Platelet-derived growth factor receptor alpha (PDGFRα) is a cell-surface receptor tyrosine kinase for platelet-derived growth factors. Correct timing and level of Pdgfra expression is crucial for ...embryo development, and deletion of Pdgfra caused developmental defects of multiple endoderm and mesoderm derived structures, resulting in a complex phenotypes including orofacial cleft, spina bifida, rib deformities, and omphalocele in mice. However, it is not clear if deletion of Pdgfra at different embryonic stages differentially affects these structures.
To address the temporal requirement of Pdgfra in embryonic development.
We have deleted the Pdgfra in Pdgfra-expressing tissues at different embryonic stages in mice, examined and quantified the developmental anomalies.
Current study showed that (i) conditional deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele, and (ii) the day of Pdgfra deletion influenced the combinations, incidence and severities of these anomalies. Deletion of Pdgfra caused apoptosis of Pdgfra-expressing tissues, and developmental defects of their derivatives.
Orofacial cleft, spina bifida and omphalocele are among the commonest skeletal and abdominal wall defects of newborns, but their genetic etiologies are largely unknown. The remarkable resemblance of our conditional Pdgfra knockout embryos to theses human congenital anomalies, suggesting that dysregulated PDGFRA expression could cause these anomalies in human. Future work should aim at defining (a) the regulatory elements for the expression of the human PDGFRA during embryonic development, and (b) if mutations / sequence variations of these regulatory elements cause these anomalies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Postoperative ileus is a common occurrence among children undergoing major operations, including gastrointestinal and spinal surgeries. Preliminary evidence in adults suggests that chewing gum plays ...a role in accelerating the return of postoperative gastrointestinal function. However, evidence is scarce in the paediatric population. The aim of this study was to investigate whether chewing gum has benefits for children.
We searched PubMed, Medline, Embase, and Cochrane Trials databases for randomised controlled trials that compare gum chewing with standard care after elective surgery in children from 1st Jan 2005 to 31st July 2021. We assessed the identified trials for quality and performed a systematic review and meta-analysis in accordance with PRISMA and registered in PROSPERO (CRD42022358801). The main outcome measures examined were time to flatus and stool postoperatively, time to tolerate oral intake, and length of hospital stay, which were analysed using fixed effects models. We also examined clinical complication rates and postoperative pain control.
We included six eligible trials, with a total of 357 enrolled patients. The intervention was well tolerated without complications. There was no significant difference in time to flatus (-2.86 h; 95 % CI: -6.2 to 0.47 h, p = 0.09), time to stool (-6.39 h; 95 % CI: -13.9 to 1.2 h, p = 0.1), time to tolerate oral intake (-0.03 days; 95 % CI: -0.15 to 0.1 days, p = 0.68), and length of hospital stay (0.08 days; 95 % CI: -0.07 to 0.22 days, p = 0.29). Postoperative pain control (opioid consumption, pain score, nausea score) was similar in both groups (p > 0.05).
Current evidence demonstrates that gum chewing is not associated with earlier postoperative gastrointestinal recovery in children. Future adequately powered and well-designed trials are necessary to evaluate any clinical benefit of chewing gum for children and whether it could result differences in healthcare satisfaction.
I.
Background & Aims Biliary atresia (BA) is a rare and most severe cholestatic disease in neonates, but the pathogenic mechanisms are unknown. Through a previous genome wide association study (GWAS) on ...Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was replicated in Chinese and Thai populations. This study aims to fully characterize the genetic architecture at 10q24.2 and to reveal the link between the genetic variants and BA. Methods We genotyped 107 single nucleotide polymorphisms (SNPs) in 10q24.2 in 339 Han Chinese patients and 401 matched controls using Sequenom. Exhaustive follow-up studies of the association signals were performed. Results The combined BA-association p -value of the GWAS SNP (rs17095355) achieved 6.06 × 10−10 . Further, we revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 p = 5.32 × 10−11 ; odds ratio, OR: 2.38; confidence interval, CI: (2.14-2.62). Through Sanger sequencing, no deleterious rare variants (RVs) residing in the risk haplotype were found, dismissing the theory of “synthetic” association. Moreover, in bioinformatics and in vivo genotype-expression investigations, the BA-associated potentially regulatory SNPs correlated with ADD3 gene expression (n = 36; p = 0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus, suggesting a possible role for the BA-associated common variants in shaping the general population diversity. Conclusions Common genetic variants in 10q24.2 can alter BA risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population.
Abstract
The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. We previously established ...long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. We further optimized 2-dimensional (2D) airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt ...surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA proposes that during the perinatal period, a still unknown exogenous factor meets the innate immune system of a genetically predisposed individual and induces an uncontrollable and potentially self-limiting immune response, which becomes manifest in liver fibrosis and atresia of the extrahepatic bile ducts. Genetic factors that could account for the disease, let alone for its high incidence in Chinese, are to be investigated. To identify BA susceptibility loci, we carried out a genome-wide association study (GWAS) using the Affymetrix 5.0 and 500 K marker sets. We genotyped nearly 500 000 single-nucleotide polymorphisms (SNPs) in 200 Chinese BA patients and 481 ethnically matched control subjects. The 10 most BA-associated SNPs from the GWAS were genotyped in an independent set of 124 BA and 90 control subjects. The strongest overall association was found for rs17095355 on 10q24, downstream XPNPEP1, a gene involved in the metabolism of inflammatory mediators. Allelic chi-square test P-value for the meta-analysis of the GWAS and replication results was 6.94 × 10−9. The identification of putative BA susceptibility loci not only opens new fields of investigation into the mechanisms underlying BA but may also provide new clues for the development of preventive and curative strategies.
Enteroviruses, such as EV-A71 and CVA16, mainly infect the human gastrointestinal tract. Human coronaviruses, including SARS-CoV and SARS-CoV-2, have been variably associated with gastrointestinal ...symptoms. We aimed to optimize the human intestinal organoids and hypothesize that these optimized intestinal organoids can recapitulate enteric infections of enterovirus and coronavirus. We demonstrate that the optimized human intestinal organoids enable better simulation of the native human intestinal epithelium, and that they are significantly more susceptible to EV-A71 than CVA16. Higher replication of EV-A71 than CVA16 in the intestinal organoids triggers a more vigorous cellular response. However, SARS-CoV and SARS-CoV-2 exhibit distinct dynamics of virus-host interaction; more robust propagation of SARS-CoV triggers minimal cellular response, whereas, SARS-CoV-2 exhibits lower replication capacity but elicits a moderate cellular response. Taken together, the disparate profile of the virus-host interaction of enteroviruses and coronaviruses in human intestinal organoids may unravel the cellular basis of the distinct pathogenicity of these viral pathogens.
•An optimized differentiation protocol improves maturation of intestinal organoids•SARS-CoV-2 and SARS-CoV infection triggers less robust response than enteroviruses•Coronaviruses show lower sensitivity to type III IFNs than enteroviruses•Intestinal organoids recapitulate disparate pathogenicity of CoVs and enteroviruses
Zhao and colleagues modified the composition of differentiation medium and demonstrated that the optimized medium improves the maturation state of human intestinal organoids. Two coronaviruses, SARS-CoV-2 and SARS-CoV, and two enteroviruses, EV-A71 and CVA16, reveal distinct profiles of virus-host interaction in the optimized intestinal organoids. Overall, human intestinal organoids adequately recapitulate disparate pathogenicity of coronaviruses and enteroviruses in the human intestines.
Hirschsprung's disease (HSCR), or aganglionic megacolon, is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. RET is a ...well-established susceptibility locus, although existing evidence strongly suggests additional loci contributing to sporadic HSCR. To identify these additional genetic loci, we carried out a genome-wide association study using the Affymetrix 500K marker set. We successfully genotyped 293,836 SNPs in 181 Chinese subjects with sporadic HSCR and 346 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Aside from SNPs in RET, the strongest overall associations in plausible candidate genes were found for 2 SNPs located in intron 1 of the neuregulin1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 CI₉₅%:(1.40, 2.00), P = 1.80 x 10⁻⁸ and 1.98 CI₉₅%:(1.59, 2.47), P = 1.12 x 10⁻⁹, respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and NRG1 (P = 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote, indicating that NRG1 is a modifier of HSRC penetrance. Our highly significant association findings are backed-up by the important role of NRG1 as regulator of the development of the enteric ganglia precursors. The identification of NRG1 as an additional HSCR susceptibility locus not only opens unique fields of investigation into the mechanisms underlying the HSCR pathology, but also the mechanisms by which a discrete number of loci interact with each other to cause disease.
Correspondence to Prof Kenneth Kak Yuen Wong; kkywong@hku.hk In this era of an exponentially growing cyber world, social media has become an integral part of children’s and adolescents’ lives. Since ...the beginning of the COVID-19 pandemic, there has been a drastic rise in internet access and media device usage.1 However, concerns about the potential negative impact of social media on children have grown given the recently increasing number of children harmed by the intake of a street snack after the viral spread of a TikTok video. ...a safety alert had aready been issued by the US Food and Drug Administration (FDA) in 2018 for a potential risk of severe injury, including skin burns, caustic oesophageal injury and perforation. ...children could have access to explicit and inappropriate content, suggestive themes and challenges without restriction, with a quick hashtag search on the app. The European Commission of the European Union has established alliance to protect minors online through by self-regulation as well as agreement among internet providers to take positive action to make internet a safer place for kids which includes optimising reporting tools for users, age-appropriate privacy settings, wider availability and use of parental controls, etc.
Aim of the study
The objective of this study is to identify risk factors associated with the development of post-operative enterocolitis (HAEC), in short segment Hirschsprung’s disease (HSCR-S).
...Methods
A retrospective study was carried out for post-operative patients with HSCR-S from 1997 to 2017. HSCR-S was defined as the most proximal extension of aganglionosis limited to the sigmoid colon. An episode of HAEC was defined as the presence of (1) vomiting or explosive diarrhea; (2) abdominal distension; (3) fever and (4) leukocytosis. Risk factors for the development of HACE were determined using multivariate logistic regression.
Main results
The medical records of 96 patients were reviewed. The overall incidence of HAEC was 20.8% (
n
= 20) and 65.0% (
n
= 13) of HAEC occurred within the first year of operation. After a univariate logistic regression analysis, three risk factors for HAEC were identified: (1) presence of other major anomalies OR: 1.43 (1.12–2.32),
p
= 0.041; (2) creation of pre-operative defunctioning stoma OR: 2.28 (1.47–3.23),
p
= 0.035; (3) extension of aganglionosis to the sigmoid colon OR: 1.89 (1.05–3.19),
p
= 0.049. After multivariate logistic regression analysis, a significant association was demonstrated for creation of pre-operative defunctioning stoma OR: 1.81 (1.08–3.22),
p
= 0.045 and extension of aganglionosis to the sigmoid colon OR: 1.91 (1.37–2.98),
p
= 0.038.
Conclusions
The requirement of pre-operative defunctioning stoma and a more proximal extension of aganglionosis are risk factors for the development of post-operative HAEC in HSCR-S. Patients with these risk factors should be closely followed up especially during the first year after the operation.
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