-specific and highly diverse depending on the TE family. In contrast with previous studies based on SNP variants, no geographical structure was observed for TE abundance or TE divergence in European populations. We further identified de novo individual insertions using two available programs and, as expected, most of the insertions were present at low frequencies. Nevertheless, we identified a subset of TEs present at high frequencies and located in genomic regions with a high recombination rate. These TEs are candidates for being the target of positive selection, although neutral processes should be discarded before reaching any conclusion on the type of selection acting on them. Finally, parallel patterns of association between the frequency of TE insertions and several geographical and temporal variables were found between European and North American populations, suggesting that TEs can be potentially implicated in the adaptation of populations across continents.

TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia.

OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.

Insights for integrated conservation from attitudes of people toward protected areas near Hwange National Park, Zimbabwe.

Increase in human settlements at the edge of protected areas (PAs) is perceived as a major threat to conservation of biodiversity. Although it is crucial to integrate the interests of surrounding communities into PA management, key drivers of changes in local populations and the effects of conservation on local livelihoods and perceptions remain poorly understood. We assessed population changes from 1990 to 2010 in 9 villages located between 2 PAs with different management policies (access to natural resources or not). We conducted semi-directive interviews at the household level (n =217) to document reasons for settlement in the area and villager's attitudes toward the PAs. We examined drivers of these attitudes relative to household typology, feelings about conservation, and concerns for the future with mixed linear models. Population increased by 61% from 2000 to 2010, a period of political and economic crisis in Zimbabwe. Forty-seven percent of immigrants were attracted by the area; others had been resettled from other villages or were returning to family lands. Attitudes toward PAs were generally positive, but immigrants attracted by the area and who used resources within the PA with fewer restrictions expressed more negative attitudes toward PAs. Household location, losses due to wild animals, and restrictions on access to natural resources were the main drivers of this negative attitude. Profit-seeking migrants did not expect these constraints and were particularly concerned with local overpopulation and access to natural resources. To avoid socio-ecological traps near PAs (i.e., unforeseen reduced adaptive capacity) integrated conservation should address mismatches between management policy and local expectations. This requires accounting for endogenous processes, for example, local socio-ecological dynamics and values that shape the coexistence between humans and wildlife.

Morphometric variance, evolutionary constraints and their change through time in Late Devonian Palmatolepis conodonts.

Phenotypic variation is the raw material of evolution. Standing variation can facilitate response to selection along "lines of least evolutionary resistance", but selection itself might alter the structure of the variance. Shape was quantified using 2D geometric morphometrics in Palmatolepis conodonts through the Late Devonian period. Patterns of variance were characterized along the record by the variance-covariance matrix (P-matrix) and its first axis (Pmax). The Late Frasnian was marked by environmental oscillations culminating with the Frasnian/Famennian mass extinction. A shape response was associated with these fluctuations, together with a deflection of the Pmax and the P-matrix. Thereafter, along the Famennian, Palmatolepis mean shape shifted from broad elements with a large platform to slender elements devoid of platform. This shift in shape was associated with a reorientation of Pmax and the P-matrix, due to profound changes in the functioning of the elements selecting for new types of variants. Both cases provide empirical evidences that moving adaptive optimum can reorient phenotypic variation, boosting response to environmental changes. On such time scales, the question seems thus not to be whether the P-matrix is stable, but how it is varying in response to changes in selection regimes and shifts in adaptive optimum.

Heat exposure and socio-economic vulnerability as synergistic factors in heat-wave-related mortality.

Heat waves may become a serious threat to the health and safety of people who currently live in temperate climates. It was therefore of interest to investigate whether more deprived populations are more vulnerable to heat waves. In order to address the question on a fine geographical scale, the spatial heterogeneity of the excess mortality in France associated with the European heat wave of August 2003 was analysed. A deprivation index and a heat exposure index were used jointly to describe the heterogeneity on the Canton scale (3,706 spatial units). During the heat wave period, the heat exposure index explained 68% of the extra-Poisson spatial variability of the heat wave mortality ratios. The heat exposure index was greater in the most urbanized areas. For the three upper quintiles of heat exposure in the densely populated Paris area, excess mortality rates were twofold higher in the most deprived Cantons (about 20 excess deaths/100,000 people/day) than in the least deprived Cantons (about 10 excess deaths/100,000 people/day). No such interaction was observed for the rest of France, which was less exposed to heat and less heterogeneous in terms of deprivation. Although a marked increase in mortality was associated with heat wave exposure for all degrees of deprivation, deprivation appears to be a vulnerability factor with respect to heat-wave-associated mortality.

Short-term effects of using verbal instructions and demonstration at the beginning of learning a complex skill in figure skating.

This study examined whether providing verbal instructions plus demonstration and task repetition facilitates the early acquisition of a sport skill for which learners had a prior knowledge of the individual motor components. After one demonstration of the task by an expert, 18 novice skaters practiced a figure skating jump during a 15-min. period. Subjects were randomly assigned to one of 3 groups: a group provided with a verbal instruction that specified the subgoals of the task (Subgoals group), a group provided with a verbal instruction that used a metaphor (Metaphoric group), and a group not receiving any specific instruction during training (Control group). Subjects were filmed prior to and immediately following the practice session. Analysis indicated that the modifications of performance were related to the demonstration and the subsequent task repetitions only. Providing additional verbal instructions generated no effect. Therefore, guiding the learner toward a solution to the task problem by means of verbal instruction seems to be ineffective if done too early in the course of learning.

What a validation strategy means for the quantitation of cocaine and heroin?

A method of separation by gas chromatography with a flame ionisation detector was developed for quantifying cocaine and heroin in powders seized by law enforcement. The method was validated by studying parameters of calibration, trueness, precision based on trueness error (or systematic bias) and random error. Total error, which is the combination of these errors, verified its adequacy with the objectives fixed by the analyst. Accuracy profile proved to be an efficient decision tool for that purpose. Results obtained with weighted regression model were analysed and allowed to conclude that the method enables quantitation of heroin and cocaine in powders on 2-100% concentration (w/w) range with acceptance limits fixed at 10% and a risk at 5%. The possible sources of uncertainty were evaluated and measurement of their contribution was integrated. The combined standard uncertainty and expanded uncertainty were determined.

Once upon Multivariate Analyses: When They Tell Several Stories about Biological Evolution.

Geometric morphometrics aims to characterize of the geometry of complex traits. It is therefore by essence multivariate. The most popular methods to investigate patterns of differentiation in this context are (1) the Principal Component Analysis (PCA), which is an eigenvalue decomposition of the total variance-covariance matrix among all specimens; (2) the Canonical Variate Analysis (CVA, a.k.a. linear discriminant analysis (LDA) for more than two groups), which aims at separating the groups by maximizing the between-group to within-group variance ratio; (3) the between-group PCA (bgPCA) which investigates patterns of between-group variation, without standardizing by the within-group variance. Standardizing within-group variance, as performed in the CVA, distorts the relationships among groups, an effect that is particularly strong if the variance is similarly oriented in a comparable way in all groups. Such shared direction of main morphological variance may occur and have a biological meaning, for instance corresponding to the most frequent standing genetic variation in a population. Here we undertake a case study of the evolution of house mouse molar shape across various islands, based on the real dataset and simulations. We investigated how patterns of main variance influence the depiction of among-group differentiation according to the interpretation of the PCA, bgPCA and CVA. Without arguing about a method performing 'better' than another, it rather emerges that working on the total or between-group variance (PCA and bgPCA) will tend to put the focus on the role of direction of main variance as line of least resistance to evolution. Standardizing by the within-group variance (CVA), by dampening the expression of this line of least resistance, has the potential to reveal other relevant patterns of differentiation that may otherwise be blurred.

Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD.

BACKGROUND AND OBJECTIVES: Hyperkalemia affects up to 10% of patients with CKD. Sodium polystyrene sulfonate has long been prescribed for this condition, although evidence is lacking on its efficacy for the treatment of mild hyperkalemia over several days. This study aimed to evaluate the efficacy of sodium polystyrene sulfonate in the treatment of mild hyperkalemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 33 outpatients with CKD and mild hyperkalemia (5.0-5.9 mEq/L) in a single teaching hospital were included in this double-blind randomized clinical trial. We randomly assigned these patients to receive either placebo or sodium polystyrene sulfonate of 30 g orally one time per day for 7 days. The primary outcome was the comparison between study groups of the mean difference of serum potassium levels between the day after the last dose of treatment and baseline. RESULTS: The mean duration of treatment was 6.9 days. Sodium polystyrene sulfonate was superior to placebo in the reduction of serum potassium levels (mean difference between groups, -1.04 mEq/L; 95% confidence interval, -1.37 to -0.71). A higher proportion of patients in the sodium polystyrene sulfonate group attained normokalemia at the end of their treatment compared with those in the placebo group, but the difference did not reach statistical significance (73% versus 38%; P=0.07). There was a trend toward higher rates of electrolytic disturbances and an increase in gastrointestinal side effects in the group receiving sodium polystyrene sulfonate. CONCLUSIONS: Sodium polystyrene sulfonate was superior to placebo in reducing serum potassium over 7 days in patients with mild hyperkalemia and CKD.

Relationships of motor performance of adult men to anthropometry: A multivariate analysis.

Relationships between 12 anthropometric characteristics and motor performance, as measured by various fitness tests, were considered in a sample of 165 Flemish adults observed at age 30 years. In addition to a bivariate correlation study, a canonical correlation analysis was carried out. More than 72% of the variance was shared by the first three canonical variables. The first canonical variable can be explained as a general size function. Static and functional strength are clearly related to this function. The second canonical variable can be interpreted as a size-fatness function. Nearly all motor tests are projected on the second composite, indicating that in adult men, subcutaneous fatness is negatively related to physical fitness. By means of a biplot of the first two canonical variables, interrelationships between body dimensions and motor performance are clarified. A combination of the first two functions seems to provide information about physique. © 1993 Wiley-Liss, Inc.

Analysis of positive control STR experiments reveals that results obtained for FGA, D3S1358, and D13S317 condition the success rate of the analysis of routine reference samples.

About 120,000 reference samples are analyzed each year in the Forensic Laboratory of Lyon. A total of 1640 positive control experiments used to validate and optimize the analytical method in the routine process were submitted to a multivariate exploratory data analysis approach with the aim of better understanding the underlying sources of variability. The peak heights of the 16 genetic markers targeted by the AmpFℓSTR(®) Identifiler(®) STR kit were used as variables of interest. Six different 3130xl genetic analyzers located in the same controlled environment were involved. Two major sources of variability were found: (i) the DNA load of the sample modulates all peak heights in a similar way so that the 16 markers are highly correlated, (ii) the genetic analyzer used with a locus-specific response for peak height and a better sensitivity for the most recently acquired. Three markers (FGA, D3S1358, and D13S317) were found to be of special interest to predict the success rate observed in the routine process.

A new technique for analysing interacting factors affecting biodiversity patterns: crossed-DPCoA.

We developed an approach for analysing the effects of two crossed factors A and B on the functional, taxonomic or phylogenetic composition of communities. The methodology, known as crossed-DPCoA, defines a space where species, communities and the levels of the two factors are organised as a set of points. In this space, the Euclidean distance between two species-specific points is a measure of the (functional, taxonomic or phylogenetic) dissimilarity. The communities are positioned at the centroid of their constitutive species; and the levels of two factors at the centroid of the communities associated with them. We develop two versions for crossed-DPCoA, the first one moves the levels of factor B to the centre of the space and analyses the axes of highest variance in the coordinates of the levels of factor A. It is related to previous ordination approaches such as partial canonical correspondence analysis and partial non-symmetrical correspondence analysis. The second version projects all points on the orthogonal complement of the space generated by the principal axes of factor B. This second version should be preferred when there is an a priori suspicion that factor A and B are associated. We apply the two versions of crossed-DPCoA to analyse the phylogenetic composition of Central European and Mediterranean bird communities. Applying crossed-DPCoA on bird communities supports the hypothesis that allopatric speciation processes during the Quaternary occurred in open and patchily distributed landscapes, while the lack of geographic barriers to dispersal among forest habitats may explain the homogeneity of forest bird communities over the whole western Palaearctic. Generalizing several ordination analyses commonly used in ecology, crossed-DPCoA provides an approach for analysing the effects of crossed factors on functional, taxonomic and phylogenetic diversity, environmental and geographic structure of species niches, and more broadly the role of genetics on population structures.

Estimating the number of contributors to forensic DNA mixtures: does maximum likelihood perform better than maximum allele count?

Determining the number of contributors to a forensic DNA mixture using maximum allele count is a common practice in many forensic laboratories. In this paper, we compare this method to a maximum likelihood estimator, previously proposed by Egeland et al., that we extend to the cases of multiallelic loci and population subdivision. We compared both methods' efficiency for identifying mixtures of two to five individuals in the case of uncertainty about the population allele frequencies and partial profiles. The proportion of correctly resolved mixtures was >90% for both estimators for two- and three-person mixtures, while likelihood maximization yielded success rates 2- to 15-fold higher for four- and five-person mixtures. Comparable results were obtained in the cases of uncertain allele frequencies and partial profiles. Our results support the use of the maximum likelihood estimator to report the number of contributors when dealing with complex DNA mixtures.

Consensus genetic structuring and typological value of markers using multiple co-inertia analysis.

Working with weakly congruent markers means that consensus genetic structuring of populations requires methods explicitly devoted to this purpose. The method, which is presented here, belongs to the multivariate analyses. This method consists of different steps. First, single-marker analyses were performed using a version of principal component analysis, which is designed for allelic frequencies (%PCA). Drawing confidence ellipses around the population positions enhances %PCA plots. Second, a multiple co-inertia analysis (MCOA) was performed, which reveals the common features of single-marker analyses, builds a reference structure and makes it possible to compare single-marker structures with this reference through graphical tools. Finally, a typological value is provided for each marker. The typological value measures the efficiency of a marker to structure populations in the same way as other markers. In this study, we evaluate the interest and the efficiency of this method applied to a European and African bovine microsatellite data set. The typological value differs among markers, indicating that some markers are more efficient in displaying a consensus typology than others. Moreover, efficient markers in one collection of populations do not remain efficient in others. The number of markers used in a study is not a sufficient criterion to judge its reliability. "Quantity is not quality".