Plasma serotonergic biomarkers are associated with hypoxemia events in preterm neonates.

BACKGROUND: Hypoxemia is a physiological manifestation of immature respiratory control in preterm neonates, which is likely impacted by neurotransmitter imbalances. We investigated relationships between plasma levels of the neurotransmitter serotonin (5-HT), metabolites of tryptophan (TRP), and parameters of hypoxemia in preterm neonates. METHODS: TRP, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and kynurenic acid (KA) were analyzed in platelet-poor plasma at ~1 week and ~1 month of life from a prospective cohort of 168 preterm neonates <31 weeks gestational age (GA). Frequency of intermittent hypoxemia (IH) events and percent time hypoxemic (<80%) were analyzed in a 6 h window after the blood draw. RESULTS: At 1 week, infants with detectable plasma 5-HT had fewer IH events (OR (95% CI) = 0.52 (0.29, 0.31)) and less percent time <80% (OR (95% CI) = 0.54 (0.31, 0.95)) compared to infants with undetectable 5-HT. A similar relationship occurred at 1 month. At 1 week, infants with higher KA showed greater percent time <80% (OR (95% CI) = 1.90 (1.03, 3.50)). TRP, 5-HIAA or KA were not associated with IH frequency at either postnatal age. IH frequency and percent time <80% were positively associated with GA < 29 weeks. CONCLUSIONS: Circulating neuromodulators 5-HT and KA might represent biomarkers of immature respiratory control contributing to hypoxemia in preterm neonates. IMPACT: Hypoxemia events are frequent in preterm infants and are associated with poor outcomes. Mechanisms driving hypoxemia such as immature respiratory control may include central and peripheral imbalances in modulatory neurotransmitters. This study found associations between the plasma neuromodulators serotonin and kynurenic acid and parameters of hypoxemia in preterm neonates. Imbalances in plasma biomarkers affecting respiratory control may help identify neonates at risk of short- and long-term adverse outcomes.

Elevated Urine Hyaluronan Concentrations Are Associated with an Unfavorable Respiratory Outcome in Preterm Neonates at 40 Weeks Postmenstrual Age.

INTRODUCTION: Hyaluronan (HA) is a major component of the extracellular matrix. Increased pulmonary HA concentrations are associated with several respiratory disorders and is a pathophysiological feature of lung disease. We investigated whether elevated urine HA is a biomarker of an unfavorable 40-week respiratory outcome in preterm infants. METHODS: Infants comprised a cohort of preterm neonates <31 weeks gestational age (GA) from the Prematurity-Related Ventilatory Control (Pre-Vent) multicenter study. HA was quantified in urine obtained at 1 week and 1 month of age. Respiratory status at 40 weeks post-menstrual age (PMA) was classified as unfavorable [either (1) deceased at or before 40 weeks PMA, (2) an inpatient on respiratory medication, O2 or other respiratory support at 40 weeks, or (3) discharged prior to 40 weeks on medications/O2/other respiratory support], or favorable (alive and previously discharged, or inpatient and off respiratory medications, off O2, and off other respiratory support at 40 weeks PMA). The association between urine HA and the unfavorable 40 week PMA outcome was examined using a multivariate logistic generalized estimation equation model. RESULTS: Infants with higher HA at 1 week (but not 1 month) showed increased odds of unfavorable respiratory outcome at 40 weeks PMA (OR [95% CI] = 1.87 per 0.01 mg [1.27, 2.73]). DISCUSSION AND CONCLUSION: Neonatal urine screening for HA could identify infants at risk for death or need for respiratory support at term-corrected age (40 weeks PMA). The relationship between elevated HA at 1 week and an unfavorable 40 week outcome was stronger in infants with lower GA.

Familial monoallelic CYP26B1 truncating variant causes a syndromic craniosynostosis due to haploinsufficiency ?

Autosomal recessive CYP26B1 disorder is characterised by syndromic craniosynostosis of variable severity, and survival ranging from prenatal lethality to survival into adulthood. Here we report on two related individuals of Asian-Indian origin with syndromic craniosynostosis characterised by craniosynostosis, and dysplastic radial heads, caused by monoallelic CYP26B1 likely pathogenic variant NM_019885.4:c.86C > A:p. (Ser29Ter). We propose the possibility of autosomal dominant phenotype of CYP26B1 variant.

Gelatin-Based Matrices as a Tunable Platform To Study in Vitro and in Vivo 3D Cell Invasion.

Hydrogels have been used as synthetic mimics of 3D extracellular matrices (ECM) and their physical properties like stiffness, degradability, and porosity have been known to influence the behavior of encapsulated cells. However, to understand the role of individual properties, the influence of biophysical cues should be decoupled from biochemical ones. In this study, we have used hydrogels as a tunable model matrix to develop a 3D cell culture platform for studying cell invasion. Inert polyethylene (glycol) diacrylate (PEGDA) and cell adhesive gelatin methacryloyl (GELMA) were blended in varying compositions, followed by UV-mediated photo polymerization to obtain hydrogels with varying stiffness, degradation, and cell adhesive properties. We developed two hydrogel matrix systems, namely, PEGDA-GELMA (containing a larger proportion of PEGDA) and GELMA-PEGDA (containing predominantly GELMA), and characterized them for differences in pore size, swelling ratio, storage modulus, degradability, and biocompatibility of the matrix. Both hydrogel systems had similar pore dimensions and swelling behavior, but PEGDA-GELMA was found to be stiffer and nondegradable, while GELMA-PEGDA was softer and degradable. Accordingly, MDA-MB-231 breast cancer cells encapsulated in these matrices showed a spheroidal morphology in PEGDA-GELMA hydrogels and were more spindle-shaped in GELMA-PEGDA hydrogels, confirming that size and extent of spreading of cells were influenced by the type of these hydrogels. The softer GELMA-PEGDA matrices readily allowed invasion of MDA-MB-231 cells in 3D and showed differences in epithelial-mesenchymal transition (EMT) gene expression of these cells. We further demonstrated the invasion and sprouting of endothelial cells using a chick aortic arch assay, exhibiting the utility of softer matrices to study 3D cell invasion for multiple applications. We also implanted these matrices in mice and showed that soft gelatin-based hydrogels allow cell infiltration in vivo. Results from our study highlight the tunability of this matrix system and the role of matrix constitution in influencing cell invasion in a 3D microenvironment.

Efficient in situ gene delivery via PEG diacrylate matrices.

For diseases related to genetic disorders or cancer, many cellular therapies rely on the ex vivo modification of cells for attaining a desired therapeutic effect. The efficacy of such therapies involving the genetic modification of cells relies on the extent of gene expression and subsequent persistence of modified cells when infused into the patient's body. In situ gene delivery implies the manipulation of cells in their in vivo niche such that the effectiveness can be improved by minimizing post manipulation effects like cell death, lack of persistence, etc. Furthermore, material-based in situ localized gene delivery can reduce the undesired side effects caused by systemic modifications. Here, we have used polyethylene (glycol) diacrylate (PEGDA) based cryogels to genetically modify cells in vivo with a focus on immunotherapy. PEGDA cryogels were either blended with gelatin methacrylate (GELMA) or surface modified with poly-l-lysine (PLL) in order to improve cell adhesion and/or retain viruses for localized gene delivery. On using the lentiviruses encoding gene for green fluorescent protein (GFP) in in vitro experiments, we found higher transduction efficiency in HEK 293FT cells via PEGDA modified with poly-l-lysine (PEGDA-PLL) and PEGDA-GELMA cryogels compared to PEGDA cryogels. In vitro release experiments showed improved retention of GFP lentiviruses in PEGDA-PLL cryogels, which were then employed for in vivo gene delivery and were demonstrated to perform better than the corresponding bolus delivery of lentiviruses through an injection. Both physical and biological characterization studies of these cryogels show that this material platform can be used for gene delivery as well as other tissue engineering applications.