Incidence of Intermittent Hypoxemia Increases during Clinical Care and Parental Touch in Extremely Preterm Infants.

OBJECTIVES: An increased frequency of intermittent hypoxemia (IH) is associated with a higher risk for poor developmental outcomes, disability, or death in extremely preterm infants. The objective of the prFesent study is to quantify the effect of hands-on medical and parental interventions on the incidence of IH in extremely preterm infants. METHODS: An observational design with intraindividual comparisons was used. Blood oxygen saturation levels (SpO2) and time-lapse video were recorded. Frequency, duration, and time to occurrence of IH (SpO2 <80% for ≥10 s) were compared between nursing and medical care (NMC), health care by parents, skin-to-skin contact (SSC), touch in incubator, physiotherapy, and rest. Each infant was observed for six consecutive 24-h periods. Inclusion criteria were as follows: gestational age ≤28 weeks, birth weight <1500 g, postnatal age 0-6 weeks, gavage feeding, no severe illnesses or invasive procedures, no mechanical ventilation. RESULTS: The highest proportion of time with IH occurred during NMC (2.49%) and incubator touch (1.32%), the lowest during SSC (0.74%) and health care by parents (0.67%). IH frequency per hour was highest during NMC (2.95, IQR 1.19-4.01) and lowest during SSC (0.88, IQR 0.37-2.32, p < 0.001). While an increase in IH during NMC was expected, the high incidence during incubator touch was surprising. Parental touch in the incubator is intended to be soothing, not stressful. CONCLUSIONS: Future studies need to clarify how preterm infants process touch, which attributes of touch are fundamental trigger mechanisms of IH, and which handling strategies are most effective in lowering the incidence of IH during hands-on medical care.

Potent small molecule Hedgehog agonists induce VEGF expression in vitro.

Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified. SAG as well as compound 10c proven to be potent activators of VEGF expression in cultivated dermal fibroblasts. Importantly and in contrast to SAG, derivative 10c displayed no toxicity in concentrations up to 250 µm.

Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway.

Hedgehog (Hh) signaling plays an important role in cell signaling of embryonic development and adult tissue homeostasis. In vertebrates, the hh gene encodes three different unique proteins: sonic hedgehog (Shh), desert hedgehog (Dhh) and indian hedgehog (Ihh). Disruption of the Hh signaling pathway leads to severe disorders in the development of vertebrates whereas aberrant activation of the Hh pathway has been associated with several malignancies including Gorlin syndrome (a disorder predisposing to basal cell carcinoma, medulloblastoma and rhabdomyosarcoma), prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling provides a route to unique mechanism-based anti-cancer therapies. Recently the small molecule SANT-2 was identified as a potent antagonist of Hh-signaling pathway. Here, we describe the synthesis, SAR studies as well as biological evaluation of SANT-2 and its analogues. Fifteen SANT-2 derivatives were synthesized and analyzed for their interference with the expression of the Hh target gene Gli1 in a reporter gene assay. By comparison of structure and activity important molecular descriptors for Gli inhibition could be identified. Furthermore we identified derivative TC-132 that was slightly more potent than the parent compound SANT-2. Selected compounds were tested for Hh related teratogenic effects in the small teleost model medaka. Albeit Gli expression has indicated a 16-fold higher Hh-inhibiting activity than observed for the plant alkaloid cyclopamine, none of the tested compounds were able to induce the cyclopamine-specific phenotype in the medaka assay.