Schwartz Formula: Is One k-Coefficient Adequate for All Children?

Background/Objective

Plasma-creatinine-based equations to estimate the glomerular filtration rate are recommended by several clinical guidelines. In 2009, Schwartz et al. adapted the traditional Schwartz equation to children and adolescents but did not find different k-coefficients between children and adolescents (k = 36.5 for all patients). We reevaluated the coefficient of the 2009-Schwartz formula according to sex and age in a pediatric population.

Patients/Methods

We used linear mixed-effects models to reestimate the 2009-Schwartz k-coefficient in 360 consecutive French subjects aged 1 to 18 years referred to a single centre between July 2003 and July 2010 (965 measurements). We assessed the agreement between the estimated glomerular filtration rate obtained with the new formula (called Schwartz-Lyon) and the rate measured by inulin clearance. We then compared this agreement to the one between the measured glomerular filtration rate and 2009-Schwartz formula, first in the French then in a Swedish cohort.

Results

In Schwartz-Lyon formula, k was estimated at 32.5 in boys <13 years and all girls and at 36.5 in boys aged ≥13 years. The performance of this formula was higher than that of 2009-Schwartz formula in children <13 years. This was first supported by a statistically significant reduction of the overestimation of the measured glomerular filtration rate in both cohorts, by better 10% and 30% accuracies, and by a better concordance correlation coefficient.

Conclusions

The performance and simplicity of Schwartz formula are strong arguments for its routine use in children and adolescents. The specific coefficient for children aged <13 years further improves this performance.     

Environmental niche patterns of native and non-native fishes within an invaded African river system

To test ecological niche theory, this study investigated the spatial patterns and the environmental niches of native and non-native fishes within the invaded Great Fish River system, South Africa. For the native fishes, there were contrasting environmental niche breadths that varied from being small to being large and overlapped for most species, except minnows that were restricted to headwater tributaries. In addition, there was high niche overlap in habitat association among fishes with similar distribution. It was therefore inferred that habitat filtering-driven spatial organisation was important in explaining native species distribution patterns. In comparison, most non-native fishes were found to have broad environmental niches and these fishes showed high tolerance to environmental conditions, which generally supported the niche opportunity hypothesis. The proliferation of multiple non-native fishes in the mainstem section suggest that they form a functional assemblage that is probably facilitated by the anthropogenic modification of flow regimes through inter-basin water transfer. Based on the distribution patterns observed in the study, it was inferred that there was a likelihood of negative interactions between native and non-native fishes. Such effects are likely to be exacerbated by altered flow regime that was likely to have negative implications for native ichthyofauna.     

Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse

The DNA damage-dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, homo- and heterodimerize and are both involved in the base excision repair (BER) pathway. Here, we report that mice carrying a targeted disruption of the PARP-2 gene are sensitive to ionizing radiation. Following alkylating agent treatment, parp-2(-/-)-derived mouse embryonic fibroblasts exhibit increased post-replicative genomic instability, G(2)/M accumulation and chromosome mis-segregation accompanying kinetochore defects. Moreover, parp-1(-/-)parp-2(-/-) double mutant mice are not viable and die at the onset of gastrulation, demonstrating that the expression of both PARP-1 and PARP-2 and/or DNA-dependent poly(ADP-ribosyl) ation is essential during early embryogenesis. Interestingly, specific female embryonic lethality is observed in parp-1(+/-)parp-2(-/-) mutants at E9.5. Meta phase analyses of E8.5 embryonic fibroblasts highlight a specific instability of the X chromosome in those females, but not in males. Together, these results support the notion that PARP-1 and PARP-2 possess both overlapping and non-redundant functions in the maintenance of genomic stability.     

Unexpected Relationships and Inbreeding in HapMap Phase III Populations

Correct annotation of the genetic relationships between samples is essential for population genomic studies, which could be biased by errors or omissions. To this end, we used identity-by-state (IBS) and identity-by-descent (IBD) methods to assess genetic relatedness of individuals within HapMap phase III data. We analyzed data from 1,397 individuals across 11 ethnic populations. Our results support previous studies (Pemberton et al., 2010; Kyriazopoulou-Panagiotopoulou et al., 2011) assessing unknown relatedness present within this population. Additionally, we present evidence for 1,657 novel pairwise relationships across 9 populations. Surprisingly, significant Cotterman''s coefficients of relatedness K1 (IBD1) values were detected between pairs of known parents. Furthermore, significant K2 (IBD2) values were detected in 32 previously annotated parent-child relationships. Consistent with a hypothesis of inbreeding, regions of homozygosity (ROH) were identified in the offspring of related parents, of which a subset overlapped those reported in previous studies (Gibson et al. 2010; Johnson et al. 2011). In total, we inferred 28 inbred individuals with ROH that overlapped areas of relatedness between the parents and/or IBD2 sharing at a different genomic locus between a child and a parent. Finally, 8 previously annotated parent-child relationships had unexpected K0 (IBD0) values (resulting from a chromosomal abnormality or genotype error), and 10 previously annotated second-degree relationships along with 38 other novel pairwise relationships had unexpected IBD2 (indicating two separate paths of recent ancestry). These newly described types of relatedness may impact the outcome of previous studies and should inform the design of future studies relying on the HapMap Phase III resource.     

Identification of mitogen-activated protein/extracellular signal-responsive kinase kinase 2 as a novel partner of the scaffolding protein human homolog of disc-large

Human disc-large homolog (hDlg), also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family, implicated in neuronal synapses and epithelial-epithelial cell junctions whose expression and function remains poorly characterized in most tissues, particularly in the vasculature. In human vascular tissues, hDlg is highly expressed in smooth muscle cells (VSMCs). Using the yeast two-hybrid system to screen a human aorta cDNA library, we identified mitogen-activated protein/extracellular signal-responsive kinase (ERK) kinase (MEK)2, a member of the ERK cascade, as an hDlg binding partner. Site-directed mutagenesis showed a major involvement of the PSD-95, disc-large, ZO-1 domain-2 of hDlg and the C-terminal sequence RTAV of MEK2 in this interaction. Coimmunoprecipitation assays in both human VSMCs and human embryonic kidney 293 cells, demonstrated that endogenous hDlg physically interacts with MEK2 but not with MEK1. Confocal microscopy suggested a colocalization of the two proteins at the inner layer of the plasma membrane of confluent human embryonic kidney 293 cells, and in a perinuclear area in human VSMCs. Additionally, hDlg also associates with the endoplasmic reticulum and microtubules in these latter cells. Taken together, these findings allow us to hypothesize that hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway, and may improve our understanding of how scaffold proteins, such as hDlg, differentially tune MEK1/MEK2 signaling and cell responses.     

Molecular classification of scrapie strains in mice using gene expression profiling

Transmissible spongiform encephalopathy strains demonstrate specific prion characteristics, each with specific incubation times, and strain-specific patterns of deposition of the misfolded isoform of prion, PrPSc, in the brains of infected individuals. Different biochemical properties, including glycosylation profiles and the degree of proteinase resistance, have been shown to be strain-specific. However, no relationship between these properties and the phenotypic differences in the subsequent diseases has as yet been determined. Here we explore the utility of gene expression profiles to identify differences in the host response to different strains of prion agent. We identify 114 genes that exhibit significantly different levels of expression in mice infected with three strains of scrapie. These genes represent a pool of genes involved in a strain-specific response to prion disease. We have identified the most discriminatory genes from this list utilizing a wrapper-based feature selection algorithm with external cross-validation.     

Effects of surfactin on membrane models displaying lipid phase separation

Surfactin, a bacterial amphiphilic lipopeptide is attracting more and more attention in view of its bioactive properties which are in relation with its ability to interact with lipids of biological membranes. In this work, we investigated the effect of surfactin on membrane structure using model of membranes, vesicles as well as supported bilayers, presenting coexistence of fluid-disordered (DOPC) and gel (DPPC) phases. A range of complementary methods was used including AFM, ellipsometry, dynamic light scattering, fluorescence measurements of Laurdan, DPH, calcein release, and octadecylrhodamine B dequenching. Our findings demonstrated that surfactin concentration is critical for its effect on the membrane. The results suggest that the presence of rigid domains can play an essential role in the first step of surfactin insertion and that surfactin interacts both with the membrane polar heads and the acyl chain region. A mechanism for the surfactin lipid membrane interaction, consisting of three sequential structural and morphological changes, is proposed. At concentrations below the CMC, surfactin inserted at the boundary between gel and fluid lipid domains, inhibited phase separation and stiffened the bilayer without global morphological change of liposomes. At concentrations close to CMC, surfactin solubilized the fluid phospholipid phase and increased order in the remainder of the lipid bilayer. At higher surfactin concentrations, both the fluid and the rigid bilayer structures were dissolved into mixed micelles and other structures presenting a wide size distribution.     

Genome-wide hypomethylation in cancer may be a passive consequence of transformation

Epigenetics describes the study of stable, reversible alterations to the genome that affect gene expression and genome function, the most studied mechanisms are DNA methylation and histone modifications. Over recent years there has been rapid progress to elucidate the nature and role of the mechanisms involved in promoter hypermethylation during carcinogenesis, however, the mechanism behind one of the earliest epigenetic observations in cancer, genome-wide hypomethylation, remains unclear. Current evidence is divided between the hypotheses that hypomethylation is either an important early cancer-causing aberration or that it is a passive inconsequential side effect of carcinogenesis. With recent discoveries of gene–body methylation, fast cyclic methylation of hormone dependent genes and candidate proteins involved in DNA demethylation elucidation of the role of hypomethylation and the mechanism behind it appears ever closer. With the burgeoning use of DNA methyltransferase inhibitors as a cancer therapy there is an increased need to understand the mechanisms and importance of genome-wide hypomethylation in cancer. This review will discuss the timing and potential causes of genomic hypomethylation during carcinogenesis and will propose a way forward to understand the underlying mechanisms.     

ABCG transporters export cutin precursors for the formation of the plant cuticle

1. Download : Download high-res image (193KB)
2. Download : Download full-size image