BackgroundSexual dimorphism in placental size and function has been described. Whether this influences the clinically important umbilical artery (UA) waveform remains controversial, although a few cross-sectional studies have shown sex differences in UA pulsatility index (PI). Therefore, we tested whether fetal sex influences the UA Doppler indices during the entire second half of pregnancy and aimed to establish sex-specific reference ranges for UA Doppler indices if needed.MethodsOur main objective was to investigate gestational age-associated changes in UA Doppler indices during the second half of pregnancy and compare the values between male and female fetuses. This was a prospective longitudinal study in women with singleton low-risk pregnancies during 19–40 weeks of gestation. UA Doppler indices were serially obtained at a 4-weekly interval from a free loop of the umbilical cord using color-directed pulsed-wave Doppler ultrasonography. Sex-specific reference intervals were calculated for the fetal heart rate (HR), UA PI, resistance index (RI), and systolic/diastolic ratio (S/D) using multilevel modeling.ResultsComplete data from 294 pregnancies (a total of 1261 observations from 152 male and 142 female fetuses) were available for statistical analysis, and sex-specific reference ranges for the UA Doppler indices and fetal HR were established for the last half of pregnancy. UA Doppler indices were significantly associated with gestational age (P < 0.0001) and fetal HR (P < 0.0001). Female fetuses had 2–8% higher values for UA Doppler indices than male fetuses during gestational weeks 20+0–36+6 (P < 0.05), but not later. Female fetuses had higher HR from gestational week 26+0 until term (P < 0.05).ConclusionsWe have determined gestational age-dependent sex differences in UA Doppler indices and fetal HR during the second half of pregnancy, and correspondingly established new sex-specific reference ranges intended for refining diagnostics and monitoring individual pregnancies.

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We have studied epidermal growth factor receptor (EGFR) phosphorylation and localization in the pre-replicative phase of liver regeneration induced by a 70% partial hepatectomy (PH), and how a PH affects EGFR activation and trafficking. When Western blotting was performed on livers after PH with antibodies raised against activated forms of EGFR autophosphorylation sites, no marked increase in EGFR tyrosine phosphorylation was observed. However, events associated with attenuation of EGFR signals were observed. Two hours after PH, we found increased EGFR ubiquitination and internalization, followed by receptor downregulation. Furthermore, EGFR phosphorylation following an injection of EGF was reduced after PH. This reduction correlated with an increased activation of PKC and a distinct augmentation in the phosphorylation of the PKC-regulated T654-site of EGFR. When primary cultured hepatocytes were treated with tetradecanoylphorbol acetate (TPA) to induce T654-phosphorylation of EGFR, we found colocalization of a fraction of EGFR with EEA1, downregulation of EGF-mediated EGFR autophosphorylation, altered ligand-induced intracellular sorting of EGFR, and increased mitogenic signaling through the EGFR-Ras-Raf-ERK pathway. Further, we found that both TPA and a PH enhanced EGF-induced proliferation of hepatocytes. In conclusion, our results suggest that hepatocyte priming involves modulation of EGFR that enhances its ability to mediate growth factor responses without an increase in its receptor tyrosine kinase-activity. This may be a pre-replicative competence event that increases growth factor effects during G1 progression.