Plasma catecholamines in foetal and adult sheep.

1. Foetal and maternal plasma catecholamine concentrations were measured during and after hypoxia (mean maternal Pa,02 44mmHg) in chronically catheterized sheep, 118-141 days pregnant. 2. In most foetuses the initial plasma catecholamines were smaller than 0.07 ng/ml. During hypoxia plasma adrenaline and noradrenaline always rose; there was a rise in arterial pressure and a fall in heart rate. 3. The initial catecholamine concentration in the ewes was smaller than 0.05-2.3 ng/ml. During hypoxia there was no consistent change; the maternal plasma concentrations were less than the foetal. 4. Infusion of adrenaline at 0.3 mug kg(-1) min(-1) to the ewe resulted in plasma catecholamine concentrations higher than those observed during hypoxia. There was a rise in heart rate but no consistent change in arterial pressure. 5. Infusion of adrenaline 0.4 mug kg(-1) min(-1) into the foetal jugular vein caused a rise in plasma concentration similar to that seen during hypoxia. There was a rise in heart rate but no significant change in arterial pressure. 6. The half-life of adrenaline and of noradrenaline in the maternal and foetal circulation was 0.25-1 min. There was no evidence of transfer of labelled catecholamine across the placenta.     

Humoral immune responses in foetal sheep.

A total of fifty-two foetal sheep between 49 and 126 days gestation were injected with polymeric and monomeric flagellin, dinitrophenylated monomeric flagellin, chicken red blood cells, ovalbumin, ferritin, chicken gamma-globulin and the somatic antigens of Salmonella typhimurium in a variety of combinations. Immune responses were followed in these animals by taking serial blood samples from them through indwelling vascular cannulae and measuring the circulating titres of antibody. Of the antigens tested, ferritin induced immune responses in the youngest foetuses. A short time later in gestation, the majority of foetuses responded to chicken red blood cells, polymeric flagellin, monomeric flagellin and dinitrophenylated monomeric flagellin. Only older foetuses responded regularly to chicken gamma-globulin and ovalbumin. However, antibodies to all these antigens were first detected over the relatively short period of development between 64 and 82 days gestation and this made it difficult to define any precise order in the development of immune responsiveness. Of the antigens tested only the somatic antigens of S. typhimurium failed to induce a primary antibody response during foetal life. The character and magnitude of the antibody responses in foetuses changed throughout in utero development. Both the total amount of antibody produced and the duration of the response increased with foetal age. Foetuses younger than 87 days gestation did not synthesize 2-mercaptoethanol resistant antibodies or IgG1 immunoglobulin to any of the antigens tested, whereas most foetuses older than this regularly did so.     

Experimental visna in foetal Icelandic sheep.

Visna is a chronic neurological disease of sheep caused by a slow infection with a naturally occurring ovine retrovirus. The present study was focused on the influence of age on the pathogenesis of this infection and involved intrauterine inoculation of 7 sheep foetuses at about 90 days of gestation with slaughter at birth, 6 to 7 weeks later. The results were compared with prior observations in newborn lambs and adult sheep infected with the same visna virus strain.Pathological lesions of the CNS in foetal sheep were of similar character, localization and severity as those in both newborn and adult sheep. The distribution of virus, the generally low titres of free infectious virus, and the requirement for explantation to isolate virus in some instances, were similar in foetal and in older sheep. However, the more frequent virus isolations from foetal and newborn sheep indicate a slightly greater permissiveness for virus replication. In general, age apparently has little effect on the course of this slow infection.     

Structure and function in urinary bladder of foetal sheep

1. The structure and function of the epithelial lining of the urinary bladder of sheep foetuses was investigated by electron microscopic studies made in conjunction with a series of experiments in which the permeability of the bladder to sodium and water was measured in vitro. Measurements were made at gestational ages ranging from 50 to 141 days (term = 147 days) Osmolarity and electrolyte concentrations of urine found in the foetal bladder were also measured.2. The development of tight junctions between the bladder epithelial cells was investigated by incubating the tissue with solutions containing 1 mM-LaCl(3) on the mucosal surface. No penetration of the junctions by lanthanum was observed in foetuses of 90 days or older. In younger bladders, the epithelial layer was stripped by treatment with lanthanum, but tight junctions appeared to be fully developed in early bladders incubated without lanthanum.3. The surface structure of the luminal (mucosal) plasmalemma was fully developed at 50 days.4. Unidirectional fluxes of labelled sodium and water were measured with identical solutions bathing the two surfaces of the bladder wall. No net water movement occurred; the mean ratio of efflux to influx in nine bladders was 1.002 +/- 0.039 (S.E. of mean). Under these conditions, the flux ratio for sodium was 1.735 +/- 0.143 (S.E. of mean) in twelve bladders.5. Antidiuretic hormone (ADH) had no effect on net water movement but reduced the net efflux of sodium so that the flux ratio became 1.285 +/- 0.255 (S.E. of mean) n = 8. ADH also had a striking effect on the structure of the epithelium, causing marked swelling of the intercellular spaces. The tight junctions remained an effective barrier to lanthanum penetration under these conditions; lanthanum was not observed in the enlarged spaces.     

Interaction of hypocapnia,hypoxia, brain blood flow,and brain electrical activity in voluntary hyperventilation in humans

Changes in various physiological measures in voluntary hyperventilation lasting three minutes or more in humans were studied and compared. Three-minute hyperventilation, in which the rate of external ventilation increased by an average factor of 4.5-5, produced similar phasic changes in central and brain hemodynamics. The rate of circulation, indicated by rheographic data, initially increased during hyperventilation, reaching a maximum at 1-2 min of the test; there was then a reduction, to a minimum 2-3 min after the end of the test; this was followed by a further slow increase. The rate of cerebral blood flow during all 3 min of hyperventilation remained elevated in most subjects as compared with baseline and decreased during the 5 min following the end of the test. Transcutaneous carbon dioxide tension changed differently - there was a decrease to a minimum (about 25 mmHg) by the end of the test, lasting 1 min from the end of the test, this being followed by an increase to a level of 90% of baseline at 5 min after the test. Blood oxygen saturation remained at 98-100% during the test, decreasing to about 90% 5 min after the test; this, along with the decrease in cerebral blood flow, was a factor producing brain hypoxia. In different subjects, changes in the spectral power of oscillations in different EEG ranges on hyperventilation were "mirrored" to different extents by the dynamics of transcutaneous carbon dioxide tension. The duration and repetition of hyperventilation were important factors for understanding the interaction between brain hemodynamics, hypocapnia, hypoxia, and brain electrical activity. After several repetitions of 3-min hyperventilation over a period of 1 h, the increasing brain blood flow could decrease significantly on the background of relatively small changes in brain electrical activity. The data presented here were assessed from the point of view of the important role of brain tissue oxygen utilization mechanisms in adaptation to hypoxia and hypocapnia.     

Renin and angiotensin-like levels in foetal, new-born and adult sheep

1. Plasma renin (measured as rate of formation of angiotensin I ng/ml.hr(-1) in the presence of added substrate at pH 7.5 and 37 degrees C) was much lower in recently nephrectomized foetal, new-born and older lambs than in intact siblings or other similar lambs.2. Angiotensin II-like concentrations were measured using a superfusion technique in an extracorporeal circuit. Resting concentrations in acute experiments under anaesthesia were deduced by comparison of carotid blood of intact lambs with that from recently nephrectomized lambs.3. Angiotensin II-like activity (mean +/- S.E. of mean, 315 +/- 117 pg/ml.) was readily detectable in foetal blood at 123-138 days gestation. The highest concentrations (mean +/- S.E. of mean 839 +/- 96 pg/ml.) were found in lambs less than 8 hr old, delivered vaginally. The lowest concentrations of angiotensin II-like activity occurred in lambs delivered by Caesarean section (mean +/- S.E. of mean < 123 +/- 12 pg/ml.). Concentrations declined with post-natal age.4. Hypovolaemia as a result of haemorrhage evoked an increase in angiotensin II-like concentrations in foetus, new-born lambs and adult sheep. The greatest increase of angiotensin-like concentrations was seen in new-born lambs. This rise was associated with increase of plasma renin.5. The rise of arterial pressure during bilateral carotid occlusion in new-born lambs was accompanied by an increase of angiotensin II-like concentration.6. It is concluded that the renin-angiotensin system is functional and can be stimulated during intra-uterine life. The increase of angiotensin II-like concentration following parturition is probably transient and associated with the trauma of delivery. This contrasts with observations made in the rabbit which suggest that full functional maturity of the renin angiotensin system is delayed until the second week of life.     

Maternal and foetal ECG separation using blind source separation methods

The separation of the maternal and foetal electrocardiograms(ECGs) from skin electrodes located on the mother's body maybe modelled as a blind source separation (BSS) problem. Thisconsists in the reconstruction of a set of unknown mutuallyindependent source signals from the sole knowledge of anotherset of linear mixtures of the sources, where the mixture patternis also unknown. Three BSS methods based on cumulants are considered:principal-component analysis (PCA), higher-order singular-valuedecomposition (HOSVD), and higher-order eigenvalue decomposition(HOEVD). All these methods are applied to the foetal-ECG extractionproblem by using real ECG data. The last two methods appearto provide a more satisfactory separation than the first method,with HOEVD offering slightly better results.     

The development of a blood-brain barrier mechanism in foetal sheep

1. The penetration of a metabolically inert, small molecular radius lipid insoluble substance ([(13)C] and [(4)H]sucrose), from blood into brain and c.s.f., has been studied in developing sheep from 50 days gestation (term, 150 days) through to the new-born stage. Around 50 days gestation sucrose accumulated rapidly into brain and c.s.f., and reached a steady-state level in brain of about 12% of the plasma level by 3 hr. By 60 days sucrose penetrated less freely into brain and c.s.f.; the brain steady-state level was 10% by 4(1/2) hr. A large decrease in sucrose penetration occurred by 70 days gestation, and by 123 days (just before the time when a foetal lamb becomes viable) both the rate of penetration and the brain steady-state level of sucrose were similar to those of the adult of other species.2. The rate of c.s.f. secretion at different ages has been estimated by dye dilution during ventriculo-cisternal perfusion. The turnover of c.s.f. in 60 day foetuses was high (1.36%/min.g wet weight brain). From 123 days gestation to the adult stage the turnover was much lower, 0.02%/min.g at 123 and 137 days gestation and 0.01%/min.g in the adult ewe.3. A simple new method for measuring c.s.f. volume is described. The volume at 51 days was estimated to be 0.14 ml., S.E. +/- 0.03, n = 4 (brain weight = 0.87 g +/- 0.11), at 59 days it was 0.45 ml., S.E. +/- 0.04, n = 6 (brain weight = 2.0 g +/- 0.1) and near term it was 7.28 ml S.E. +/- 1.29, n = 4 (brain weight 42.0 g +/- 0.5).4. The results are discussed in relation to possible changes in permeability of the cerebral capillary endothelium, the sink effect of c.s.f., and changes in extracellular space of the brain during its development. It is concluded that the high rate of penetration and raised brain steady-state level of sucrose in immature sheep foetuses is probably due to immaturity of a permeability barrier at the level of the cerebral capillary endothelium or its associated glial processes. Some clinical implications of these findings are considered briefly.     

The response of foetal sheep and lambs to pulmonary inflation

1. Pulmonary inflation through a tracheostomy consistently produces an inspiratory response or gasp in the foetal lamb. This response is reversibly removed by vagal cooling or xylocaine local anaesthesia to the air passages. It is abolished by bilateral vagotomy. It is therefore suggested that this gasp response involves a reflex whose afferent pathway is in the vagus nerve.

2. This gasp reflex is also found in lambs aged 1 hr to 30 days.

3. Lambs and foetuses possess a cough reflex.

4. A Hering—Breuer inflation reflex can be demonstrated in lambs.

5. The gasp reflex is distinct from either of these last two.

6. The significance of the gasp reflex in pre- and post-natal life is discussed.

     

Maternal antibodies in human foetal sera at different stages of gestation

Complement-fixing antibodies to ten viral antigens and/or mercaptoethanol treated anti-streptolysin-O and anti-staphylolysin-α were determined in thirty human sera from foetuses at different stages of gestation, in fifty-seven full-term cord sera, and in the corresponding maternal sera. In the smallest foetuses (crown—heel length of 125–150 mm), no antibody was found. In those of length 155–215 mm, antibody was detectable if the corresponding maternal value was high. In foetuses of 230–380 mm, antibody was detected occasionally even when the maternal value was low. Sera of foetuses of 390 mm or more contained the same antibodies as the maternal sample, and foetal titres sometimes exceeded those of the mother. Titres in the full-term cord sera were significantly higher than the maternal titres for seven of the twelve antibodies studied.