Two to eight days after surgery, we determined biventricular cardiac output with the microsphere-dilution method and individual ventricular output with an electromagnetic flow sensor in 12 fetal lambs. Mean biventricular output was 462 ml.min-1.kg-1. Right ventricular output was 60%, pulmonary blood flow was 6%, blood flow in the ductus arteriosus was 54%, flow through the foramen ovale was 34%, and flow in the descending thoracic aorta above the ductus arteriosus was 12% of the biventricular cardiac output. Foramen ovale flow did not correlate with the pressure difference between the atria. The flow though the foramen ovale correlated positively with the flow in the inferior caval vein. It was concluded the shunt flow through the foramen ovale is mainly determined by the kinetic energy of the blood in the "lower atrial inflow tract." Fetal systemic somatic blood flow showed a reliable negative correlation with the oxygen tension in the fetal arterial blood. This was taken as presumptive evidence for long-term autoregulation of flow in the peripheral tissues.

Jonker SS, Faber JJ, Anderson DF, Thornburg KL, Louey S, Giraud GD. Sequential growth of fetal sheep cardiac myocytes in response to simultaneous arterial and venous hypertension. Am J Physiol Regul Integr Comp Physiol 292: R913-R919, 2007. First published October 5, 2006; doi:10.1152/ajpregu.00484.2006.-While the fetal heart grows by myocyte enlargement and proliferation, myocytes lose their capacity for proliferation in the perinatal period after terminal differentiation. The relationship between myocyte enlargement, proliferation, and terminal differentiation has not been studied under conditions of combined arterial and venous hypertension, as occurs in some clinical conditions. We hypothesize that fetal arterial and venous hypertension initially leads to cardiomyocyte proliferation, followed by myocyte enlargement. Two groups of fetal sheep received intravascular plasma infusions for 4 or 8 days (from 130 days gestation) to increase vascular pressures. Fetal hearts were arrested in diastole and dissociated. Myocyte size, terminal differentiation (%binucleation), and cell cycle activity cells as a % of mononucleated myocytes) were measured. We found that chronic plasma infusion greatly increased venous and arterial pressures. Heart (but not body) weights were ϳ30% greater in hypertensive fetuses than controls. The incidence of cell cycle activity doubled in hypertensive fetuses compared with controls. After 4 days of hypertension, myocytes were (ϳ11%) longer, but only after 8 days were they wider (ϳ12%). After 8 days, %binucleation was ϳ50% greater in hypertensive fetuses. We observed two phases of cardiomyocyte growth and maturation in response to fetal arterial and venous hypertension. In the early phase, the incidence of cell cycle activity increased and myocytes elongated. In the later phase, the incidence of cell cycle activity remained elevated, %binucleation increased, and cross sections were greater. This study highlights unique fetal adaptations of the myocardium and the importance of experimental duration when interpreting fetal cardiac growth data.hypertrophy; hyperplasia; terminal differentiation; cardiomyocyte THE FETAL HEART GROWS BY PROLIFERATION and enlargement of cardiac myocytes (23). Among mammals, proliferative growth of cardiac myocytes ceases at or soon after birth through a process known as terminal differentiation (18). Thereafter, the postnatal heart grows almost exclusively by cellular enlargement. In the fetal sheep, as in many other species, terminal differentiation is marked by the appearance of two nuclei in cardiac myocytes that were formerly mononucleated. The rate of proliferation during intrauterine life and the occurrence of terminal differentiation in the perinatal period together determine the maximum number of myocytes in the heart for life.Intrauterine conditions affect cardiac myocyte proliferation, enlargement, and terminal differentiation, but myocyte responses to abnormal conditions depend on the level of maturity of the heart. Increased systolic or diastolic hemo...

Our objective was to test the hypothesis that fetal urine contains a substance(s) that regulates amniotic fluid volume by altering the rate of intramembranous absorption of amniotic fluid. In late gestation ovine fetuses, amniotic fluid volumes, urine, and lung liquid production rates, swallowed volumes and intramembranous volume and solute absorption rates were measured over 2-day periods under control conditions and when urine was removed and continuously replaced at an equal rate with exogenous fluid. Intramembranous volume absorption rate decreased by 40% when urine was replaced with lactated Ringer solution or lactated Ringer solution diluted 50% with water. Amniotic fluid volume doubled under both conditions. Analysis of the intramembranous sodium and chloride fluxes suggests that the active but not passive component of intramembranous volume absorption was altered by urine replacement, whereas both active and passive components of solute fluxes were altered. We conclude that fetal urine contains an unidentified substance(s) that stimulates active intramembranous transport of amniotic fluid across the amnion into the underlying fetal vasculature and thereby functions as a regulator of amniotic fluid volume.

We designed experiments to allow direct measurement of amniotic fluid volume and continuous measurement of lung liquid production, swallowing, and urine production in fetal sheep. From these values, the rate of intramembranous absorption was calculated. Using this experimental design, the contribution of lung liquid to the control of amniotic fluid volume was examined. Fetuses were assigned to 1 of 4 protocols, each protocol lasting 3 days: control, isovolemic replacement of lung liquid, supplementation of amniotic fluid inflow by 4 L/day, and supplementation of amniotic inflow during isovolemic replacement of lung liquid. We found no effect of lung liquid replacement on any of the known flows into and out of the amniotic fluid. Although intramembranous absorption increased greatly during supplementation, the amniochorionic function curves were not altered by isovolemic lung liquid replacement. We conclude that lung liquid does not appear to contain a significant regulatory substance for amniotic fluid volume control.

Aims/background-Proton beam radiotherapy can eVectively treat primary uveal melanomas of any size. Some patients, however, develop adverse late effects following treatment and the purpose of this study was to determine which factors give rise to a poor local outcome. Methods-The hospital records from a first cohort of 127 patients treated by protons from 1989 to 1992 were reviewed retrospectively. The presence of rubeosis was selected as a measure of significant ocular damage. Split file analysis was performed with 73 cases forming a test group with the remaining 54 cases acting as a validation group. Results-Large tumour size and the presence of retinal detachment were significant, independent risk factors for developing rubeosis for both the test and validation groups. These factors also predicted subsequent enucleation for uncontrolled ocular pain. Patients with tumours too large to plaque and with an associated retinal detachment had a 90% chance of developing rubeosis within 4 years of proton beam radiotherapy. Conclusions-Patients with a uveal melanoma too large for plaque therapy and an associated retinal detachment run a very high risk of developing rubeosis after proton beam radiotherapy and one third of individuals developing rubeosis required enucleation for pain even if local tumour control was satisfactory. (Br J Ophthalmol 1997;81:748-754)