Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide

Pharmaceutical Research - The aim of this work is to investigate the roles of solute carrier family 22 member 18 (SLC22A18) in lipid metabolism and in establishing the tumor phenotype of HepG2...     

Gremlin 1 depletion in vivo causes severe enteropathy and bone marrow failure

The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1 ^flx/flx) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally, and reproduced successfully. Following Grem1 depletion, the mice became unwell and were euthanised (at 7–13 days). Post-mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy, and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Does skin-to-skin contact reduce stress during diaper change in preterm infants?

Background

Skin-to-skin contact reduces pain response in preterm infants subjected to minor painful procedures, such as heel lance. Diaper change is a procedure performed several times daily in hospitalized preterm infants. Routine care giving tasks such as diaper change may be stressful for the infant.

Aims

The purpose of this study was to investigate whether diaper change induces stress and if skin-to-skin contact could reduce such stress, measured by changes in skin conductance.

Study design

This was a randomized crossover pilot study in 19 preterm infants with gestational age between 28 and 34 weeks. The diaper change procedure was done twice in each infant, once during skin-to-skin contact, and once in incubator or bed with the mother present.

Outcome measures

During diaper change heart rate (HR), peripheral oxygen saturation (SpO₂), and changes in skin conductance (SC) peaks per sec, using the Skin Conductance Algesimeter (SCA), were registered.

Results

The mean SC peaks/sec increased/decreased significantly under/after change of diapers which thereby underpins that this is a stressful procedure for the preterm infant.Skin-to-skin contact (SSC) entails significantly lower stress levels (p < 0.05) compared to diaper changed in an incubator/bed measured by the SCA.

Conclusions

Diaper change is a stressful procedure for preterm infants and may be ameliorated by skin-to-skin contact.     

Paediatric diagnostic reference levels for common radiological examinations using the European guidelines

Objective:The purpose of this study was to explore the feasibility to determine regional diagnostic reference levels (RDRLs) for paediatric conventional and CT examinations using the European guidelines and to compare RDRLs derived from weight and age groups, respectively.Methods:Data were collected from 31 hospitals in 4 countries, for 7 examination types for a total of 2978 patients. RDRLs were derived for each weight and age group, respectively, when the total number of patients exceeded 15.Results:It was possible to derive RDRLs for most, but not all, weight-based and age-based groups for the seven examinations. The result using weight-based and age-based groups differed substantially. The RDRLs were lower than or equal to the European and recently published national DRLs.Conclusion:It is feasible to derive RDRLs. However, a thorough review of the clinical indications and methodologies has to be performed previous to data collection. This study does not support the notion that DRLs derived using age and weight groups are exchangeable.Advances in knowledge:Paediatric DRLs should be derived using weight-based groups with access to the actual weight of the patients. DRLs developed using weight differ markedly from those developed with the use of age. There is still a need to harmonize the method to derive solid DRLs for paediatric radiological examinations.     

Higher spatial resolution improves the interpretation of the extent of ventricular trabeculation

The ventricular walls of the human heart comprise an outer compact layer and an inner trabecular layer. In the context of an increased pre‐test probability, diagnosis left ventricular noncompaction cardiomyopathy is given when the left ventricle is excessively trabeculated in volume (trabecular vol >25% of total LV wall volume) or thickness (trabecular/compact (T/C) >2.3). Here, we investigated whether higher spatial resolution affects the detection of trabeculation and thus the assessment of normal and excessively trabeculated wall morphology. First, we screened left ventricles in 1112 post‐natal autopsy hearts. We identified five excessively trabeculated hearts and this low prevalence of excessive trabeculation is in agreement with pathology reports but contrasts the prevalence of approximately 10% of the population found by in vivo non‐invasive imaging. Using macroscopy, histology and low‐ and high‐resolution MRI, the five excessively trabeculated hearts were compared with six normal hearts and seven abnormally trabeculated and excessive trabeculation‐negative hearts. Some abnormally trabeculated hearts could be considered excessively trabeculated macroscopically because of a trabecular outflow or an excessive number of trabeculations, but they were excessive trabeculation‐negative when assessed with MRI‐based measurements (T/C <2.3 and vol <25%). The number of detected trabeculations and T/C ratio were positively correlated with higher spatial resolution. Using measurements on high resolution MRI and with histological validation, we could not replicate the correlation between trabeculations of the left and right ventricle that has been previously reported. In conclusion, higher spatial resolution may affect the sensitivity of diagnostic measurements and in addition could allow for novel measurements such as counting of trabeculations.     

Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.