Normal values of signal-averaged electrocardiographic parameters and QT dispersion in infants and children

Ventricular late potentials, and dispersion of the QT interval, are markers for risk of ventricular arrhythmias. Normal values for these parameters are well established in adults, but may not apply for children. This study has investigated the age dependency of signal averaged electrocardiographic parameters and QT dispersion in 111 normal children aged from 5 days to 16 years. The results indicate that parameters change with age: duration of filtered QRS and low amplitude (< 40 μV) terminal signal increase with age, especially in the younger patients. Filtered QRS is 88.9 ± 7.87 ms in infants, and increases to 108.7 ± 8.51 in teenagers (p<0.001). Low amplitude terminal signals are 17.0 ± 3.44 ms in infants, and 24.5 ± 5.64 ms in teenagers (p< 0.001). Root mean square of the last 40 ms decreases with age, but remains stable after the age of 10 years (122.4 ± 33.30 μV in infants, 60.9 ± 31.27 in teenagers,p<0.001). QT dispersion, on the other hand, does not change significantly with age. The mean value for the whole group is 36 ± 13.7 ms. A weak but significant correlation exists between QT dispersion and filtered QRS. Thus, age must be taken into consideration when interpreting signal-averaged electrocardiograms, but not when measuring QT dispersio

Characterization of mouse Dactylaplasia mutations: a model for human ectrodactyly SHFM3

SHFM3 is a limb malformation characterized by the absence of central digits. It has been shown that this condition is associated with tandem duplications of about 500 kb at 10q24. The Dactylaplasia mice display equivalent limb defects and the two corresponding alleles (Dac 1j and Dac 2j ) map in the region syntenic with the duplications in SHFM3. Dac 1j was shown to be associated with an insertion of an unspecified ETn-like mouse endogenous transposon upstream of the Fbxw4 gene. Dac 2j was also thought to be an insertion or a small inversion in intron 5 of Fbxw4, but the breakpoints and the exact molecular lesion have not yet been characterized. Here we report precise mapping and characterization of these alleles. We failed to identify any copy number differences within the SHFM3 orthologous genomic locus between Dac mutant and wild-type littermates, showing that the Dactylaplasia alleles are not associated with duplications of the region, in contrast with the described human SHFM3 cases. We further show that both Dac 1j and Dac 2j are caused by insertions of MusD retroelements that share 98% sequence identity. The differences between the nature of the human and mouse genomic abnormalities argue against models proposed so far that either envisioned SHFM3 as a local trisomy or Dac as a mutant allele of Fbxw4. Instead, both genetic conditions might lead to complex alterations of gene regulation mechanisms that would impair limb morphogenesis. Interestingly, the Dac 2j mutation occurs within a highly conserved element that may represent a regulatory sequence for a neighboring gen

Spiral Galaxies with HST/NICMOS. I. Nuclear Morphologies, Color Maps and Distinct Nuclei

This is the first of two papers where we present the analysis of an HST NICMOS-Cam2 near-infared (NIR) snapshot survey in the F160W (H) filter for a sample of 78 spiral galaxies selected from the UGC and ESOLV catalogs. For 69 of these objects we provide nuclear color information derived by combining the H data either with additional NICMOS F110W (J) images or with V WFPC2/HST data. Here we present the NIR images and the optical-NIR color maps. We focus our attention on the properties of the photometrically-distinct `nuclei' which are found embedded in most of the galaxies, and provide measurements of their half-light radii and magnitudes in the H (and when available, in the J) band. We find that: (i) In the NIR, the nuclei embedded in the bright early- to intermediate-type galaxies span a much larger range in brightness than the nuclei which are typically found embedded in bulgeless late-type disks; (ii) Nuclei are found in both non-barred and barred hosts, in large-scale (\gta 1 kpc) as well as in nuclear (up to a few 100pc) bars; (iii) There is a significant increase in half-light radius with increasing luminosity of the nucleus in the early/intermediate types; (iv) The nuclei of early/intermediate-type spirals cover a large range of optical-NIR colors, from $V-H\approx$ -0.5 to 3. Some nuclei are bluer and others redder than the surrounding galaxy, indicating the presence of activity or reddening by dust in many of these systems; (v) Some early/intermediate nuclei are elongated and/or slightly offset from the isophotal center of the host galaxy. On average, however, these nuclei appear as centered, star-cluster-like structures similar to those which are found in the late-type disks. [abridged]Comment: Astronomical Journal, accepted, January 2002 Issue; higher-res Figs 1, 2 and 9 available upon reques

Human Hepatocyte-Derived Induced Pluripotent Stem Cells: MYC Expression, Similarities to Human Germ Cell Tumors, and Safety Issues

Induced pluripotent stem cells (iPSC) are a most promising approach to the development of a hepatocyte transplantable mass sufficient to induce long-term correction of inherited liver metabolic diseases, thus avoiding liver transplantation. Their intrinsic self-renewal ability and potential to differentiate into any of the three germ layers identify iPSC as the most promising cell-based therapeutics, but also as drivers of tumor development. Teratoma development currently represents the gold standard to assess iPSC pluripotency. We analyzed the tumorigenic potential of iPSC generated from human hepatocytes (HEP-iPSC) and compared their immunohistochemical profiles to that of tumors developed from fibroblast and hematopoietic stem cell-derived iPSC. HEP-iPSC generated tumors significantly presented more malignant morphological features than reprogrammed fibroblasts or CD34+ iPSC. Moreover, the protooncogene myc showed the strongest expression in HEP-iPSC, compared to only faint expression in the other cell subsets. Random integration of transgenes and the use of potent protooncogenes such as myc might be a risk factor for malignant tumor development if hepatocytes are used for reprogramming. Nonviral vector delivery systems or reprogramming of cells obtained from less invasive harvesting methods would represent interesting options for future developments in stemcell-based approaches for liver metabolic diseases

Chromosome Conformation Capture Uncovers Potential Genome-Wide Interactions between Human Conserved Non-Coding Sequences

Comparative analyses of various mammalian genomes have identified numerous conserved non-coding (CNC) DNA elements that display striking conservation among species, suggesting that they have maintained specific functions throughout evolution. CNC function remains poorly understood, although recent studies have identified a role in gene regulation. We hypothesized that the identification of genomic loci that interact physically with CNCs would provide information on their functions. We have used circular chromosome conformation capture (4C) to characterize interactions of 10 CNCs from human chromosome 21 in K562 cells. The data provide evidence that CNCs are capable of interacting with loci that are enriched for CNCs. The number of trans interactions varies among CNCs; some show interactions with many loci, while others interact with few. Some of the tested CNCs are capable of driving the expression of a reporter gene in the mouse embryo, and associate with the oligodendrocyte genes OLIG1 and OLIG2. Our results underscore the power of chromosome conformation capture for the identification of targets of functional DNA elements and raise the possibility that CNCs exert their functions by physical association with defined genomic regions enriched in CNCs. These CNC-CNC interactions may in part explain their stringent conservation as a group of regulatory sequences

Human Hepatocyte-Derived Induced Pluripotent Stem Cells: MYC Expression, Similarities to Human Germ Cell Tumors, and Safety Issues

Induced pluripotent stem cells (iPSC) are a most promising approach to the development of a hepatocyte transplantable mass sufficient to induce long-term correction of inherited liver metabolic diseases, thus avoiding liver transplantation. Their intrinsic self-renewal ability and potential to differentiate into any of the three germ layers identify iPSC as the most promising cell-based therapeutics, but also as drivers of tumor development. Teratoma development currently represents the gold standard to assess iPSC pluripotency. We analyzed the tumorigenic potential of iPSC generated from human hepatocytes (HEP-iPSC) and compared their immunohistochemical profiles to that of tumors developed from fibroblast and hematopoietic stem cell-derived iPSC. HEP-iPSC generated tumors significantly presented more malignant morphological features than reprogrammed fibroblasts or CD34+ iPSC. Moreover, the protooncogene myc showed the strongest expression in HEP-iPSC, compared to only faint expression in the other cell subsets. Random integration of transgenes and the use of potent protooncogenes such as myc might be a risk factor for malignant tumor development if hepatocytes are used for reprogramming. Nonviral vector delivery systems or reprogramming of cells obtained from less invasive harvesting methods would represent interesting options for future developments in stem cell-based approaches for liver metabolic diseases

PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis.

T helper 9 (TH9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in TH9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in TH cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human TH9 cells

Pharmacological induction of a progenitor state for the efficient expansion of primary human hepatocytes

The liver is an organ with strong regenerative capacity, yet primary hepatocytes have a low amplification potential in vitro, a major limitation for the cell-based therapy of liver disorders and for ex vivo biological screens. Induced pluripotent stem cells (iPSCs) may help to circumvent this obstacle but often harbor genetic and epigenetic abnormalities, limiting their potential. Here, we describe the pharmacological induction of proliferative human hepatic progenitor cells (HPCs) through a cocktail of growth factors and small molecules mimicking the signaling events involved in liver regeneration. Human HPCs from healthy donors and pediatric patients proliferated vigorously while maintaining their genomic stability and could be redifferentiated in vitro into metabolically competent cells that supported the replication of hepatitis B and delta viruses. Redifferentiation efficiency was boosted by three-dimensional culture. Finally, transcriptome analysis showed that HPCs were more closely related to mature hepatocytes than iPSC-derived hepatocyte-like cells were. Conclusion: HPC induction holds promise for a variety of applications such as ex vivo disease modeling, personalized drug testing or metabolic studies, and development of a bioartificial liver