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Biomedical subjects

J C Kingdom

Publications and source records attributed to J C Kingdom.

At least 19 recordsLinked to original sources
PubMed2001

Undernutrition during the first half of gestation increases the predominance of fetal tissue in late-gestation ovine placentomes.

OBJECTIVE: To investigate, in sheep, the effects of maternal undernutrition during the first half of pregnancy on placental growth and development and fetal growth. STUDY DESIGN: Six ewes (R) were subjected to a 15% reduction in nutrient intake for the first 70 days of gestation and thereafter received the recommended daily intake. Another group of six ewes (C) received the recommended daily intake throughout pregnancy. At 130 days gestation the ewes were killed and morphological and morphometrical measurements were carried out on the placenta and fetus. RESULTS: Undernutrition resulted in a significant alteration in placental morphology, which was seen as increased growth of the fetal side of the placenta in R animals. However, fetal size in late gestation was not affected by the undernutrition, suggesting that placental adaptation was successful in maintaining fetal growth. CONCLUSION: Placental adaptations, including changes in gross morphology, may preserve fetal growth if maternal undernutrition is not severe. The mechanisms remain to be elucidated.

Animals↗
PubMed2001

Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women.

Impaired invasion of uteroplacental arteries by extravillous trophoblast cells is a key pathogenic mechanism of preeclampsia. We previously demonstrated that reduced trophoblast invasion into uteroplacental spiral arteries was associated with an excess of macrophages in and around these arteries. To explore the significance of these observations, we correlated the extent of extravillous trophoblast apoptosis in placental bed biopsy specimens with macrophage distribution and studied the effect of macrophages upon trophoblast apoptosis in vitro. Extravillous trophoblast hybrid cells were cocultured with activated macrophages exposed to exogenous tumor necrosis factor alpha (TNFalpha), anti-tumor necrosis factor receptor I (TNF-RI), and tryptophan depletion, and the rates of trophoblast apoptosis were measured. Extravillous trophoblast hybrid cells showed increased rates of apoptosis following exposure to exogenous TNFalpha, with tryptophan depletion, and when cocultured with activated macrophages. The proapoptotic effects of macrophages in vitro were completely inhibited only by simultaneous addition of tryptophan and anti-TNF-RI. Our data indicate that macrophages, residing in excess in the placental bed of preeclamptic women, are able to limit extravillous trophoblast invasion of spiral arterial segments through apoptosis mediated by the combination of TNFalpha secretion and tryptophan depletion. The mechanisms by which macrophages are activated and recruited to the placental bed are presently unknown but are likely central to the pathogenesis of preeclampsia.

Adult↗
PubMed2000

Effect of early maternal iron stores on placental weight and structure.

BACKGROUND: Large placental size and low birthweight have been implicated as factors predicting high blood pressure in adulthood. Maternal anaemia has been suggested as a link. We investigated the interaction between maternal iron status and other factors known to influence birthweight and placental size. METHODS: In a prospective study of 1650 low-risk, singleton, caucasian pregnancies, we related placental size and birthweight to maternal iron status, socioeconomic status, and parity. Placental morphology was assessed in 17 randomly chosen primigravid pregnancies. FINDINGS: Parity was an important determinant of birthweight (mean standard deviation score -0.13 [SD 0.90] para 0; -0.24 [0.90] para 1; 0.32 [1.1] para 2; 0.21 [1.1] para > or = 3; p<0.0001) and placental weight (mean 655 g [SD 130]; 679 g [122]; 675 g [139]; 694 g [157], respectively; p=0.01). Cigarette smoking influenced birthweight only. Socioeconomic status had little effect after correction for parity. In addition to parity, the factors influencing placental weight were maternal height, weight, and serum ferritin concentration at booking, but not haemoglobin concentration. Serum ferritin concentrations were associated with folate intake and parity. In the placental morphology subset, serum ferritin concentration was inversely related to overall measures of peripheral villous capillarization. Haemoglobin concentration showed no such association. INTERPRETATION: These findings show a relation between maternal anaemia and placental size and birthweight across the normal range for these measures. Low ferritin concentrations in early pregnancy were associated with increased placental vascularisation at term. The association between ferritin concentration and folate supplementation emphasises the importance of preconceptional health, particularly in women at high risk of iron deficiency.

Adult↗
PubMed2000

Fetal cerebral blood flow redistribution in late gestation: identification of compromise in small fetuses with normal umbilical artery Doppler.

OBJECTIVE: To evaluate the role of middle cerebral artery Doppler in small fetuses during the late third trimester. DESIGN: Prospective observational study of structurally normal fetuses with an estimated fetal weight < 5th percentile for gestation. Perinatal outcome was determined using a structured datasheet sent to each referring obstetrician. SUBJECTS: Structurally normal fetuses at 35 or more weeks of gestation referred during a 2-year period to the fetal growth clinic of a regional fetal medicine unit in North London. Fetuses with aneuploidy and/or major structural abnormalities were excluded. METHODS: Umbilical artery and middle cerebral artery (MCA) Doppler waveforms were recorded and considered abnormal if above 95th or below 5th percentiles, respectively. Amniotic fluid was considered reduced if the maximum vertical cord-free pool was < 2 cm. The placenta was considered mature if the Grannum grade was II or III. The head circumference (HC)/abdominal circumference (AC) ratio was considered abnormal if > 95th percentile for gestation. Fetal growth, amniotic fluid, biophysical profile score and umbilical artery Doppler were used to advise the referring obstetrician about fetal well-being and he/she independently decided both the timing and mode of delivery. RESULTS: Forty-seven fetuses fulfilled the entry criteria. Thirty-four (72%) demonstrated normal umbilical artery Doppler waveforms. Sixteen (34%) demonstrated middle cerebral artery redistribution, of which nine (56%) had normal umbilical artery Doppler waveforms. MCA blood flow redistribution was associated with an increased incidence of cesarean delivery and need for neonatal admission. Of all gray-scale parameters, an elevated HC/AC ratio has the strongest association with MCA blood flow redistribution (15/16 vs. 1/31; P < 0.01). CONCLUSIONS: MCA Doppler may be a useful tool to assess the health of small fetuses in the late third trimester. Redistribution may occur in the presence of normal umbilical artery Doppler and should be suspected when the HC/AC ratio is elevated.

Adult↗
PubMed2000

Ontogeny of beta 2 glycoprotein I and annexin V in villous placenta of normal and antiphospholipid syndrome pregnancies.

beta2-glycoprotein I (beta2GPI) and annexin V (AV) have been implicated in the pathophysiology of the antiphospholipid syndrome (APS). We investigated their placental expression in normal villous tissues throughout gestation; first trimester n = 10, early second trimester; n = 4, preterm; n = 5) and term; n = 7 and in APS (2 first trimester, 1 preterm and 8 term deliveries). beta2GPI and AV were both expressed by the placenta from as early as seven weeks gestation and were colocalised to the syncytiotrophoblast. beta2GPI staining was also observed in stromal cells, being present in phagocytic Hofbauer cells and surrounding newly formed fetal vessels in a perivascular pattern, from seven to seventeen weeks gestation. An abnormal morphological distribution of AV was noted in one first trimester APS placenta, and for beta2GPI in a further first trimester placenta. When placental proteins were extracted from villous tissue, the concentration of AV/mg protein in term APS placentas (median, interquartile range) (aPS; 8.16, 7.879.72 microg/mg) was significantly higher (p <0.005) than normal term levels (normal; 2.47, 2.28-2.54 microg/mg). beta2GPI increased with advancing gestation (first trimester; 0.93, 0.64-1.26 microg/mg, term; 3.67, 2.58-4.48 microg/mg) in normal pregnancy. Term APS placentas had a reduced beta2GPI content (2.31, 1.87-2.49 microg/mg), p <0.05. The placental role of these proteins remains to be identified.

Abortion, Habitual↗
PubMed1999

Oxygen and placental vascular development.

Human embryogenesis takes place in a hypoxic environment because the trophoblast shell excludes entry of maternal blood. The first fetal-placental villi develop as trophoblast sprouts. These are invaded by allantoic mesoderm to form secondary villi and are transformed, by vasculogenesis, into tertiary villi. The placental barrier to maternal blood is gradually breached between 8-12 weeks of gestation, due to invasion of placental-bed uteroplacental spiral arteries by the extravillous trophoblast (EVT). Placental oxygen tension thus rises and a phase of branching angiogenesis continues until 24 weeks. Thereafter a gradual shift takes place favoring non-branching angiogenesis. Gas-exchanging terminal villi thus form which are essential for rapid fetal growth and development of a high-flow, low-resistance fetal-placental circulation. Inadequate invasion of the uteroplacental spiral arteries by EVT results in placental ischemia and the development of obstetrical complications--preeclampsia and/or intrauterine growth restriction (IUGR). Placental villi often show evidence of continued branching angiogenesis, as is the case with anemic pregnancy, and pregnancy at high altitude. These structural alterations may reflect continued hypoxia-driven activity of vascular endothelial growth factor (VEGF). By contrast, a minority of severe early-onset IUGR pregnancies exhibit reduced fetal-placental blood flow with elongated maldeveloped villous capillaries. Placenta-like growth factor (PIGF) expression is increased while trophoblast proliferation is reduced, suggesting "hyperoxia" in the placental villous tree. IUGR may thus have two phenotypes--a more common hypoxic and a rarer hyperoxic type. While this concept is gaining acceptance, we have no insight as to the initiating mechanism(s).

Animals↗
PubMed1999

Maternal cardiolipin, beta 2-glycoprotein-I and prothrombin antibody expression in high-risk pregnancies with bilateral abnormal uterine artery Doppler waveforms.

OBJECTIVE: To compare the frequency of maternal serum antiphospholipid antibodies (to cardiolipin, beta 2-glycoprotein I and prothrombin) in pregnancies presenting with bilateral abnormal uterine artery Doppler waveforms. DESIGN: Retrospective analysis of stored serum. SUBJECTS: Cases comprised 47 singleton pregnancies with bilateral abnormal uterine artery Doppler waveforms at 24 weeks of gestation, followed from 20 weeks, and controls were 100 healthy pregnancies with normal uterine artery Doppler waveforms. METHODS: Ultrasound examination utilized a 5-MHz curvilinear transabdominal transducer with pulsed and color Doppler facilities. Antiphospholipid antibodies were analyzed by ELISA methodology, and reference ranges were established using the geometric mean +/- 2 SD of healthy non-pregnant adults. Human chorionic gonadotropin (hCG) levels were obtained from patient notes. RESULTS: Anticardiolipin antibodies were detected in 11 (23%) of the cases (IgG, n = 7; IgM, n = 6) compared with ten (10%) of the controls (p < 0.05). Low titer anticardiolipin IgG (range, 5.5-35.3; median, 6.3 GPL units) and anticardiolipin IgM (range, 3.4-14.7; median, 5.3 MPL units) were detected in cases. Amongst the cases, adverse perinatal outcomes were more common in the presence of raised levels of anticardiolipin antibodies. Anti-beta 2-glycoprotein I IgG was not detected in any of the cases. Antiprothrombin IgG was not detected, but antiprothrombin IgM occurred in 10.6% of cases compared with 2% of controls. CONCLUSIONS: Women with persistent bilateral abnormal uterine artery. Doppler waveforms in mid-gestation were more likely to express raised levels of anticardiolipin antibodies than healthy controls with normal uteroplacental perfusion. Anticardiolipin antibodies without anti-beta 2-glycoprotein I binding may be involved in the pathogenesis of uteroplacental ischemia in a proportion of high-risk pregnancies.

Adolescent↗
PubMed1999

Intrauterine growth restriction is associated with persistent juxtamedullary expression of renin in the fetal kidney.

BACKGROUND: Intrauterine growth restriction (IUGR) has been linked to impaired renal function and hypertension, suggesting that an adverse prenatal environment could alter kidney development and renin production. METHODS: Immunohistochemistry and in situ hybridization were employed to localize renin-containing cells (RCCs) in the deep, middle, and superficial zones of autopsy kidney sections, in parallel with histologic maturation, from unexplained stillborn fetuses of normal weight (N = 26) and stillborn fetuses with IUGR (N = 17). RESULTS: In the control group, the number of RCC per 100 glomeruli in the deep zone decreased with advancing gestation from 40 at 20 weeks gestation to five at term (P < 0.001), whereas the opposite change was found in the superficial zone (increase from 5 per 100 to 55 per 100; P < 0.001). In the IUGR group, the density of RCCs in both the superficial and deep zones was similar to the control group at 20 weeks, and no shift in renin gene expression was observed as gestation advanced. Histologic maturation was unaltered. CONCLUSIONS: Renin gene expression persists and predominates in the deep renal cortex of the stillborn IUGR fetus, and could contribute to the pathogenesis of neonatal oliguria and/or hypertension during postnatal life.

Embryonic and Fetal Development↗
PubMed1999

Affinity purified human antiphospholipid antibodies bind normal term placenta.

Antiphospholipid antibodies (aPL) are associated with an increased incidence of fetal loss, but the pathophysiology remains unclear. One mechanism may involve the binding of aPL directly to the placenta where they may initiate placental thrombosis and infarction. We have developed an immunofluorescent technique to detect human aPL binding to human placenta. Endogenous immunoglobulins were eluted by extensive washing and residual staining was prevented by incorporating multiple blocking steps. APL were affinity purified on both cardiolipin and phosphatidylserine liposomes from the sera of six patients with aPL (five antiphospholipid syndrome (APS) patients and one post bone marrow transplant patient). Heterogeneous binding to normal term placenta, involving either the trophoblast microvillous surface, stromal and peri-vascular regions was demonstrated by affinity purified aPL from five of six patients. Preliminary sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting studies have demonstrated that aPL bind a number of placental proteins. beta2GPI was not the predominant protein bound by aPL using this technique. This study provides further evidence for the involvement of aPL in mediating placental damage.

Abortion, Spontaneous↗
PubMed1998

Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta.

Villous trophoblast in the human placenta consists of a population of proliferating stem cells which differentiate and individually fuse into the syncytiotrophoblast. We studied the apoptotic cascade in this complex epithelial layer by immunohistochemical localization of Fas, FasL, Bcl-2, Mcl-1, pro-caspase-3 and caspase-3, T-cell-restricted intracellular antigen-related protein (TIAR), poly(ADP-ribose) polymerase (PARP), lamin B, topoisomerase IIalpha, and transglutaminase II in cryostat and paraffin-fixed tissue sections from normal human first-trimester and term placental villi. The relationship between the apoptotic cascade and syncytial fusion was studied by coincubation of intact villi with FITC-coupled annexin-V, to detect the phosphatidylserine flip, and propidium iodide, to detect plasma membrane permeability. The final events of the apoptotic cascade were studied by the TUNEL reaction and ultrastructural appearance of the trophoblast. The phosphatidylserine flip was identified in some of the villous cytotrophoblastic cells, but the presence of both Bcl-2 and Mcl-1 proteins presumably prevented continuation of the apoptotic cascade. The syncytiotrophoblast demonstrated heterogeneous findings, suggesting variable progression along the apoptotic cascade. In some areas Bcl-2 and Mcl-1 predominated, with preservation of the nuclear proteins PARP, lamin B, and topoisomerase IIalpha; in other areas, especially in and around syncytial sprouts, Bcl-2 and Mcl-1 were absent, accompanied by loss of nuclear proteins, presence of phosphatidylserine flip, and TUNEL positivity. These data suggest that the apoptotic cascade is initiated in the villous cytotrophoblast, which in turn promotes syncytial fusion. Donation of anti-apoptotic proteins into the syncytium, such as Bcl-2 and Mcl-1, focally inhibits further progression along this cascade. Completion of the apoptotic cascade takes place in and around syncytial sprouts, providing further evidence that these are the sites of trophoblast shedding into the maternal circulation.

Apoptosis↗
PubMed1997

Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction does not support placental hypoxia at delivery.

In view of the pathological placental features of pre-eclampsia and intrauterine growth restriction (IUGR), and the angiogenic effects of vascular endothelial growth factor (VEGF), the aim of this study was to determine the expression of VEGF in placentae from normal pregnancies and to compare the results with placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction (IUGR). ELISA was used to measure circulating VEGF immunoreactivity in umbilical vein serum samples and immunohistochemistry was used to determine tissue expression of the protein. Since VEGF is known to be upregulated by hypoxia, the expression pattern of VEGF would provide further clues to the oxygen status in the placentae at the time of sampling, presently a subject under great debate. The geometric mean concentration of VEGF immunoreactivity in umbilical vein serum of normal pregnant women was 112.46 pg/ml, in women with pre-eclampsia 50.23 pg/ml and in IUGR alone 175.35 pg/ml. These values were not statistically different from each other. Immunolocalization of VEGF in normal term villous placenta was observed in the syncytiotrophoblast with less intense staining in stromal cells. No qualitative differences in localization of staining between the groups (normal pregnancies, pre-eclampsia, pre-eclampsia plus IUGR, and IUGR) was found. Intensity of staining in stromal cells was also similar in the groups studied. However, intensity of VEGF immunostaining in syncytiotrophoblast was significantly reduced in the three pathological groups (P < 0.02) compared with the control group. These results suggest that reduced VEGF may be responsible, at least in part, for the impaired vascular development which occurs in these conditions. Our results are therefore not consistent with villous placental hypoxia at the time of sample collection.

Adult↗
PubMed1997

Oxygen and placental villous development: origins of fetal hypoxia.

The increasing practice of preterm delivery in the fetal interest for conditions such as pre-eclampsia or intrauterine growth restriction (IUGR) has provided an opportunity to study placental structure in pregnancies with prenatal evidence of fetal compromise. These data suggest that the origin of fetal hypoxia in IUGR with absent end-diastolic flow in the umbilical arteries is due to a failure of oxygen transport from intervillous space to umbilical vein. Failure of the fetoplacental circulation to extract oxygen from the intervillous space under such circumstances means intervillous PO2 is closer to maternal arterial values than under physiological conditions. Correspondingly the placental villi are chronically exposed to a higher oxygen tension than under normal circumstances--the term ¿hyperoxia', relative to normal intraplacental oxygenation, is proposed to describe this situation. Both the trophoblast and villous core react to increased oxygen despite fetal hypoxia. These results challenge the generally accepted concept of ¿placental hypoxia' in all circumstances where fetal hypoxia might arise. Therefore three categories are proposed for the origins of fetal hypoxia: (1) preplacental hypoxia; (2) uteroplacental hypoxia; and (3) postplacental hypoxia. Examples for these three disease states are listed in this review and the structural reaction patterns of placental villi to these differences in oxygenation are discussed.

Animals↗
PubMed1997

Platelet sodium/hydrogen ion exchange in normal pregnancy and non-proteinuric pre-eclampsia.

In non-pregnant individuals, abnormalities in cation transport in vascular tissues have been linked to essential hypertension. In the present study, we consider whether Na+/H+ exchange (NHE) is affected in non-proteinuric pre-eclampsia (NPP). Platelet NHE characteristics and plasma cholesterol were measured in a cross-sectional study of normal primigravidae at 14 +/- 0.5 (n = 9), 29 +/- 0.7 (n = 7), 39 +/- 0.4 (n = 8) weeks gestation, in women with NPP (n = 15) and in non-pregnant women (n = 8). Amiloride-sensitive 22Na uptake was measured in platelets which had been acid loaded, to stimulate NHE, by suspension in isotonic potassium propionate buffer (pH 6.7). Intraplatelet radioactivity was used to calculate the affinity (Km) and the capacity (Vmax) of Na+ uptake. In normotensive women, Vmax (mean +/- s.e.) at 14, 29, 39 weeks gestation and 6 weeks postpartum were 452 +/- 46, 469 +/- 33, 713 +/- 101 and 562 +/- 77 pmolNa+/10(6) cells/min respectively; the third trimester values were higher (P < 0.05) than those in the first and second trimester and were also higher than those of non-pregnant women (415 +/- 20). Vmax of patients with NPP in the third trimester (712 +/- 44) was not different from gestational age-matched controls. Km values were not affected by gestational age or NPP. Plasma cholesterol concentration was positively correlated with Vmax values during normotensive pregnancy (r = 0.493, P < 0.05). In conclusion, the capacity for amiloride-sensitive Na+ uptake by platelets correlates positively with gestational age during normal pregnancy. However, neither the capacity nor affinity for Na+ was altered in NPP platelets suggesting that NHE is not implicated in the pathophysiology of this condition.

Adult↗
PubMed1997

The use of umbilical artery Doppler ultrasonography in modern obstetrics.

In contrast to the reduction in perinatal mortality in high-risk pregnancies, screening of low-risk pregnancies with umbilical artery Doppler ultrasonography has shown no benefit. Advances in pathophysiology question the assumption that the placenta is hypoxic in fetal growth restriction, with absent end-diastolic frequencies in the umbilical artery. The timing of delivery in relation to Doppler findings is uncertain, and so trials that relate Doppler findings to neurodevelopmental outcome are necessary to refine the role of this technique in obstetric practice.

Blood Pressure↗