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Biomedical subjects

M Fraser

Publications and source records attributed to M Fraser.

At least 19 recordsLinked to original sources
PubMed1992

Expression and immunochemical analysis of rat and human fibroblast growth factor receptor (flg) isoforms.

Potentially 96 splice variants among four genes that code for the human heparin-binding fibroblast growth factor receptor family complicate study of structure, metabolism, and function of single isoforms in mammalian cells. As an alternative, we expressed structural subdomains and isoforms of the flg receptor gene in bacteria and baculoviral-infected insect cells. We developed and characterized a panel of 16 isoform and domain-specific polyclonal and monoclonal antibodies. The panel of antibodies was used to distinguish mature glycosylated ligand-binding and kinase-active and -inactive recombinant isoforms in baculoviral insect cells and transfected mammalian cells and natural isoforms in rat prostate and human liver cells. The results revealed a cell type-specific expression of the flg gene and isoforms that result from combinations of splice variations. Reactive epitopes of monoclonal antibodies against both the three (alpha) and two (beta) immunoglobulin-like disulfide loop extracellular domain isoforms were mapped by cross-reactivity with synthetic polypeptide sequences and deletion mutants expressed in bacteria. The native alpha and beta receptor isoforms differed in display of shared epitopes and suggested that the NH2-terminal Loop I and COOH-terminal Loops II and III of the alpha isoform are interactive. Although the common Loops II and III appear qualitatively sufficient for ligand binding, the results suggest that tertiary relationships among loops in the three and two loop isoforms are distinct and, therefore, the two isoforms may have distinct activities. Spatial models for arrangement of immunoglobulin-like loops in the extracellular domain of the two isoforms are presented.

Amino Acid Sequence↗
PubMed1992

Gastrin releasing peptide immunoreactivity is present in ovine amniotic fluid and fetal and maternal circulations. MRC Group in Fetal and Neonatal Health and Development.

Using antisera directed towards the C-terminal region of gastrin releasing peptide (GRP), significant quantities of GRP-like immunoreactivity (GRPLI) were detected in ovine amniotic fluid and in the fetal and maternal circulations. The highest GRPLI levels were found in amniotic fluid (2135 +/- 829 fmol/ml, n = 12; mean +/- SEM), followed by those in ovine fetal (604 +/- 267 fmol/ml, n = 13) and maternal plasma (229 +/- 89 fmol/ml, n = 13). On gel filtration chromatography, the predominant GRPLI form in each fluid eluted in an identical position consistent with the entity being of apparently larger molecular size than porcine GRP1-27. Certain fetal plasma samples contained a second GRPLI peak eluting at the void volume. Hence, during ovine pregnancy a GRPLI entity circulates in fetal and maternal plasma; the entity is of apparently larger molecular size than GRP1-27 but contains a structure immunologically indistinguishable from the bioactive c-terminal region of GRP1-27. Given the recognized bioactivities of GRP, this entity may be an important hormone during ovine fetal life.

Amniotic Fluid↗
PubMed1991

Identification of cell surface receptors for murine macrophage inflammatory protein-1 alpha.

We have produced recombinant proteins for a cytokine, L2G25BP (macrophage inflammatory protein-1 alpha) (MIP-1 alpha). By using the recombinant protein (rMIP-1 alpha), receptors for MIP-1 alpha were identified on Con A-stimulated and unstimulated CTLL-R8, a T cell line, and LPS-stimulated RAW 264.7, a macrophage cell line. The 125I-rMIP-1 alpha binds to the receptor in a specific and saturable manner. Scatchard analysis indicated a single class of high affinity receptor, with a Kd of approximately 1.5 x 10(-9) M and approximately 1200 binding sites/Con A-stimulated CTLL-R8 cell and a Kd of 0.9 x 10(-9) M and approximately 380 binding sites/RAW 264.7 cell. 125I-rMIP-1 alpha binding was inhibited by unlabeled rMIP-1 alpha in a dose-dependent manner, but not by IL-1 alpha or IL-2. rMIP-1 alpha inhibited the proliferation of unstimulated CTLL-R8 cells. Rabbit anti-rMIP-1 alpha antibodies blocked the growth-inhibitory effect of the rMIP-1 alpha on CTLL-R8 cells.

Animals↗
PubMed1991

Where are they now? The career paths of graduates from post-registration degrees in nursing in England.

Degree courses for experienced nurses through part-time study are relatively new in Britain. The first course started in 1979, but their number has dramatically increased during the past decade, particularly in England. Due to this increase it is important that analysis of career paths of the graduates should occur. As no suitable questionnaire was found from the literature one was devised. Posting this to all graduates from three courses gave a response from 113 graduates (77.4%). Results showed graduates to be continuing in nursing. They showed life-long motivation to study and felt personal growth from the degree. Movement of graduates predominantly from clinical areas into nurse education was found.

Adult↗
PubMed1990

Correlation of absorbance at 650 nm with the presence of phosphatidylglycerol in amniotic fluid.

Amniotic fluid absorbance at 650 nm was correlated with the presence of phosphatidylglycerol (PG) in the isolated surfactant fraction (10,000-g pellet). Shake test results were included. Two hundred ninety-seven samples were analyzed. PG was present in 222 of 226 samples in which the absorbance was greater than or equal to 0.250 and absent from 48 of 71 with an absorbance less than 0.250. PG was present in all 166 samples with a positive shake test and absent in 52 of 131 samples with a negative one. In 65 samples in which the shake test was negative and the absorbance greater than or equal to 0.250, PG was present in all but 4. The false-positive rate for the prediction of respiratory distress syndrome was 0.8% for the Shake test and 0.6% for the absorbance measurement. The results support the usefulness of the absorbance measurement as a simple and reliable procedure for assessing fetal lung maturity.

Amniotic Fluid↗
PubMed1989

Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution.

The x-ray crystal structure of recombinant human renin has been determined. Molecular dynamics techniques that included crystallographic data as a restraint were used to improve an initial model based on porcine pepsinogen. The present agreement factor for data from 8.0 to 2.5 angstroms (A) is 0.236. Some of the surface loops are poorly determined, and these disordered regions border a 30 A wide solvent channel. Comparison of renin with other aspartyl proteinases shows that, although the structural cores and active sites are highly conserved, surface residues, some of which are critical for specificity, vary greatly (up to 10A). Knowledge of the actual structure, as opposed to the use of models based on related enzymes, should facilitate the design of renin inhibitors.

Aspartic Acid Endopeptidases↗
PubMed1989

Gestation-dependent effects of the combined treatment of glucocorticoids and thyrotropin-releasing hormone on surfactant production by fetal rabbit lung.

The effects of cortisol (0.1 mg per dose, administered intraperitoneally to fetal rabbits at 24 to 27 days' gestation), thyrotropin-releasing hormone (40 micrograms/kg per dose administered intravenously to the doe at 24 to 26 days' gestation), or a combination of the two on surfactant pool size (both intracellular and extracellular) at 27 or 28 days' gestation was investigated. Cortisol increased both surfactant pools only when administered on the twenty-fourth or twenty-fifth gestational day. Thyrotropin-releasing hormone, whether administered in single or multiple doses, had no effect on the extracellular pool but increased the intracellular pool; the magnitude of the response (approximately twofold) was similar to that observed with the cortisol response. All combinations of cortisol and thyrotropin-releasing hormone resulted in an increased response over either drug given alone. The greatest response (almost tenfold) resulted from cortisol administration at 24 days' gestation plus thyrotropin-releasing hormone administration at 24+ 25+ 26 days. These data demonstrate differential effects of glucocorticoids and thyrotropin-releasing hormone on developing lung and furthermore show that the timing of their combined treatment may be crucial to achieving maximal response.

Animals↗
PubMed1989

The effect of cortisol on thyroid hormone kinetics in the ovine fetus.

The mechanism underlying the association of rising concentrations of circulating triiodothyronine (T3) with the prepartum surge in the concentration of cortisol was investigated in 11 fetal sheep. The concentrations and metabolic clearance rates of T3 and thyroxine (T4) were measured prior to and following a continuous intravascular infusion of cortisol (1 mg/h for 84 h). Mean plasma T3 concentrations increased 10-fold following cortisol infusion whereas the concentrations of T4 either remained stable or exhibited a variable decline. Cortisol induced a 5-fold decrease in the metabolic clearance rate of T3 and a 6-fold increase in that of T4. The corresponding mean production rates of T3 and T4 increased significantly although the magnitude of the change varied between fetuses. We conclude that the prepartum rise in plasma T3 concentrations is likely to be a consequence of both a decreased metabolic clearance of T3 and increased peripheral conversion of T4 to T3 caused by rising concentrations of cortisol in fetal plasma.

Animals↗
PubMed1988

Umbilical cord knots and encirclements.

Although cord knots and/or encirclements account for 1 in 10 stillbirths of infants weighing 2,500 g or more, no problem due to this cause was encountered in a prospective study of 1,115 vaginal deliveries. In this study there were 6 cases of cord knot (0.5%) and 158 of cord encirclement (14.2%). The range of cord length was 27-122 cm, the 10th, 50th and 90th percentiles being 40, 52 and 69 cm respectively. In this study there was no clinical warning (fetal distress) of cord encirclement or knot during pregnancy, labour or delivery.

Asphyxia Neonatorum↗
PubMed1988

Cardiovascular effects of the novel cardiotonic agent DPI 201-106 in the anaesthetized rat.

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole -2- carbonitrile) was given intravenously to anaesthetized male rats. DPI caused an increase in left ventricular dP/dt (LV dP/dt), giving a significant increase at 0.03 mumol/kg. At this dose DPI had no effect on either mean arterial pressure (MAP) or heart rate (HR). At higher doses, MAP decreased transiently. At 0.3 and 1 mumol/kg, HR was decreased. The results indicate that DPI produces positive inotropic and negative chronotropic effects in the anaesthetized rat.

Animals↗
PubMed1988

Inhibition of cardiac phosphodiesterase III by the novel cardiotonic agent 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride.

The novel cardiotonic agent 6[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154) was investigated for its cardiovascular effects and its mechanism of action. In the anaesthetized rat MCI-154 (0.01-0.3 mumol/kg i.v., bolus injection) produced a dose-dependent increase in left ventricular dP/dt, and a decrease in mean arterial pressure. A relatively small increase in heart rate was observed. The drug inhibited selectively canine cardiac phosphodiesterase III (IC50 2.5 +/- 0.6 mumol/l). In skinned porcine trabeculae, MCI-154 produced only a small increase in the Ca2+-sensitivity of the contractile proteins. The results suggest that MCI-154 is a potent cardiotonic agent, and that inhibition of phosphodiesterase III may be a important component of this effect.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Thyroid hormone kinetics during late pregnancy in the ovine fetus.

The factors responsible for the changes in the plasma concentrations of thyroid hormones in the ovine fetus in late pregnancy were investigated by making serial measurements of the concentrations, metabolic clearance rates and production rates of T3 and T4 in 17 fetuses. The concentrations of T3 in fetuses of 135-145 days gestational age were four times higher than in those of 110-125 days but the concentrations of T4 were unchanged. The metabolic clearance rate of T3 halved over this period whereas that of T4 rose slightly. The production rate of T3 more than doubled and of T4 increased slightly but not significantly. We conclude that the concentration of T4 shows little change with increasing gestational age because the trends in metabolic clearance rates and production rates are weak and in the same direction. The sharp rise in the concentration of T3 is attributable to a fall in metabolic clearance rate coupled with a rise in production rate.

Animals↗
PubMed1987

Diagnosis of gestational diabetes by capillary blood samples and a portable reflectance meter: derivation of threshold values and prospective validation.

Paired capillary-venous samples were obtained from 255 women undergoing a glucose challenge test and 116 women undergoing an oral glucose tolerance test. The capillary equivalents for the venous threshold values were calculated by regression analysis. The glucose challenge test predictions of either normal or abnormal agreed in 82%. The sensitivity, specificity, and positive and negative predictive values for the capillary oral glucose tolerance test were 89%, 90%, 62%, and 98%, respectively. These capillary equivalents were then applied prospectively to 147 women undergoing a glucose challenge test and 141 women undergoing an oral glucose tolerance test. The concurrence rate of the glucose challenge test in the prospective group was 90%. The sensitivity, specificity, and positive and negative predictive values for the capillary oral glucose tolerance test were 64%, 95%, 75%, and 92%. When the venous threshold recommendations of the American Diabetes Association were used instead of those standard at our institution, these values increased to 75%, 98%, 83%, and 96%, respectively. The recommended capillary values of the American Diabetes Association were 100% sensitive but had a positive predictive value of only 20%. Based on the prospective group, the cost per case of gestational diabetes identified would decline 63% if both a capillary glucose challenge test and an oral glucose tolerance test were used and 25% if the capillary glucose challenge test and venous oral glucose tolerance test were used. Combining the data set for new regression equations, the following venous-capillary threshold sets emerged: glucose challenge test, 140 mg/dl/150 mg/dl; fasting oral glucose tolerance test, 105 mg/dl/114 mg/dl; 1 hour, 190 mg/dl/211 mg/dl; 2 hours, 165 mg/dl/183 mg/dl; 3 hours, 145 mg/dl/157 mg/dl. The sensitivity, specificity, and negative predictive values for the capillary oral glucose tolerance test with these thresholds were 80%, 97%, 80%, and 97%. In conclusion, capillary glucose testing for diabetes during pregnancy is feasible and cost-effective.

Blood Glucose↗
PubMed1986

The relationship between capillary and venous glucose concentration during pregnancy.

Previous attempts to construct capillary equivalents of venous glucose values for prognostic purposes have failed. We examined the relationship between capillary and venous glucose concentration during pregnancy in 258 women who had samples taken at four different time intervals in relation to two different standardized meals. Capillary glucose concentration was determined with the Chemstrips bG and an Accu-Chek reflectance colorimeter and venous plasma glucose concentration was measured by the hexose kinase technique on an AutoAnalyzer. The capillary: venous relationship was constant over time for a given meal but the magnitude of the difference was affected by time. The capillary: venous relationship differed significantly between the two standard meals. The findings indicate that meal size and sampling time must be controlled for when one is attempting to construct capillary equivalents for venous derived norms. The failure of previous studies to control for these variables may explain their inability to construct useful capillary equivalents for venous glucose values. Our findings also indicate that attainment of venous norms with capillary specimens represent, in reality, tighter control.

Blood Glucose↗
PubMed1986

Quantification of surfactant pool sizes in rabbit lung during perinatal development.

Methods are presented for the quantitative isolation of surfactants from fetal and newborn rabbit alveolar lavage returns and post-lavaged lung tissue homogenates. The phospholipid content of both fractions progressively increased between 27 days gestation and term (31 days). The tissue-stored fraction increased approximately 16-fold (from 0.48 +/- 0.13 to 7.83 +/- 0.86 mg/g dry lung) and the alveolar fraction more than 30-fold (from 0.08 +/- 0.02 to 2.69 +/- 0.52 mg/g dry lung). Developmental changes in phospholipid composition were also observed. Tissue-stored surfactant was prepared using differential and density gradient centrifugation. Alveolar surfactant was isolated during fetal development as a high-speed pellet following a one-step differential centrifugation. There was little change in the phospholipid content of fetal alveolar lavage supernatant (range 0.12 +/- 0.04 to 0.28 +/- 0.09 mg/g dry lung). By the first postnatal day the phospholipid content of both lavage fractions significantly increased (pellet, 7.51 +/- 1.79; supernatant, 4.01 +/- 1.36 mg/g dry lung) and both were identified as surfactant. This increase in alveolar surfactant was accompanied by an approximately twofold decrease (to 3.81 +/- 1.1 mg/g dry lung) in the tissue-stored fraction. These data provide a quantitative profile of surfactant accumulation and secretion in developing rabbit lung.

Animals↗