Aeromedical Aspects of Commercial Air Travel.
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Journal Article↗
Biomedical subjects
R Harding
Publications and source records attributed to R Harding.
Measurement of lung diffusing capacity and functional residual capacity in lambs during the first postnatal month.
The diffusing capacity of the lung for carbon monoxide (DLCO) is an important index of lung function but is not easily measured in spontaneously breathing animals with small lung volumes. Our aim was to devise a simple rebreathing method that would allow us to make serial measurements of DLCO in spontaneously breathing lambs during their first month after birth. By adding He to the rebreathing gas mixture, we were also able to measure functional residual capacity (FRC), enabling us to normalize DLCO with respect to FRC. We have compared FRC measured by the rebreathing technique with that measured by a closed-circuit helium dilution method (FRCcc). Using the rebreathing method we found highly significant positive correlations between DLCO and body weight (r = 0.70, P < 0.001) and between FRC and body weight (r = 0.79, P < 0.001). There was no significant change in DLCO/FRC over the first postnatal month; the mean value was 8.1 +/- 0.6 mL/min/mmHg/mL. Rebreathing FRC was highly correlated with FRCcc (r = 0.88, P < 0.001), but was lower than FRCcc by about 18%. In normal lambs DLCO and FRC, but not DLCO/FRC, increased during the first month after birth, suggesting that the increase in DLCO parallels lung growth. We conclude that the modified rebreathing method is suitable for measuring DLCO in small uncooperative spontaneously breathing animals.
Analysis of Variance↗
Swallowing of lung liquid and amniotic fluid by the ovine fetus under normoxic and hypoxic conditions.
OBJECTIVE: The lungs of the mammalian fetus secrete large volumes of fluid daily. The purpose of this study was to estimate the fraction of the lung liquid that is swallowed as it exits the fetal trachea versus that which enters the amniotic fluid under normoxic and hypoxic conditions. STUDY DESIGN: In chronically catheterized fetal sheep at 119 to 133 days' gestation the volume of fluid swallowed by the fetus was monitored five times per day for three consecutive 24-hour periods: control, hypoxia, and recovery. The Na+, K+, and Cl- concentrations of the swallowed fluid, lung liquid, and amniotic fluid were measured simultaneously. The fraction of the swallowed fluid that originated from the lungs or amniotic fluid was calculated from 24-hour average compositions and the assumption that the fetus swallowed only amniotic fluid and lung liquid. RESULTS: During the control, hypoxia, and recovery periods the fetuses swallowed 264 +/- 43 (SE), 92 +/- 23, and 271 +/- 24 ml/kg of fetal weight per day, respectively. As determined from Cl- concentrations, this swallowed fluid was composed of 17.7% +/- 2.7%, 24.8% +/- 5.8%, and 11.9% +/- 3.4% lung liquid, respectively, with the remainder being amniotic fluid. Throughout the three 24-hour observation periods there was an inverse relationship between the net 24-hour swallowed volume and the fraction of the swallowed fluid that originated from the lungs. Calculations based on Na+ concentrations yielded essentially the same results with slightly more scatter, whereas calculations based on K+ concentrations were unreliable. CONCLUSIONS: (1) Chloride concentrations provide the best of the three index values for a compositional analysis of fluids swallowed by the fetus. (2) Under normoxic conditions around 18% of swallowed fluid is derived from the fetal lungs. (3) On the basis of published fluid secretion rates for the fetal lung, an average of 50% of the liquid that exits the fetal trachea is swallowed and the rest mixes with the amniotic fluid.
Amniotic Fluid↗
Oxytocin receptor blockade and prostaglandin release in late pregnant sheep.
The oxytocin receptor inhibitor 1-deamino-2-D-Tyr-(oET)-4-Thr-8-orn-oxytocin (CAP) was infused into late pregnant sheep. Basal and oxytocin-induced prostaglandin (PG) concentrations in maternal and fetal plasma were determined. CAP had no significant effect on maternal PGFM or PGE2 or fetal PGF2 alpha, PGFM or PGE2 concentrations during late pregnancy or at term. PGF2 alpha was not detectable in maternal peripheral plasma. CAP infusion did not affect fetal well-being. Oxytocin injection to the mother caused a significant, dose-dependent, increase in maternal plasma PGFM concentrations but did not alter maternal PGE2 concentrations or fetal PGF2 alpha and PGE2 concentrations. The increase in maternal PGFM concentrations brought about by oxytocin injection was decreased during intrauterine infusion of CAP over the range of 12.5-100 micrograms/min. A rationale for the use of oxytocin receptor blockade for the prevention of premature labor is thus provided.
Animals↗
The effects of twenty-four hours of reduced uterine blood flow on fetal fluid balance in sheep.
OBJECTIVE: Our aim was to determine the effects of a sustained reduction in uteroplacental perfusion, leading to fetal hypoxia, on determinants of amniotic fluid volume in sheep. STUDY DESIGN: Surgery was performed on five pregnant ewes 110 to 116 days after mating. At 127.3 +/- 2.2 days uterine blood flow was reduced for 24 hours, which reduced fetal SaO2 from 61.9% +/- 1.2% to 24.9% +/- 0.8%. RESULTS: Fetal urine production was increased from a control value of 193.0 +/- 24.0 ml/kg per 24 hours to 279.3 +/- 30.0 ml/kg per 24 hours during periods of reduced uterine blood flow and remained above control values for up to 48 hours after the reduced uterine blood flow period. A substantial loss of fetal water and electrolytes occurred through urine, which was associated with changes in the composition of fetal plasma and fetal tracheal, fetal swallowed, and amniotic fluids. Fetal swallowing was reduced throughout the reduced uterine blood flow period from a control value of 200.8 +/- 56.0 ml/kg per 24 hours to 32.7 +/- 8.4 ml/kg per 24 hours and returned to control levels after the cessation of the reduced uterine blood flow. CONCLUSION: We conclude that 24 hours of reduced uterine blood flow causes major changes in fetal renal function and fetal swallowing that, in spite of an expected reduction in lung liquid production, would increase the flow of fluid and electrolytes from the fetus into the amniotic sac.
Amniotic Fluid↗
Effects of inhibition of prostaglandin synthesis on flow and composition of fetal urine, lung liquid, and swallowed fluid in sheep.
OBJECTIVE: Our aim was to determine the effects of blocking prostaglandin synthesis, by infusion of indomethacin into the fetal circulation, on factors regulating amniotic fluid volume and on plasma composition in the mother and fetus. STUDY DESIGN: Indomethacin was administered to fetal sheep during 8 hours at 124.0 +/- 1.2 days of gestation (n = 7) and at 134.7 +/- 0.8 days of gestation (n = 7) (term approximately 147 days). Vehicle infusions were performed at 128.8 +/- 1.4 days of gestation (n = 5). RESULTS: Fetal urine production was significantly reduced and both fetal urine osmolality and plasma arginine vasopressin concentrations were significantly elevated in response to indomethacin infusions at both gestational ages. Fetal blood and urine lactate concentrations were elevated in response to indomethacin. Later in gestation, fetal lung liquid flow was significantly changed from a net efflux to a net influx. There was no significant effect of indomethacin on the volume of fluid swallowed by the fetus. CONCLUSION: Inhibition of fetal prostaglandin synthesis profoundly reduces the production of the two major fetal fluids contributing to amniotic fluid, namely, urine and lung liquid. These findings may explain why indomethacin reduces amniotic fluid volume.
Amniotic Fluid↗
Role of fetal sac fluids during maternal water deprivation in sheep.
Our aim was to determine the importance of amniotic and allantoic fluids for the maintenance of fetal plasma composition during maternal dehydration when water transfer from mother to fetus is likely to be reduced. Eight pregnant ewes were studied before, during and after water deprivation (36 h), firstly with the fetal fluid sacs intact and then with them drained of fluid for 5 days. When water deprivation was combined with drainage, the increases in the osmolalities, [Na+] and [Cl-] in maternal plasma, in fetal plasma and in lung liquid; the increases in fetal urinary osmolality and [Na+]; and the increases in maternal plasma and fetal plasma arginine vasopressin concentrations were greater than those resulting from water deprivation alone. Our results show that during maternal water deprivation, an absence of fluid in the fetal sacs increases both the osmotic stimulus to the fetus and the fetal responses resulting in conservation of water and salt. We conclude that, when the mother is deprived of water, fluid in the fetal sacs is used to limit the degree of maternal and fetal dehydration.
Allantois↗
Swallowing and urine flow responses of ovine fetuses to 24 h of hypoxia.
The aim of this study was to determine the effects of 24 h of hypoxia on fetal swallowing and urine flow rates. The study design included successive 24-h control, hypoxia, and recovery periods. To induce hypoxia, we infused nitrogen into the trachea of late-gestation pregnant sheep. During hypoxia, there were decreases in fetal arterial oxygen saturation [from 62.7 +/- 2.2 to 30.9 +/- 2.9% (SE)] and PO2 (from 21.1 +/- 1.0 to 14.1 +/- 0.9 mmHg) (n = 7). Fetal arterial pH decreased maximally by 0.04 +/- 0.01 at 6 h and returned to control thereafter. Fetal swallowing decreased from 13.4 +/- 2.1 to 0.6 +/- 0.2 ml.h-1.kg fetal wt-1 with the onset of hypoxia and gradually increased, but only to one-half control levels, during the last 12 h of hypoxia. Fetal urine flow gradually decreased from 9.6 +/- 1.6 ml.h-1.kg-1 to a minimum of 5.3 +/- 0.5 ml.h-1.kg-1 at 2-3 h of hypoxia and returned to control thereafter. During the first hour of the recovery period, fetal swallowing transiently increased to twice control levels before returning to control. This was followed by a delayed, transient increase in urine flow to 63% above control levels at 2-6 h after hypoxia. We conclude that the fetal swallowing and urine flow responses to prolonged hypoxia in the absence of acidemia are distinctly different from the initial inhibitory responses, in that swallowing partially and urine flow fully recovers from the initial suppression.
Animals↗
Arginine vasopressin and secretion of fetal lung liquid.
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Amiloride↗
Systematic study of human alpha beta T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes.
The variation of the alpha beta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two V beta 2 loci and the V alpha 8.1 locus, we found that all exhibited a coding polymorphism. One of the V beta 2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second V beta 2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a V beta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first V beta 2 segment on the known map to define haplotypes with two other polymorphic segments: V beta 1 and V beta 6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that V beta regions are highly variable between individuals. Two alleles exist at the V alpha 8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.
Alleles↗
Allelic polymorphism of human T-cell receptor V alpha gene segments.
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Alleles↗
States take lead on health care reform.
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Health Care Reform↗
Changes in lung expansion alter pulmonary DNA synthesis and IGF-II gene expression in fetal sheep.
Our aim was to determine the effect of short-term (7 days) alterations in fetal lung liquid volume on pulmonary DNA synthesis rates and insulin-like growth factor-II (IGF-II) mRNA levels. Fifteen chronically catheterized fetal sheep were divided into three groups. In one, the trachea was obstructed, in another lung liquid was drained by gravity, and the third group served as controls. After 7 days, [3H]thymidine was injected into each fetus and 8 h later fetal tissues were collected. Fetal lung-to-body weight ratios and total lung DNA contents were greatly increased in fetuses with tracheal obstruction compared with control fetuses, whereas the drainage of lung liquid did not affect these measurements. DNA synthesis rates in pulmonary tissue were significantly reduced from a mean control value of 153.3 +/- 25.1 disintegrations per minute (dpm)/microgram DNA to 57.2 +/- 8.6 dpm/microgram DNA by lung liquid drainage (P < 0.05) and were significantly increased to 236.0 +/- 24.0 dpm/microgram DNA by tracheal obstruction (P < 0.05). Following tracheal obstruction, lung IGF-II mRNA levels were increased to 177.0 +/- 18.2% (P < 0.05) of the mean value for control fetuses, whereas they were reduced to 56.1 +/- 7.1% of control in lung liquid-drained fetuses. We conclude that altering fetal lung expansion has a potent and rapid effect on pulmonary DNA synthesis and that this effect may, in part, be mediated by an alteration in IGF-II gene expression.
Animals↗
Amiloride blocks the inhibition of fetal lung liquid secretion caused by AVP but not by asphyxia.
We have examined whether the activation of Na+ channels, located on the luminal surface of pulmonary epithelial cells, mediates the inhibitory effects of both arginine vasopressin (AVP) and moderate asphyxia on fetal lung liquid secretion. Lung liquid secretion rates were measured in chronically catheterized fetal sheep during AVP infusions and during periods of asphyxia with and without an Na+ transport blocker (amiloride; 10(-4) M) present in lung liquid. Lung liquid secretion rates were also measured during epinephrine infusions with amiloride present in lung liquid. These secretion rates were compared with measurements made during a preceding control period. Both asphyxia and an infusion of AVP significantly reduced the rate of secretion of fetal lung liquid from 8.4 +/- 1.5 and 18.0 +/- 3.7 to 3.6 +/- 1.0 (P < 0.01) and 5.5 +/- 2.1 ml/h (P < 0.01), respectively. The addition of amiloride to lung liquid did not reverse the inhibitory effects of asphyxia on lung liquid secretion (8.6 +/- 0.8 vs. 0.7 +/- 0.4 ml/h) but did block the inhibitory effects of both epinephrine (14.8 +/- 4.4 vs. 13.8 +/- 3.1 ml/h) and AVP (18.0 +/- 3.7 vs. 19.5 +/- 5.0 ml/h). The addition of amiloride to lung liquid during fetal normoxia did not significantly affect fetal lung liquid secretion rates (8.2 +/- 1.1 vs. 7.4 +/- 0.7 ml/h). We conclude that the inhibitory effect of AVP on fetal lung liquid secretion, like that of epinephrine, involves the activation of luminal surface Na+ channels, whereas the inhibitory effect of asphyxia does not.
Amiloride↗
Role of fetal breathing movements in control of fetal lung distension.
Our aim was to determine the role of fetal breathing movements (FBM) in the maintenance of fetal lung liquid volume. Experiments were performed in 14 chronically catheterized fetal sheep. FBM were selectively abolished for 48 h by the infusion of tetrodotoxin (TTX) onto the phrenic nerves of five fetuses. Lung liquid volumes and secretion rates were measured before each treatment, 46-48 h after the start of the TTX infusion, and 22-24 h after the end of the infusion. Blockade of the phrenic nerves reduced fetal lung liquid volumes from 27.6 +/- 1.9 to 21.8 +/- 2.6 ml/kg and increased lung liquid secretion rates from 3.8 +/- 0.6 to 6.2 +/- 1.1 ml.h-1.kg-1. Control experiments confirmed the lack of effect of TTX infused intravenously and saline infused intrapleurally on changes in fetal lung liquid volume and secretion rate. To measure the static relaxation volume of the fetal lung, in six fetuses we combined skeletal muscle paralysis with bypass of the upper airway for 48 h. This reduced fetal lung liquid volume from 39.1 +/- 3.1 to 23.0 +/- 2.5 ml/kg and increased lung liquid secretion rates from 4.1 +/- 0.7 to 5.8 +/- 0.9 ml.h-1.kg-1. This experiment demonstrates that the fetal lung is normally maintained at a level of expansion that is much greater than its static relaxation volume. We conclude that the volume of luminal liquid in the fetal lungs is dependent on the diaphragmatic contractions associated with FBM. Their effect is to resist the elastic recoil of the fetal lungs, thereby reducing the loss of liquid from the lungs via the trachea.
Animals↗
Abolition of fetal breathing movements by spinal cord transection leads to reductions in fetal lung liquid volume, lung growth, and IGF-II gene expression.
Fetal breathing movements (FBM) are considered necessary for normal growth and structural maturation of the fetal lung, but the underlying mechanisms are unclear. The small fluctuations in lung dimensions caused by FBM have been proposed as a stimulus to lung growth, but it is equally possible that FBM act by maintaining the basal level of lung luminal volume, which is an established determinant of fetal lung growth. Our aim, therefore, was to determine the effects of abolishing FBM, while retaining the integrity of the diaphragm, on the volume and rate of production of fetal lung liquid, gene expression for IGF-II, and fetal lung growth. FBM were abolished in seven fetal sheep by high spinal cord transection at 114 +/- 1.2 d of gestation; seven intact fetuses served as controls. At 119 to 124, 125 to 130, and 131 to 136 d, we measured the volume and secretion rate of lung liquid by dye dilution. At these three age ranges, the lungs of cord-transfected fetuses contained 27 to 53% less lung liquid than controls (p = 0.004), and their rates of secretion were 65 to 138% greater (p = 0.001). At postmortem (135 +/- 0.1 d), the lungs of the cord transected fetuses contained less DNA per kg body weight and tended to be lighter and to contain less protein than controls. IGF-II gene expression in the lungs of cord-transected fetuses was significantly less than that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Respiratory function in lambs after prolonged oligohydramnios during late gestation.
Our aim was to determine the effects of oligohydramnios during the last third of ovine gestation on respiratory function in lambs during their first postnatal month. To induce oligohydramnios, amniotic and allantoic fluids were drained from pregnant ewes, starting at 109.0 +/- 2.3 d of pregnancy (term approximately 148 d). In 10 lambs born at term, respiratory function was studied four times at weekly intervals; a group of nine lambs from normal pregnancies served as controls. Over the 4-wk study period, treated lambs had significantly higher breathing rates and smaller tidal volumes than controls, although the differences diminished with age. Minute ventilation and O2 consumption were the same in each group, and when related to body weight, both declined with age. Treated lambs were normoxemic but were hypercapnic compared with controls for up to 4 wk. Functional residual capacity, measured by helium dilution, was the same in each group and increased with age. Static compliance of the respiratory system was lower in treated lambs up to 4 wk; lung compliances were the same in each group, but chest wall compliance was lower in treated lambs than in controls for 4 wk. Postmortem measurements, at 27-28 d, of pulmonary dry weights, DNA contents, and protein contents suggest that the lungs of treated lambs may have been mildly hypoplastic. We conclude that oligohydramnios causes a decreased chest wall compliance, which leads to rapid, shallow breathing and a mild hypercapnia lasting for at least 4 postnatal wk.
Animals↗