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F Stewart

Publications and source records attributed to F Stewart.

At least 19 recordsLinked to original sources
PubMed2006

Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.

BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. METHODS: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. RESULTS: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. CONCLUSIONS: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

Abnormalities, Multiple↗
PubMed2005

Placentation in the African elephant, Loxodonta africanus: III. Ultrastructural and functional features of the placenta.

Successful transfer of nutrients to the elephant fetus during pregnancy relies on a variety of placental modifications. Our light and electron microscopical investigations show that the structure is endotheliochorial from implantation to term, with unicellular, never syncytial trophoblast. Light and electron microscope immunocytochemistry shows the restriction of the glucose transporter 1 isoform to the basolateral surfaces of the trophoblast, with the glucose transporter 3 restricted to the apical plasmalemma of the trophoblast. Glucose transport to the fetus therefore requires a sequential use of both isoforms. Light and electron microscope cytochemistry indicate the presence of iron deposits only in the haemophagous zones confirming their iron transport function. No trophoblast areas with high concentrations of Calcium binding protein, specialised for Calcium transport were found. In situ hybridisation demonstrated the presence of IGF-II mRNA in the trophoblast from the earliest stage, with TGFbeta1 and HGF-SF mRNA expressed subsequently but only IGF-II and HGF mRNA present in the second half of pregnancy. The results are briefly discussed in terms of placental growth and function and indicate that the elephant placenta is another example of a unique solution to the variety of problems posed by a resident fetus.

Animals↗
PubMed2004

Fetal cord plasma lipoprotein status in uncomplicated human pregnancies and in pregnancies complicated by pre-eclampsia and intrauterine growth restriction.

Maternal lipids have been studied extensively in pre-eclampsia (PE) and intrauterine growth restriction (IUGR) but little is known about fetal lipids. We hypothesised that the maternal lipid perturbations in PE and IUGR pregnancies would result in similar alterations in the fetal lipid profile. We performed a cross-sectional case control study of maternal and fetal (delivery venous cord blood) lipid and lipoprotein concentrations in third trimester uncomplicated pregnancies (n = 81) and in pregnancies complicated by PE (n = 23) or IUGR (n = 17). In uncomplicated pregnancies, fetal log total cholesterol (TC), log triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were significantly affected by mode of delivery. Fetal log TC (r = 0.37, P = 0.02), log TG (r = 0.34, P = 0.04) and TC/HDL-C ratio (r = 0.31, P = 0.05) were positively correlated with placental weight. Maternal TC (r = 0.35, P = 0.03) and LDL levels (r = 0.36, P = 0.02) were associated with fetal HDL-C levels. Maternal TC was significantly elevated in PE [mean 6.75 (standard deviation 1.14) mmol/L] compared to BMI-matched controls [5.94 (0.89) mmol/L P = 0.04]. In PE, fetal log TC [mean 0.36 (0.23) versus 0.11 (0.15) log mmol/L, P = 0.03], fetal log TG [-0.21 (0.32) versus -0.49 (0.26) log mmol/L, P = 0.02] and fetal TC/HDL-C ratio [3.64 (1.62) versus 1.80 (0.86), P = 0.001] were higher than in controls, after adjustment for mode of delivery. In IUGR, fetal log TG [-0.17 (0.35) versus -0.57 (0.10) log mmol/L, P = 0.01] was higher than controls, after adjustment for mode of delivery. There were no correlations between maternal and fetal lipid levels, or between fetal birth weight and either maternal or fetal lipids in the PE or IUGR groups. We conclude that although fetal lipids do not show a direct correlation with maternal lipids in PE or IUGR, these complications of pregnancy significantly impact upon fetal lipid levels possibly due to increased fetal stress or compromised placental lipid transport. Our findings are potentially pertinent to understanding the future cardiovascular health of the offspring.

Adult↗
PubMed2002

The influence of maternal size on placental, fetal and postnatal growth in the horse. II. Endocrinology of pregnancy.

Within-breed artificial insemination and between-breed embryo transfer were carried out in small pony (P) and large Thoroughbred (Tb) mares to create 4 types of horse pregnancy in which the fetus experienced spatial and nutritional deprivation (Tb-in-P; n=8), luxury (P-in-Tb; n=7) or normality (Tb-in-Tb; n=7 and P-in-P; n=7) in utero. Measurement of equine chorionic gonadotrophin (eCG), total conjugated oestrogens and progestagen concentrations in serial peripheral serum samples recovered from all the mares throughout gestation showed that the amount of eCG produced during the first half of gestation was dependent upon the breed of the mare rather than the breed of the fetus being carried. In contrast, the mean total amounts of oestrogens produced, as measured by area under the curve, were significantly greater (P=0.003) in the two types of pregnancy in which a Thoroughbred fetus was being carried (Tb-in-Tb and Tb-in-P) than those in which a pony fetus was gestated (P-in-P and P-in-Tb); the evidence suggests that the Tb fetus may have larger gonads than the P fetus and thereby secrete more C-19 precursor steroids for aromatisation to oestrogens by the placenta. In the final weeks of pregnancy mean plasma progestagen concentrations rose much earlier, and to significantly higher levels (P<0.001), in the Tb-in-P than in the P-in-Tb pregnancies, thereby reflecting the increased fetal stress in the former causing premature maturation of the fetal adrenal gland. This, in turn, resulted in increased secretion of pregnenolone by the adrenal cortex for conversion to progestagens by the placenta.

Analysis of Variance↗
PubMed2002

Influence of maternal size on placental, fetal and postnatal growth in the horse. I. Development in utero.

The interacting influences of maternal size and fetal genotype on placental and fetal development in the mare were assessed by comparing conventional within-breed Thoroughbred (Tb-in-Tb, n = 7) and Pony (P-in-P, n = 7) control pregnancies established by artificial insemination (AI) with between-breed (Tb-in-P, n = 8; deprived in utero condition and P-in-Tb, n = 7; luxurious in utero condition) experimental pregnancies established by embryo transfer. All foals were born spontaneously and the mean (+/- SEM) duration of gestation in the two groups of control mares was significantly different (P < 0.001) at 325 +/- 3.0 days for the P-in-P pregnancies and 339 +/- 3.0 days for the Tb-in-Tb pregnancies, whereas the durations of gestation for the two experimental groups were very similar and midway between those of the control pregnancies at 332 +/- 2.8 days for the Tb-in-P and 331 +/- 2.7 days for the P-in-Tb. Mean (+/- SEM) foal birth weight and the mean (+/- SEM) values for the mass, gross area and volume of the allantochorion were all highest in the seven Tb-in-Tb pregnancies (53.1 +/- 2.6 kg, 3.8 +/- 0.3 kg, 12.9 +/- 0.3 x 10(3) cm(2), 3.5 +/- 0.2 l, respectively) and lowest in the seven P-in-P control pregnancies (24.0 +/- 1.3 kg, 1.7 +/- 0.1 kg, 8.3 +/- 0.3 x 10(3) cm(2), 1.8 +/- 0.1 l, respectively). These parameters were higher in the seven P-in-Tb pregnancies (37.9 +/- 2.1 kg, 2.7 +/- 0.1 kg, 10.1 +/- 0.5 x 10(3) cm(2), 2.5 +/- 0.1 l, respectively) than in the eight Tb-in-P (33.0 +/- 2.4 kg, 2.3 +/- 0.2 kg, 9.0 +/- 0.5 x 10(3) cm(2), 2.1 +/- 0.1 l) experimental pregnancies. Foal birth weight was positively correlated with the mass (r = 0.84, P < 0.001), gross area (r = 0.87, P < 0.001) and volume (r = 0.91, P < 0.001) of the allantochorion, and maternal weight was also positively correlated with both the mass and gross area of the allantochorion (r = 0.64 and 0.69, respectively; both P < 0.001). Application of stereology to multiple random biopsies recovered from each placenta produced mean values for the surface density of microcotyledons on the allantochorion (S(v)). Values were higher in Thoroughbred than in Pony mares regardless of the breed of fetus being carried. Multiplication of S(v) by the volume of the allantochorion to give the total microscopic area of fetomaternal contact at the placental interface was also positively correlated with foal birth weight (r = 0.84, P < 0.001). Foal birth weight was determined by the microscopic area of fetomaternal contact of the placenta and there were no differences in foal weight per m(2) of placenta regardless of fetal or maternal genomes. Thus, the results indicate that in equids, maternal size interacts with both the maternal and fetal genotypes to control the rate and extent of fetal growth by influencing the gross area of the diffuse allantochorion, and the density, complexity and depth of the microcotyledons on its surface.

Analysis of Variance↗
PubMed2001

Uterocalin, a lipocalin provisioning the preattachment equine conceptus: fatty acid and retinol binding properties, and structural characterization.

The equine conceptus is surrounded by a fibrous capsule that persists until about day 20 of pregnancy, whereupon the capsule is lost, the conceptus attaches to the endometrium and placentation proceeds. Before attachment, the endometrium secretes in abundance a protein of the lipocalin family, uterocalin. The cessation of secretion coincides with the end of the period during which the conceptus is enclosed in its capsule, suggesting that uterocalin is essential for the support of the embryo before direct contact between maternal and foetal tissues is established. Using recombinant protein and fluorescence-based assays, we show that equine uterocalin binds the fluorescent fatty acids 11-(dansylamino)undecanoic acid, dansyl-D,L-alpha-amino-octanoic acid and cis-parinaric acid, and, by competition, oleic, palmitic, arachidonic, docosahexaenoic, gamma-linolenic, cis-eicosapentaenoic and linoleic acids. Uterocalin also binds all-trans-retinol, the binding site for which is coincident or interactive with that for fatty acids. Molecular modelling and intrinsic fluorescence analysis of the wild-type protein and a Trp-->Glu mutant protein indicated that uterocalin has an unusually solvent-exposed Trp side chain projecting from its large helix directly into solvent. This feature is unusual among lipocalins and might relate to binding to, and uptake by, the trophoblast. Uterocalin therefore has the localization and binding activities for the provisioning of the equine conceptus with lipids including those essential for morphogenesis and pattern formation. The possession of a fibrous capsule surrounding the conceptus might be an ancestral condition in mammals; homologues of uterocalin might be essential for early development in marsupials and in eutherians in which there is a prolonged preimplantation period.

Animals↗
PubMed2001

Evaluation of a media campaign to increase knowledge about emergency contraception.

Our objective was to evaluate a media campaign designed to increase knowledge about emergency contraception. Random telephone surveys were conducted before and after the campaign to measure changes in knowledge about emergency contraception. Change in the volume of calls to the Emergency Contraception Hotline (1-888-NOT-2-LATE) was a secondary measure of impact. Significant increases occurred in the proportions of women who knew that something could be done after intercourse to prevent pregnancy, who knew the term emergency contraception, who knew of the 72-h time limit, and who had heard of the Hotline. In addition, the number of calls to the Hotline increased substantially. A public education media campaign resulted in significant increases in knowledge about emergency contraception. The first contraception advertisement ever shown on television did not provoke controversy.

Advertising↗
PubMed2001

Emergency contraception.

Emergency contraceptives are methods that prevent pregnancy when used shortly after unprotected sex. Three different emergency contraceptive methods are safe, simple, and widely available in the United States. These are: (1) ordinary combined oral contraceptives containing ethinyl estradiol and levonorgestrel taken in a higher dose for a short period of time and started within a few days after unprotected intercourse; (2) levonorgestrel-only tablets used similarly; and (3) copper-bearing intrauterine devices inserted within approximately 1 week after unprotected intercourse. Emergency contraceptive use is best known for women who have been raped, but the methods are also appropriate for women who have experienced condom breaks, women who did not use any method because they were not planning on having sex, or women who had unprotected intercourse for any other reason. Unfortunately, few women know about emergency contraceptives, and few clinicians think to inform their patients routinely about the option. A nationwide toll-free hotline (1-888-NOT-2-LATE) and a website (http://not-2-late.com) can help women learn about these options. Sharing "family planning's best-kept secret" widely with women could prevent as many as a million unwanted pregnancies annually in the United States.

Contraceptives, Oral, Combined↗
PubMed2001

Equine placentation.

A tough, elastic glycoprotein capsule envelops the equine blastocyst between Days 6 and 23 after ovulation. It maintains the spherical configuration of, and provides physical support for, the embryo as it traverses the entire uterine lumen during Days 6-17, propelled by myometrial contractions that are stimulated by pulsatile release of prostaglandin F2alpha and prostaglandin E2. The capsule also accumulates constituents of the exocrine secretions of the endometrial glands ('uterine milk') as nutrients for the mobile embryo as it releases its antiluteolytic maternal recognition-of-pregnancy signal to the whole of the surface of the endometrium. Mobility ceases abruptly on Day 17 with a sudden increase in uterine tonicity that 'fixes' the conceptus at the base of one of the uterine horns. At Day 35, the trophoblast of the spherical conceptus has separated into its invasive and non-invasive components. The former, distinguished as the thickened, annulate chorionic girdle, invades the maternal endometrium to form the unique endometrial cups. These secrete a chorionic gonadotrophin that synergizes with pituitary follicle-stimulating hormone to induce secondary luteal development in the maternal ovaries. The cup cells express foreign fetal antigens that stimulate strong maternal humoral and cell-mediated immune responses, which curtail their lifespan. The non-invasive trophoblast of the allantochorion establishes a stable microvillous contact with the endometrial epithelium around Day 40 and, over the next 100 days, develops a complex multibranched interdigitation with the endometrium to form the microcotyledonary haemotrophic exchange units that cover the entire surface of the diffuse epitheliochorial placenta. Reduction in the effective total area of fetomaternal contact at this placental interface, by competition between twin conceptuses for the limited area of available endometrium, by attachment of the allantochorion to an imperfect endometrium in a mare with endometrosis, or following cross-breeding or embryo transfer between a sire and dam of dissimilar size, will all induce intrauterine growth retardation of the fetus and runting of the foal, which persists into adult life. Over 40 years ago, Professor Roger Short and his colleagues determined that the high concentrations of conventional and unique ring B unsaturated oestrogens in the blood and urine of mares during the second half of pregnancy stem from placental aromatization of large quantities of C-19 precursor molecules secreted by the temporarily hypertrophic fetal gonads. Placental production of progesterone and 5alpha-reduced progestagens, on the other hand, depends on both maternal and fetal adrenal sources of pregnenelone.

Allantois↗
PubMed2000

A novel uterine lipocalin supporting pregnancy in equids.

Horses, donkeys, and therefore, probably all equids, secrete a nonglycosylated, progesterone-dependent, 19-kDa protein (P19) into the uterine lumen during early pregnancy, and significant quantities of it are taken up by the developing conceptus. Sequence analysis and structural modelling have identified P19 as a lipocalin with greatest similarity to the murine major urinary protein lipocalins. However, lack of strong identity with any particular group of lipocalins and several unusual structural features, including a unique amino acid triplet within one of the invariant domains and an unusual external tryptophan residue, classify it as a new member of the lipocalin family. P19 is therefore likely to be a transport protein involved in supporting early embryonic development. Preliminary evidence using recombinant-derived P19 and fluorescently tagged ligands suggests that it may transport a fatty acid or retinol-like molecule. Although an initial search failed to identify homologues of P19 in other mammals, they may nevertheless exist but are synthesised and secreted in much smaller quantities, making them difficult to detect. Equids appear to need particularly large quantities of the protein during early pregnancy because of the unusually late implantation in this species and the presence of a capsule surrounding the conceptus until about day 23 of gestation.

Animals↗
PubMed2000

Horse conceptuses secrete insulin-like growth factor-binding protein 3.

Insulin-like growth factor-I (IGF-I) promotes early embryonic development in several species. In the rabbit, IGF-I binds to the embryonic coats from Day 3 of development onward by a 38-kDa protein that is probably insulin-like growth factor-binding protein 3 (IGFBP3). In the present study, ligand, Western, and Northern blot analyses were used to demonstrate the presence of IGF-I-binding activity, several immunoreactive IGFBP3 proteins, and IGFBP3 mRNA in horse conceptuses with particularly large amounts of immunoreactive IGFBP3 in the conceptus capsule. In addition, immunoprecipitation of radiolabeled proteins showed that cultured horse conceptuses secreted IGFBP3 into the culture medium. Endometrial samples from mares also contained IGFBP3 mRNA and protein; but there was no evidence of secretion of IGFBP3 into the uterine lumen by ligand blot analysis, and there was evidence of only very small amounts by Western blot analysis. These results indicate that the horse conceptus secretes significant quantities of IGFBP3 toward the conceptus capsule from as early as Day 10 after ovulation. Thus, most of the IGFBP3 contained within the capsule, which binds IGF-I to this special extracellular matrix of the preimplantation horse conceptus, is likely to be embryonic in origin. IGFBP3 in the horse conceptus capsule may enhance or modulate the action of IGFs on the developing conceptus.

Animals↗
PubMed2000

In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation.

Previous investigations have demonstrated an increased release of von Willebrand factor (VWF; also known as vWF) in endothelial cells after high single-dose irradiation in vitro. We have also found increased levels of Vwf protein in mouse glomeruli after a high single dose of renal irradiation in vivo. In addition, increased numbers of leukocytes were observed in the renal cortex after irradiation in vivo. The aim of the present study was to investigate and quantify these biological processes after clinically relevant fractionated irradiation and to relate them to changes in renal function. A significantly greater increase in release of VWF was observed in cultured human umbilical vein endothelial cells (HUVECs) after fractionated irradiation (20 x 1.0 Gy) than after a single dose of 20 Gy (147% compared to 115% of control, respectively, P < 0.0005). In contrast with the in vitro observations, glomerular Vwf staining was lower after fractionated irradiation in vivo (20 x 2.0 Gy or 10 x 1.6 Gy +/- re-irradiation) than after a single dose of 16 Gy. The number of leukocytes accumulating in the renal cortex was also lower after fractionated in vivo irradiation than after a single radiation dose. The onset of these events preceded renal functional and histopathological changes by approximately 10 weeks. These data indicate that radiation-induced changes in endothelial VWF expression after in vivo irradiation may be distinct from the in vitro observations. Increased VWF expression may reflect pivotal processes in the pathogenesis of late radiation nephropathy and provide a clue to appropriate timing of pharmacological intervention.

Animals↗
PubMed2000

Rapid onset of stupor.

Catatonia is a syndrome with many causes that can be difficult to diagnose. In this report, we describe a case of rapid onset of stupor and loss of consciousness, subsequent evaluation, and treatment of catatonia in an HIV-positive man.

Adult↗
PubMed1999

Factors controlling epidermal growth factor (EGF) gene expression in the endometrium of the mare.

Previous studies showed a dramatic increase in EGF gene expression in the endometrial glands of pregnant mares around day 40 after ovulation. To investigate how the steroid hormones of pregnancy might regulate this expression, in situ hybridization was used to monitor the levels of EGF mRNA in endometrial biopsies obtained from seasonally anoestrous or ovariectomised mares given exogenous progesterone and oestrogen, alone or in combination, for up to 46 days. Biopsies were also taken from mares during the non-pregnant cycle, during normal pregnancies and pregnancies compromised by endometrial pathology (endometriosis) or because of incompatible extraspecific embryo transfers (donkey-in-horse pregnancies). Only a few samples showed weak EGF expression during the late luteal phase of the oestrous cycle. During normal pregnancy, the previously observed dramatic increase of expression after day 40 of gestation was confirmed. Although aged mares suffering from endometriosis and mares carrying an extraspecific donkey conceptus showed the same increase of EGF mRNA in normal glands, this was virtually absent from gland cross-sections compromised due to inflammatory or fibrotic changes. Administration of various doses and combinations of progesterone and oestrogen for < 35 days yielded negative or only weakly positive hybridization results, whereas progesterone alone for > or = 40 days upregulated EGF expression strongly irrespective of additional treatment with oestrogen. This is the first experimental evidence that EGF expression in the endometrium can be induced by progesterone alone. The requirement for prolonged progesterone priming is of considerable interest in the context of the unusually late stage of gestation at which placental attachment commences in equids.

Animals↗
PubMed1999

Clearance kinetics of CD34+ cells from peripheral blood: an independent predictor of hematologic recovery after high-dose chemotherapy and hematopoietic stem cell transplantation.

We measured the concentration of CD34+ cells in peripheral blood (PB) (1/2) h prior to and (1/2), 1, 3, 6, and 12 h following hematopoietic stem cell (HSC) infusion in 34 breast cancer patients treated with high-dose chemotherapy (HDC). The decrease in these concentrations over time enabled us to determine the clearance kinetics of CD34+ cells from PB. The absolute number of CD34+ cells in PB generally peaked at (1/2) h after infusion, then rapidly declined from 1 to 3 h post infusion and continued to fall until 12 h post transplant, but more slowly. In univariate analysis, CD34+cells/kg infused, CFU-GM/kg infused, the CD34+ count at (1/2) h, and the 12-h clearance of CD34+ cells from PB were predictors of hematologic recovery, as were each of the two phases of clearance when the slope was divided into rapid and slow phases (from (1/2) to 3 and from 3 to 12 h post transplant, respectively). We then stratified our population by the number of CD34+ cells/kg infused. In group 1, patients received </=7.5 x 10(6) CD34+ cells/kg; in group 2, >7.5 x 10(6) CD34+ cells/kg. After adjusting for CD34+ cells injected, age, and purged or unpurged graft in multivariate analysis, the 12 h clearance remained a predictor of hematologic recovery in group 1. In addition, the second phase of clearance (from 3 to 12 h after infusion) was an even better predictor than the 12 h clearance. In group 2, however, no statistically significant correlation was observed, even with the number of HSC injected. Results suggest that rapidity of clearance of CD34+cells from PB is an independent indicator of hematologic recovery in patients receiving lower doses of CD34+ cells. When the cell dose injected is over a threshold, PB clearance correlations with hematologic recovery are masked.

Adult↗