Risk of cardio-respiratory abnormalities in preterm infants placed in car seats: a cross-sectional study

BACKGROUND: Little is known about the factors that predispose to the occurrence and severity of cardio-respiratory symptoms during the placement of a prematurely born infant in a car seat. The impact of gestational age, weight at discharge and infant's pre-existing cardio-respiratory status (in the supine position) on cardio-respiratory function during pre-discharge testing in a car seat (semi-upright position) has not been investigated. METHODS: The cardio-respiratory function of 42 preterm neonates with gestational age 24 to 35 weeks and discharge weight 1790 to 2570 grams were monitored for 45 minutes before, during, and after placement in a car seat. The occurrence of periodic breathing, apnea, bradycardia, or decreased oxygen saturation (SaO2) was analyzed. RESULTS: Prior to the car seat testing, 15 (35.7%) infants displayed one or more abnormalities of cardio-respiratory function. During the car seat testing, 25 (59.6%) infants had periodic breathing, 33 (78.2%) had oxygen saturation <90%, 14 (33.3%) had bradycardia less than 80 beats per minute, and 35 (83.3%) had a combination of these symptoms. Infants, both with and without pre-existing cardio-respiratory abnormalities, had an almost equal probability (80% vs. 83.3%) for the development of cardio-respiratory symptoms during placement in the car seat. Weight at discharge ([less than or equal to] 2,000 grams) but not the gestational age (<28 weeks or [greater than or equal to] 28<37 weeks), was associated with either increased episodes of oxygen desaturation or the combination of cardio-respiratory symptoms that were seen during the placement of these infants in the car seat. Repositioning from the car seat to the supine position showed normalization of cardio-respiratory function in the majority (83%) of the tested infants. None of the tested clinical factors were associated with the severity of the cardio-respiratory symptoms. CONCLUSION: Pre-discharge testing of the cardio-respiratory function of preterm infants during placement in a car seat is important for the prevention of cardio-respiratory symptoms during their transportation. However, the high risk for developing cardio-respiratory symptoms will require the consideration of an alternative mode of safe home transportation for preterm infants; especially those with a discharge weight less than 2,000 grams

Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells

Peer reviewedPublisher PD

A Novel Chemically Differentiated Mouse Embryonic Stem Cell-Based Model to Study Liver Stages of Plasmodium berghei.

Asymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated in-vitro-differentiated human hepatocyte-like cells (iHLCs) to study LS of P. berghei and found it to be a sub-optimal infection model. Overall, our results present a new mouse ESC-based P. berghei LS infection model that can be utilized to study the impact of host genetic variation on parasite development

A Novel Chemically Differentiated Mouse Embryonic Stem Cell-Based Model to Study Liver Stages of Plasmodium berghei.

Asymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated in-vitro-differentiated human hepatocyte-like cells (iHLCs) to study LS of P. berghei and found it to be a sub-optimal infection model. Overall, our results present a new mouse ESC-based P. berghei LS infection model that can be utilized to study the impact of host genetic variation on parasite development

Comparison of Wolbachia Bacterial Density in Females of Four Thelythokous Strains of Trichogramma cordubensis and T. evanescens (Hymenoptera, Trichogrammatidae)

The endosymbionts of the genus Wolbachia infect numerous arthropods and nematods, and often cause different effects on the reproduction of these hosts. The endosymbiotic bacteria Wolbachia induces the thelytokous mode of reproduction in the egg parasitoids of the genus Trichogramma. The Dot-blot technique was performed to compare the symbiont Wolbachia density using the wsp gene of Wolbachia and the 18S gene of Trichogramma. It was established that Wolbachia density is not different in two host species, Trichogramma cordubensis Vargas et Cabello and T. evanescens Haliday.Эндосимбиотические бактерии рода Wolbachia заражают различных артропод и нематод, оказывая различный эффект на их репродуктивные особенности. Бактерии рода Wolbachia вызывают телитокию у яйцеедов рода Trichogramma. Использована техника Dot-blot для сравнения плотности симбионта Wolbachia, с помощью выделения гена wsp у симбионта Wolbachia и гена 18S у Trichogramma. Экспериментально установлено, что плотность Wolbachia у двух видов, Trichogramma cordubensis Vargas et Cabello и T. evanescens Haliday, одинаковая

Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells.

Non-CG methylation is an unexplored epigenetic hallmark of pluripotent stem cells. Here we report that a reduction in non-CG methylation is associated with impaired differentiation capacity into endodermal lineages. Genome-wide analysis of 2,670 non-CG sites in a discovery cohort of 25 phenotyped human induced pluripotent stem cell (hiPSC) lines revealed unidirectional loss (Δβ=13%, P<7.4 × 10(-4)) of non-CG methylation that correctly identifies endodermal differentiation capacity in 23 out of 25 (92%) hiPSC lines. Translation into a simplified assay of only nine non-CG sites maintains predictive power in the discovery cohort (Δβ=23%, P<9.1 × 10(-6)) and correctly identifies endodermal differentiation capacity in nine out of ten pluripotent stem cell lines in an independent replication cohort consisting of hiPSCs reprogrammed from different cell types and different delivery systems, as well as human embryonic stem cell (hESC) lines. This finding infers non-CG methylation at these sites as a biomarker when assessing endodermal differentiation capacity as a readout.We thank Kerra Pearce (UCL Genomics) for array processing, and Tim Fell and Jonathan Best (CellCentric), Jason Wray (UCL) and Rosemary Drake (TAP Biosystems) for discussions. We also thank Minal Patel, Chris Kirton, Anja Kolb-Kokocinski, Willem H. Ouwehand, Richard Durbin and Fiona M. Watt on behalf of the Human Induced Pluripotent Stem Cell Initiative (HipSci) funded by grant WT098503 from the Wellcome Trust and the Medical Research Council, for sharing data and materials. This work was supported in part by a TSB/EPSRC grant (TS/H000933/1). The Vallier lab is supported by the Cambridge Hospitals National Institute for Health Research Biomedical Research Center and an ERC Starting Grant (Relieve IMDS). F.A.C.S. is funded by a PhD studentship from Fundação para a Ciência e a Tecnologia (SFRH/BD/69033/2010). The Ferguson-Smith lab is supported by grants from the MRC and Wellcome Trust, and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510). The Beck lab is supported by the Wellcome Trust (084071), a Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1045

Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark.

Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin-SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs.We thank Andrew Knights for the technical support and helpful discussion, and the Wellcome-Trust Sanger Institute Microarray and Next-Generation Sequencing facilities for the technical support. We also thank the Sanger Institute Mouse Genetics Projects for mouse production and genotyping. This work was supported by the European Research Council starting grant Relieve-IMDs and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre (L.V.), a British Heart Foundation Ph.D. Studentship (A.B.), a Federation of European Biochemical Societies (FEBS) long-term fellowship and EU Fp7 grant InnovaLIV (S.P.), EU Fp7 grant TissuGEN (S.M.), and Wellcome Trust grant 098051 (D.G.). A.B. conceived the research, performed and analyzed the experiments, and wrote the manuscript. P.M. computationally analyzed ChIP-seq data sets and performed statistical analyses. N.C.H., S.B., and R.A.P. provided technical support. A.G. performed embryo dissections and dysmorphology assessments. I.M. and D.B. performed teratoma assays. D.G. supervised the bioinformatics data analysis. S.P., S.M., and L.V. conceived the research and wrote the manuscript.This is the final published version. It first appeared at http://genesdev.cshlp.org/content/29/7/702.full

A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial.

BACKGROUND: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response. METHODS: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion. RESULTS: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes. CONCLUSION: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials

Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue.

Pediatric liver transplantation is often required as a consequence of biliary disorders because of the lack of alternative treatments for repairing or replacing damaged bile ducts. To address the lack of availability of pediatric livers suitable for transplantation, we developed a protocol for generating bioengineered biliary tissue suitable for biliary reconstruction. Our platform allows the derivation of cholangiocyte organoids (COs) expressing key biliary markers and retaining functions of primary extra- or intrahepatic duct cholangiocytes within 2 weeks of isolation. COs are subsequently seeded on polyglycolic acid (PGA) scaffolds or densified collagen constructs for 4 weeks to generate bioengineered tissue retaining biliary characteristics. Expertise in organoid culture and tissue engineering is desirable for optimal results. COs correspond to mature functional cholangiocytes, differentiating our method from alternative organoid systems currently available that propagate adult stem cells. Consequently, COs provide a unique platform for studies in biliary physiology and pathophysiology, and the resulting bioengineered tissue has broad applications for regenerative medicine and cholangiopathies