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Biomedical subjects

M G Davey

Publications and source records attributed to M G Davey.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of talpid3 and wild-type chicken embryos reveals roles for Hedgehog signalling in development of the limb bud vasculature.

Chicken talpid(3) mutant embryos have a wide range of Hedgehog-signalling related defects and it is now known that the talpid(3) gene product encodes a novel protein essential for Hedgehog signalling which is required for both activator and repressor functions of Gli transcription factors (Davey, M.G., Paton, I.R., Yin, Y., Schmidt, M., Bangs, F.K., Morrice, D.R., Gordon-Smith, T., Buxton, P., Stamataki, D., Tanaka, M., Münsterberg, A.E., Briscoe, J., Tickle, C., Burt, D.W. (2006). The chicken talpid(3) gene encodes a novel protein essential for Hedgehog signalling. Genes Dev 20 1365-77). Haemorrhaging, oedema and other severe vascular defects are a central aspect of the talpid(3) phenotype (Ede, D.A. and Kelly, W.A (1964a). Developmental abnormalities in the head region of the talpid(3) mutant fowl. J. Embryol. exp. Morp. 12:161-182) and, as Hedgehog (Hh) signalling has been implicated in every stage of development of the vascular system, the vascular defects seen in talpid(3) are also likely to be attributable to abnormal Hedgehog signalling. Gene expression of members of the VEGF and Angiopoietin families of angiogenic growth factors has been linked to haemorrhaging and oedema and we find widespread expression of VEGF-D, rigf and Ang2a in the talpid(3) limb. Furthermore, ectopic expression of these genes in talpid(3) limbs points to regulation via Gli repression rather than activation. We monitored specification of vessel identity in talpid(3) limb vasculature by examining expression of artery-specific genes, Np1 and EphrinB2, and the vein-specific genes, Np2a and Tie2. We show that there are supernumerary subclavian arteries in talpid(3) limb buds and abnormal expression of an artery-specific gene in the venous submarginal sinus, despite the direction of blood flow being normal. Furthermore, we show that Shh can induce Np1 expression but has no effect on Np2a. Finally, we demonstrate that induction of VEGF and Ang2a expression by Shh in normal limb buds is accompanied by vascular remodelling. Thus Hedgehog signalling has a pivotal role in the cascade of angiogenic events in a growing embryonic organ which is similar to that proposed in tumours.

Animals↗
PubMed2002

Pulmonary epithelial liquid absorption, expressed in relation to alveolar surface area, is reduced in fetal lambs following in utero tracheal occlusion.

We examined the effect of accelerated lung growth, induced by in utero tracheal occlusion (TO), on lung liquid uptake in near-term fetal sheep. In utero TO was performed in five fetal sheep at 110 days of gestation (term, approximately 145 days); six SHAM operated fetuses served as controls. The rate of liquid movement across the pulmonary epithelium was measured, using a previously established technique, in anesthetized fetal sheep between 133-137 days of gestation during a 2-hr adrenaline infusion (0.50 microg/min/kg, I.V.) and while lung luminal pressure was maintained at 5 mmHg. The rate of fetal lung liquid uptake was linear in all fetuses (mean r(2) < 0.97, n = 11). Mean values of lung liquid uptake expressed in relation to dry lung weight and luminal surface area of the right lung were significantly lower in TO fetuses (1.8 +/- 0.3 mL/hr/g and 1.0 +/- 0.2 mL/hr/m(2)) than in SHAM fetuses (2.6 +/- 0.2 mL/hr/g and 1.8 +/- 0.1 mL/hr/m(2)); surface area of the right lung was 140% greater in TO fetuses than in SHAM fetuses. There was a linear relationship between lung liquid uptake and pulmonary epithelial surface area in SHAM animals, but not in TO fetuses. We hypothesize that loss of alveolar epithelial type-II cells induced by increased levels of fetal lung expansion may impair alveolar liquid clearance in the perinatal period.

Animals↗
PubMed2001

Stimulation of lung growth in fetuses with lung hypoplasia leads to altered postnatal lung structure in sheep.

Increased lung expansion in the fetus stimulates lung growth and is being trialed clinically to reverse severe fetal lung hypoplasia. Our aim was to examine the effects of increased fetal lung expansion in the presence of lung hypoplasia on lung structure in sheep at term and 8 weeks after birth. Lung hypoplasia was induced in 15 fetal sheep by continuous drainage of tracheal fluid, commencing at approximately 113 days of gestation (term, approximately 148 days). In 10 of these fetuses, tracheal obstruction (TO) was performed from 137-147 days of gestation (treated lung hypoplasia, TLH), while lung liquid drainage continued until term in the remaining 5 fetuses (untreated lung hypoplasia, ULH). Lung tissues were obtained from 5 TLH, 5 ULH, and 5 control lambs at birth, and from 5 TLH and 5 control lambs at 8 weeks after birth. At birth, alveolar number, surface area, and interalveolar wall thickness were not different between TLH and control lambs, whereas airspace diameter was greater in TLH lambs (72.7 +/- 3.0 microm) than in controls (58.4 +/- 4.3 microm). Diameters of airspaces were not different between ULH and control lambs; however, alveolar numbers and surface area were reduced, while interalveolar wall thickness was increased in ULH lambs compared to controls. At 8 weeks after birth, alveolar number (928.0 +/- 66.1 x 10(6)) and surface area (30.3 +/- 2.2 m(2)) in TLH lambs were lower, whereas interalveolar wall thickness (83.0 +/- 3.1 microm) was greater than in control lambs (2,263.6 +/- 261.6 x 10(6), 46.7 +/- 4.8 m(2), and 68.6 +/- 2.1 microm, respectively). Our data show that TO restores most aspects of lung structure to normal in fetuses with lung hypoplasia but leads to altered alveolar development. The presence of fewer, larger alveoli in postnatal TLH animals may predispose these animals to respiratory complications during later life.

Analysis of Variance↗
PubMed2001

Compromised respiratory function in postnatal lambs after placental insufficiency and intrauterine growth restriction.

Epidemiologic studies have shown persistent effects of low birth weight on respiratory function and lung health, but underlying mechanisms are not understood. Our aim was to determine the effects of intrauterine growth restriction (IUGR), a major cause of low birth weight, on postnatal respiratory function. IUGR was induced by umbilico-placental embolization during late gestation in chronically catheterized sheep. Umbilico-placental embolization was performed between 120 d of gestation and term ( approximately 146 d) during which fetuses were hypoxemic and hypoglycemic relative to controls. Umbilico-placental embolization led to a 48% reduction in birth weight compared with controls, and throughout the postnatal study period IUGR lambs (n = 8) remained lighter than controls (n = 8). Respiratory function was repeatedly studied in lambs for 8 wk after birth; during this period, IUGR lambs were mildly hypoxemic and tended to be hypercapnic compared with controls. In IUGR lambs, relative to controls, O(2) consumption (mL/min/kg) and minute ventilation (mL/kg) were increased and pulmonary diffusing capacity (adjusted for functional residual capacity) was decreased. Functional residual capacity, measured by helium dilution, and total lung capacity (measured at 30 cm H(2)O) were smaller in IUGR lambs than in controls. When adjusted for functional residual capacity, static lung compliance was reduced and chest wall compliance was increased in IUGR lambs. At 8 wk, pulmonary DNA and protein concentrations were decreased in IUGR lambs relative to controls. We conclude that restriction of fetal growth by placental insufficiency induces alterations in the lungs and chest wall that result in persistent impairments in respiratory function during early postnatal life.

Animals↗
PubMed2001

Effect of increased lung expansion on surfactant protein mRNA levels in lambs.

Increased fetal lung expansion profoundly inhibits surfactant protein gene expression and stimulates cellular proliferation in the fetal lung. Our aim was to determine whether increased expansion of the lung after birth, by the application of a continuous positive airway pressure (CPAP) for 12 h, inhibits surfactant protein gene expression and stimulates cell division in lambs. Two week-old lambs were randomly divided into 2 groups (n = 5 for each), sedated, and exposed to either no CPAP (controls) or 10 cm H(2)O of CPAP during a 12-hour treatment period. After 2 h of the treatment, (3)H-thymidine was administered to each lamb (iv) to measure pulmonary DNA synthesis rates over the following 10 h of treatment. To assess the increase in lung expansion, functional residual capacity (FRC) was measured before the start of the treatment period and again at 6 and 12 h. Compared with control lambs, a CPAP of 10 cm H(2)O increased FRC from 26.8 +/- 3.8 mL/kg to 62.9 +/- 19.7 mL/kg at 6 h and it remained elevated at 12 h (56.2 +/- 5.7 mL/kg). Despite this large increase in end expiratory lung volume (FRC), the mRNA levels for SP-A, SP-B, and SP-C and DNA synthesis rates in lung tissue were not altered. The results of this study indicate that, in contrast to the fetus, an increase in end expiratory lung volume of approximately 100% does not affect surfactant protein gene expression or pulmonary DNA synthesis rates in 2 week old lambs. Thus, the response of the lung to increases in lung expansion varies markedly before and after birth.

Animals↗
PubMed2000

The compromised intra-uterine environment: implications for future lung health.

1. Epidemiological studies of infants, children and adults indicate that prenatal compromises that restrict fetal growth and cause low birthweight increase the risk of respiratory deficiencies after birth. 2. It is apparent that the lung has a limited ability to recover from early developmental compromises and that altered development can permanently impair lung architecture. 3. Lung development in utero can be adversely affected by factors associated with fetal growth restriction, namely fetal hypoxaemia, reduced substrate supply and hypercortisolaemia. 4. We have conducted a series of studies of respiratory development in chronically catheterized ovine fetuses and postnatal lambs in which growth restriction was induced during late gestation by embolizing the umbilico-placental vascular bed, a technique that replicates key aspects of human placental insufficiency. 5. During late gestation, restricting the growth of the ovine fetus did not alter lung weight or lung liquid secretion or volume when each factor was related to bodyweight, but it did lead to increased lung DNA concentrations and an increased thickness of the air-blood barrier. Expression of pulmonary surfactant proteins A, B and C were not altered and, hence, it was unlikely that surfactant protein synthesis had been impaired by growth restriction. 6. When growth restriction continued to term, lambs were born with a low birthweight and remained small compared with controls for 8 weeks after birth. Low-birthweight lambs were mildy hypoxaemic and compliances of their lungs and chest wall were, respectively, decreased and increased relative to controls. Pulmonary surfactant proteins A, B and C were not deficient, indicating that decreased lung compliance most likely had a structural basis.

Animals↗
PubMed1999

Collecting duct morphogenesis.

The collecting duct system of the metanephric kidney develops from the ureteric bud, an outgrowth from the caudal end of the Wolffian duct. The ureteric bud is induced to form by signals emanating from a specific area of intermediate mesoderm, which it immediately invades. In response to further mesenchyme-derived signals, the ureteric bud ramifies to form a tree-like collecting duct system, which in turn signals clumps of the mesenchyme cells that surround it to differentiate into epithelial nephrons. The morphogenesis of the collecting duct system is driven by two processes--growth and branching--which are to some extent separable. Each depends on diffusible signals, a number of which have been identified in recent years; growth promoters include hepatocyte growth factor and activin, while ramogens include glial cell line-derived neurotrophic factor, neurturin and persephin. Arborisation also depends on matrix components, including proteoglycans, integrins and their ligands, and metalloproteinases, such as matrix metalloproteinase-9, that are involved in matrix remodelling. So far, little progress has been made in elucidating the intracellular pathways responsible for translating growth factor "instructions" into morphological change, but a role for some intracellular components, such as protein kinase C, formins and the cytoskeleton, is implied by recent experimental data. More information on these internal pathways of control is expected over the next few years.

Aging↗
PubMed1999

Respiratory function in lambs after in utero treatment of lung hypoplasia by tracheal obstruction.

Tracheal obstruction (TO) stimulates growth of hypoplastic lungs in the fetus, but there is little knowledge of subsequent postnatal respiratory function. We have determined the effectiveness of TO in fetal sheep with existing lung hypoplasia in restoring postnatal respiratory function. Lung hypoplasia was induced by lung liquid drainage from 112 days of gestation to term ( approximately 148 days). We used an untreated group (ULH), a treated group (TLH) in which the trachea was obstructed for 10 days, and a control group. ULH lambs died within 4 h of birth. TLH lambs were hypoxic for the first week and were hypercapic at 2 days. Pulmonary diffusing capacity, gas volumes, and respiratory compliances were not different between control and TLH lambs. Minute ventilation was not different between the two groups; however, tidal volumes were lower and respiratory frequencies were higher in TLH lambs than in controls for 2 wk after birth. We conclude that 10 days of TO in the presence of initial lung hypoplasia prevents death at birth and returns most aspects of pulmonary function to normal by 1-2 wk after birth.

Aging↗
PubMed1998

Postnatal development of respiratory function in lambs studied serially between birth and 8 weeks.

We have quantified developmental changes in major aspects of respiratory function in 12 pentobarbitone-sedated lambs by making repeated measurements during the first 8 postnatal weeks, between term birth and post-weaning. Pulmonary diffusing capacity for CO increased with age due to increases in both the diffusing capacity of the alveolar capillary membrane (Dm) and pulmonary capillary blood volume (Vc). Total lung capacity measured at a lung inflation pressure of 30 cmH2O decreased from 74.4 +/- 3.2 ml/kg at 3 days to 47.2 +/- 2.9 ml/kg at 8 weeks. Static respiratory system compliance, measured between FRC and TLC fell rapidly during the first 3 weeks, then remained unchanged; the early postnatal fall was largely due to a reduction in chest wall compliance as lung compliance was constant. FRC declined from 32.3 +/- 1.7 ml/kg at 3 days to 25.1 +/- 1.5 ml/kg at 2 weeks, then fell to 21.4 +/- 1.2 ml/kg by 8 weeks. Specific pulmonary conductance (conductance/FRC) during mid-inspiration and mid-expiration did not change with age (0.195 +/- 0.012 and 0.194 +/- 0.019 L x sec(-1) x cmH2O(-1) x L(-1)-FRC, respectively). Breathing frequency, and weight-adjusted tidal volume and minute ventilation declined after birth until 4 weeks after which they did not change. This study has shown that, using basic methodology, serial assessments of respiratory function can be obtained in sedated lambs from soon after birth. The age-related increase seen in pulmonary diffusing capacity is due to increases in both Dm and Vc, which are consistent with continuing alveolarisation. Our data on age-related changes in pulmonary function and volumes provide a reference for future studies on the effect of altered prenatal lung development on postnatal lung function in sheep.

Aging↗
PubMed1996

Prematurity alters hypoxic and hypercapnic ventilatory responses in developing lambs.

We have determined the effects of preterm birth on the postnatal development of ventilatory responses to progressive hypoxia and hypercapnia in awake lambs. Hypoxic and hypercapnic rebreathing tests were performed at weekly intervals in 5 preterm (born at 135 +/- 0.5 d) and 5 term (born at 146 +/- 0.2 d) lambs up to 6-7 weeks after birth. Term lambs were also studied at 25 weeks after birth. During rebreathing tests, we measured arterial PO2 and PCO2 and related them to minute ventilation (VI). Owing to variability in resting PAO2, hypoxic sensitivity was defined as the percentage increase in VI when PaO2 fell to 60% of resting values. Hypoxic sensitivities of preterm lambs did not change with age (68.9 +/- 24.4%), whereas values for term lambs more than doubled over the first 6 weeks (day 2, 73.9 +/- 15.8%; week 6, 227.4 +/- 24.9%) but returned to early postnatal values by week 25 (87.0 +/- 21.2%). Hypercapnic sensitivities (ml min-1 kg-1 mmHg CO2(-1) of preterm lambs were lower than those of term lambs between day 2 and week 2, but reached values in term lambs thereafter. We conclude that preterm birth abolishes the normal postnatal maturation of hypoxic ventilatory sensitivity, and temporarily depresses hypercapnic sensitivity.

Animals↗
PubMed1996

Development of ventilatory responsiveness to progressive hypoxia and hypercapnia in low-birth-weight lambs.

Our aim was to determine the effects of low birth weight on ventilatory responses to progressive hypoxia and hypercapnia during early postnatal life. Seven low-birth-weight (2.7 +/- 0.3 kg) and five normal-birth-weight (4.8 +/- 0.2 kg) lambs, all born at term, underwent weekly rebreathing tests during wakefulness while arterial PO2, PCO2, and pH were measured. Hypoxic ventilatory responsiveness (HOVR; percent increase in ventilation when arterial PO2 fell to 605 of resting values) increased in normal lambs from 86.6 +/- 7.1% at week 1 to 227.4 +/- 24.9% at week 6. In low-birth-weight lambs, HOVR was not significantly different at week 1 (60.1 +/- 18.7%) from that of normal lambs but did not increase with postnatal age (56.6 +/- 19.3% at week 6). HOVR of all lambs at 6 wk was significantly correlated with birth weight (r2 = 0.8). Hypercapnic ventilatory responsiveness (gradient of ventilation vs. arterial PCO2) did not change with age and was not significantly different between groups [84.7 +/- 7.5 (low-birth-weight lambs) vs. 89.4 +/- 6.6 ml.min-1.kg-1.mmHg-1 (normal lambs)]. We conclude that intrauterine conditions that impair fetal growth lead to the failure of HOVR to increase with age.

Aging↗
PubMed1980

Population study of heterophile antibodies.

Sera from 2,829 participants in a population health survey were tested for the presence of a heterophilic antibody, detectable by immunofluorescence. The antibody was found in 9.8% of the sera from women and in 12.4% of the sera from men. The age-specific prevalence of the antibody was relatively constant in women but rose steeply in men. The antibody occurred more frequently in individuals with a history of blood transfusion and in multiparous females. It is suggested that the antibody may result from immunization by a ubiquitous agent which can be transmitted by blood transfusion.

Adolescent↗
PubMed1980

Haemolytic disease of the newborn in Western Australia 1974 to 1976.

The prophylactic use of anti-Rh (D) immunoglobulin has resulted in a marked decline in the incidence of Rh haemolytic disease of the newborn (HDN) since its introduction in 1968. Nevertheless, cases still occur. Those recorded in the metropolitan area of Western Australia in the 3 years, 1974 to 1976, have been studied in detail. There were 29 cases of ABO haemolytic disease, among which there were no deaths, and 56 cases of Rh haemolytic disease with 9 perinatal deaths. Nearly half of the mothers of the infants with Rh HDN were first immunised before anti-D became available; a quarter had not been given anti-D when it was required, and a few had formed Rh antibodies in their first pregnancy or despite treatment with anti-D.

ABO Blood-Group System↗
PubMed1977

Characterization of human heterophile antibodies apparently induced by alloimmunization.

Human heterophile antibodies reactive with various tissues of different species may be detected by indirect immunofluorescence. Results of screening sera obtained after rhesus immunization and before and after blood transfusion and renal transplantation suggest that such antibodies can appear following alloimmunization of group A and O individuals. Eleven positive sera selected for detailed study were found to have anti-B isohaemagglutinins together with rat erythrocyte agglutinins. Absorption studies suggested that there may be some relationship between the group B antigen and the rat antigen concerned but the precise explanation for alloimmunization remains to be determined.

ABO Blood-Group System↗