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Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice.Kabuki syndrome 1 (KS1) is a Mendelian disorder of the epigenetic machinery caused by mutations in the gene encoding KMT2D, which methylates lysine 4 on histone H3 (H3K4). KS1 is characterized by intellectual disability, postnatal growth retardation, and distinct craniofacial dysmorphisms. A mouse model (Kmt2d+/βGeo) exhibits features of the human disorder and has provided insight into other phenotypes; however, the mechanistic basis of skeletal abnormalities and growth retardation remains elusive. Using high-resolution micro-CT, we show that Kmt2d+/βGeo mice have shortened long bones and ventral bowing of skulls. In vivo expansion of growth plates within skulls and long bones suggests disrupted endochondral ossification as a common disease mechanism. Stable chondrocyte cell lines harboring inactivating mutations in Kmt2d exhibit precocious differentiation, further supporting this mechanism. A known inducer of chondrogenesis, SOX9, and its targets show markedly increased expression in Kmt2d-/- chondrocytes. By transcriptome profiling, we identify Shox2 as a putative KMT2D target. We propose that decreased KMT2D-mediated H3K4me3 at Shox2 releases Sox9 inhibition and thereby leads to enhanced chondrogenesis, providing a potentially novel and plausible explanation for precocious chondrocyte differentiation. Our findings provide insight into the pathogenesis of growth retardation in KS1 and suggest therapeutic approaches for this and related disorders.
Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome.Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural stem/progenitor cells (NSPCs). Lysine-specific methyltransferase 2D (KMT2D) encodes a histone methyltransferase that promotes transcriptional activation and is frequently mutated in cancers and in the majority (>70%) of patients diagnosed with the congenital, multisystem intellectual disability disorder Kabuki syndrome 1 (KS1). Critical roles for KMT2D are established in various non-neural tissues, but the effects of KMT2D loss in brain cell development have not been described. We conducted parallel studies of proliferation, differentiation, transcription, and chromatin profiling in KMT2D-deficient human and mouse models to define KMT2D-regulated functions in neurodevelopmental contexts, including adult-born hippocampal NSPCs in vivo and in vitro. We report cell-autonomous defects in proliferation, cell cycle, and survival, accompanied by early NSPC maturation in several KMT2D-deficient model systems. Transcriptional suppression in KMT2D-deficient cells indicated strong perturbation of hypoxia-responsive metabolism pathways. Functional experiments confirmed abnormalities of cellular hypoxia responses in KMT2D-deficient neural cells and accelerated NSPC maturation in vivo. Together, our findings support a model in which loss of KMT2D function suppresses expression of oxygen-responsive gene programs important to neural progenitor maintenance, resulting in precocious neuronal differentiation in a mouse model of KS1.
Abdominal pain is a common and recurring problem in paediatric emergency departments.AIM: Abdominal pain is a frequent reason for paediatric emergency department visits, but specific research is lacking. Our aim was to obtain information on the diagnosis of abdominal pain and what healthcare services children with this condition need. METHODS: This retrospective study focused on patients visiting the emergency department of the Children's Hospital Iceland in 2010 with abdominal pain and any subsequent visits up to 1 January 2015. RESULTS: There were 11 340 visits to the emergency department in 2010 and 1118 children made 1414 (12%) visits due to abdominal pain. The majority (58%) with abdominal pain were girls (p < 0.001) and they were older than the boys, with an average age of 12 versus 10 years (p < 0.001). The most common diagnoses were non-specific abdominal pain (40%), constipation (22%) and viral infections (13%). During the follow-up period, 423/1118 children (38%) visited the emergency department 883 times, 58% were girls and the most common diagnosis was non-specific abdominal pain (37%). Of the 436 children initially diagnosed with non-specific abdominal pain, 154 (35%) revisited the emergency department during the follow-up period. CONCLUSION: Abdominal pain was a common reason for visits to the paediatric emergency room and a third paid more than one visit.
Bullying, pain and analgesic use in school-age children.AIM: The aim of this study was to examine whether the self-reported use of analgesics is associated with being a victim of bullying. METHODS: This cross-sectional, school-based survey included all students in grades 6 (11 years old), 8 (13 years old) and 10 (15 years old) in Iceland (response rate: 84%; n = 11 018). The students filled out an anonymous standardised questionnaire: the Icelandic Contribution to the International Health Behavior in School-Aged Children (HBSC) Study. RESULTS: Being bullied was associated with increased use of analgesics even after controlling for self-reported pain. CONCLUSION: Bullying occurs in all schools, and its effects on health are pervasive. Interventions aimed at reducing bullying and promoting health in schools are important and may reduce the use of analgesics in adolescents.
Preoperative dual antiplatelet therapy increases bleeding and transfusions but not mortality in acute aortic dissection type A repair.OBJECTIVES: Acute aortic dissection type A is a life-threatening condition, warranting immediate surgery. Presentation with sudden chest pain confers a risk of misdiagnosis as acute coronary syndrome resulting in subsequent potent antiplatelet treatment. We investigated the impact of dual antiplatelet therapy (DAPT) on bleeding and mortality using the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) database. METHODS: The NORCAAD database is a retrospective multicentre database where 119 of 1141 patients (10.4%) had DAPT with ASA + clopidogrel (n = 108) or ASA + ticagrelor (n = 11) before surgery. The incidence of major bleeding and 30-day mortality was compared between DAPT and non-DAPT patients with logistic regression models before and after propensity score matching. RESULTS: Before matching, 51.3% of DAPT patients had major bleeding when compared to 37.7% of non-DAPT patients (P = 0.0049). DAPT patients received more transfusions of red blood cells [median 8 U (Q1-Q3 4-15) vs 5.5 U (2-11), P < 0.0001] and platelets [4 U (2-8) vs 2 U (1-4), P = 0.0001]. Crude 30-day mortality was 19.3% vs 17.0% (P = 0.60). After matching, major bleeding remained significantly more common in DAPT patients, 51.3% vs 39.3% [odds ratio (OR) 1.63, 95% confidence interval (CI) 1.05-2.51; P = 0.028], but mortality did not significantly differ (OR 0.88, 95% CI 0.51-1.50; P = 0.63). Major bleeding was associated with increased 30-day mortality (adjusted OR 2.44, 95% CI 1.72-3.46; P < 0.0001). CONCLUSIONS: DAPT prior to acute aortic dissection repair was associated with increased bleeding and transfusions but not with mortality. Major bleeding per se was associated with a significantly increased mortality. Correct diagnosis is important to avoid DAPT and thereby reduce bleeding risk, but ongoing DAPT should not delay surgery.