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Objective: To examine the effect of the interval between onset of sustained fetal bradycardia and cesarean delivery on long-term neonatal neurologic prognosis., Method: A retrospective observational case-series performed with patients who had sudden-onset and sustained (<100 beats per minute) fetal bradycardia during labor. Fetal heart rate was monitored closely until cesarean delivery. The effect of the interval between the onset of bradycardia and delivery on neonatal neurologic prognosis was examined., Results: Among 2267 deliveries in 2002-2003 at Kitasato University Hospital, 19 pregnancies met the inclusion criteria. Episodes of fetal bradycardia were due to umbilical cord prolapse (n=5), placental abruption (n=4), uterine rupture (n=3), maternal respiratory failure (n=1), and other causes (n=6). Mean onset of fetal bradycardia to delivery interval (BDI) was 20.5±8.9 minutes. Mean decision-to-cesarean delivery interval was 11.4±3.9 minutes. BDI was negatively correlated with umbilical arterial pH at delivery. There were 3 postnatal deaths. Neurologic assessment at the age of 2 years revealed that 15 of 16 children were neurologically normal. When the BDI was less than 25 minutes, all term pregnancies led to normal neonatal neurologic development., Conclusion: In the event of sustained intrapartum fetal bradycardia, delivery by emergency cesarean within 25 minutes improved long-term neonatal neurologic outcome., (Copyright © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3-/-) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1-/-, EP2-/-, and EP4-/- were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3-/- mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3-/- mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3-/- bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF.

We evaluated the significance of the host kallikrein-kinin system in tumor angiogenesis and tumor growth using two rodent models genetically deficient in a kallikrein-kinin system. Inoculation of Walker 256 carcinoma cells into the s.c. tissues of the back of normal Brown Norway Kitasato rats (BN-Ki rats) resulted in the rapid development of solid tumors with marked angiogenesis. By contrast, in kininogen-deficient Brown Norway Katholiek rats (BN-Ka rats), which cannot generate intrinsic bradykinin (BK), the weights of the tumors and the extent of angiogenesis were significantly less than those in BN-Ki rats. Daily administration of B(2) receptor antagonists significantly reduced angiogenesis and tumor weights in BN-Ki rats to levels similar to those in BN-Ka rats but did not do so in BN-Ka rats. Angiogenesis and tumor growth were significantly suppressed in B(2) receptor knockout mice bearing sarcoma 180 compared with their wild-type counterparts. Immunoreactive vascular endothelial growth factor (VEGF) was localized in Walker tumor stroma more extensively in BN-Ki rats than in BN-Ka rats, although immunoreactive B(2) receptor also was detected in the stroma to the same extent in both types of rats. Cultured stromal fibroblasts isolated from BN-Ki rats and BN-Ka rats produced VEGF in response to BK (10(-8)-10(-6) m), and this stimulatory effect of BK was abolished with a B(2) receptor antagonist, Hoe140 (10(-5) m). These results suggest that BK generated from kininogens supplied from the host may facilitate tumor-associated angiogenesis and tumor growth by stimulating stromal B(2) signaling to up-regulate VEGF production mainly in fibroblasts.