Risk stratification to improve Pediatric Early Warning Systems: it is all about the context

Contains fulltext : 208059.pdf (publisher's version ) (Open Access

Mutations in <i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) transferase in patients with X-linked intellectual disability

Contains fulltext : 177227.pdf (publisher's version ) (Open Access)N-Acetylglucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential and dynamic post-translational modification. The O-GlcNAc modification is present on numerous nuclear and cytosolic proteins and has been implicated in essential cellular functions such as signaling and gene expression. Accordingly, altered levels of protein O-GlcNAcylation have been associated with developmental defects and neurodegeneration. However, mutations in the OGT gene have not yet been functionally confirmed in humans. Here, we report on two hemizygous mutations in OGT in individuals with X-linked intellectual disability (XLID) and dysmorphic features: one missense mutation (p.Arg284Pro) and one mutation leading to a splicing defect (c.463-6T>G). Both mutations reside in the tetratricopeptide repeats of OGT that are essential for substrate recognition. We observed slightly reduced levels of OGT protein and reduced levels of its opposing enzyme O-GlcNAcase in both patient-derived fibroblasts, but global O-GlcNAc levels appeared to be unaffected. Our data suggest that mutant cells attempt to maintain global O-GlcNAcylation by down-regulating O-GlcNAcase expression. We also found that the c.463-6T>G mutation leads to aberrant mRNA splicing, but no stable truncated protein was detected in the corresponding patient-derived fibroblasts. Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding and exhibited reduced glycosylation activity against a complex array of glycosylation substrates and proteolytic processing of the transcription factor host cell factor 1, which is also encoded by an XLID-associated gene. We conclude that defects in O-GlcNAc homeostasis and host cell factor 1 proteolysis may play roles in mediation of XLID in individuals with OGT mutations

Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants

Aims Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. Methods A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m(2) every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. Results In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. Conclusion Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments

Optical imaging in vivo with a focus on paediatric disease: technical progress, current preclinical and clinical applications and future perspectives

To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue

Sjögren-Larsson Syndrome - clinical perspectives

Contains fulltext : 139497.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 17 april 2015Promotor : Willemsen, M.A.A.P. Co-promotor : Theelen, T

Neurocysticercose: een importziekte om aan te denken.

Contains fulltext : 48949.pdf (publisher's version ) (Open Access

Clinician Perceptions of an Early Warning System on Patient Safety

Item does not contain fulltextBACKGROUND AND OBJECTIVES: The Pediatric Early Warning Score (PEWS) aims to improve early recognition of clinical deterioration and is widely used despite lacking evidence of effects on outcome measures such as hospital mortality. In this qualitative study, we aimed to study effects of both PEWS and the locally designed risk stratification system by focusing on professionals' perception of their performance. We also sought to gain insight into the perceived effects of PEWS and the risk stratification system on patient safety and to unravel the underlying mechanisms. METHODS: A single-center cross-sectional observational study whereby 16 semistructured interviews were held with selected health care professionals focusing on perceived effects and underlying mechanisms. Interviews were transcribed verbatim and coded without using a predetermined set of themes. RESULTS: Coding from semistructured interviews demonstrated that perceived value was related to effects on different levels of Endsley and co-workers' situational awareness (SA) model. PEWS mainly improved level 1 SA, whereas the risk stratification system also seemed to improve levels 2 and 3 SA. CONCLUSIONS: This study shows clear effects of PEWS on SA among professionals. It also points to the additional value of other risk factor stratification systems to help further improve PEWS functioning

[How do we help children who visit an emergency department frequently?]

Dutch research demonstrated that almost 5% of the pediatric population at an emergency department (ED) of an university hospital are so-called frequent flyers (FFs). These FFs account for more than 20% of all pediatric visits. Three-quarter of these FFs have (multiple) comorbidities. We hypothesize that among these FFs three groups can be recognized: (1) patients with acute manifestations from their comorbidity, (2) patients with medical complexity and (3) patients from families with psychosocial fragility. FFs from these groups should be recognized and offered a tailor-made care plan to reduce (unnecessary) ED visits

[Neonatal subgaleal haemorrhage; a potential life-threatening extracranial haemorrhage]

Item does not contain fulltextA female neonate delivered at term developed hypovolemic shock due to a subgaleal haemorrhage, i.e. extracranial bleeding between the galea aponeurotica and the cranial periosteum. The subgaleal haemorrhage was most likely the result of a traumatic vacuum extraction. The patient was treated with large volumes of fluids and blood products and received additional circulatory and respiratory support. The clinical features of neonatal subgaleal haemorrhage are different from other, more common causes of head swelling in neonates. Subgaleal haemorrhage is characterised by a progressive, diffuse, mobile, elastic swelling that is not confined by the sutures. In contrast, cephalic haematoma is a fixed, elastic swelling that is confined by the sutures. Caput succedaneum is a soft, poorly defined swelling that is immediately visible post partum. Traumatic vacuum extraction clearly increases the risk of developing subgaleal haemorrhage. Given the high mortality associated with subgaleal haemorrhage, we emphasise the importance of early diagnosis and adequate treatment of this disorder. Subgaleal haemorrhage carries an increased risk of having other concurrent disorders, such as intracranial haemorrhage. Therefore, further cerebral imaging should be considered in patients with subgaleal haemorrhage

Validation of a Paediatric Early Warning Score: first results and implications of usage

Contains fulltext : 154398.pdf (publisher's version ) (Closed access)Timely recognition of deterioration of hospitalised children is important to improve mortality. We developed a modified Paediatric Early Warning Score (PEWS) and studied the effects by performing three different cohort studies using different end points. Taking unplanned Paediatric Intensive Care Unit admission as end point and only using data until 2 h prior to end point, we found a sensitivity of 0.67 and specificity of 0.88 to timely recognise patients. This proves that earlier identification is possible without a loss of sensitivity compared to other PEWS systems. When determining the corresponding clinical condition in patients with an elevated PEWS dichotomously as 'sick' or 'well', this resulted in a total of 27 % false-positive scores. This can cause motivational problems for caregivers to use the system but is a consequence of PEWS design to minimise false-negative rates because of high mortality associated with paediatric resuscitation. Using the need for emergency medical interventions as end point, sensitivity of PEWS is high and it seems, therefore, that it is also fit to alert health-care professionals that urgent interventions may be needed. CONCLUSION: These data show the effectiveness of a modified PEWS in identifying critically ill patients in an early phase making early interventions possible and hopefully reduce mortality