Biomedical subjects

S C Bell

Publications and source records attributed to S C Bell.

At least 145 records · Page 8Linked to original sources

PubMed1987

Synthesis and cardiotonic activity of a series of substituted 4-alkyl-2(1H)-quinazolinones.

The synthesis, cardiac fraction III cyclic nucleotide phosphodiesterase (PDE-III) inhibition, and positive inotropic activity of a series of 2(1H)-quinazolinones are reported. A general synthesis of the series involved the cyclization of 2-aminoacetophenones with potassium cyanate in acetic acid. Modifications at the 4-position of the quinazoline nucleus were best achieved by formation of the intermediate N1-acyl-N3-phenylurea from the substituted phenyl isocyanate and appropriate carboxamide. PPA was used to ring close to the quinazoline product. Generally the SAR for the series paralleled the five-point model previously published for PDE-III inhibition. The most active analogue of the series was 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone (1) (ORF 16600), which had about twice the intravenous potency of amrinone. Compound 1 is currently under development as an orally active cardiotonic.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1987

2-Oxo-1,8-naphthyridine-3-carboxylic acid derivatives with potent gastric antisecretory properties.

The syntheses of 2-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having potent gastric antisecretory properties in the pyloric-ligated (Shay) rat model are described. Two of the more potent compounds tested that were selected for more detailed dose-response evaluation were 4-amino-1-ethyl-1,2-dihydro-2-oxonaphthyridine-3-carboxylic acid ethyl ester (35) and 1-ethyl-1,2-dihydro-7-methyl-4-(4-methyl-1-piperazinyl)-2- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (77). These compounds lowered total acid output in the rat in a dose-related fashion. Both compounds were more potent than cimetidine when tested in the rat. Both 35 and 77 showed inhibitory activity in food-stimulated acid secretion in the Pavlov-pouch, conscious dog. The mechanism of action for this series is not known. Details of structure-activity relationships are described.

Animals↗

PubMed1987

Development and validation of a radioimmunoassay for human secretory 'pregnancy-associated endometrial alpha 2-globulin' (alpha 2-PEG) and detection in serum during pregnancy.

A specific and sensitive radioimmunoassay has been developed for pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein of the human endometrium during the mid- to late-luteal phase of the menstrual cycle and first trimester of pregnancy. This assay enabled alpha 2-PEG to be measured in the cytosolic extracts of endometrium, amniotic fluid, seminal plasma and in pregnancy sera. The concentration of alpha 2-PEG in cytosols prepared from mid-secretory endometrium was 44-fold higher than in those from proliferative endometrium and a further 30-fold increase during the first trimester in comparison with mid-secretory endometrium. Levels of alpha 2-PEG in amniotic fluid (15-20 weeks) and seminal plasma were 15 +/- 4 and 55 +/- 7 micrograms/ml, respectively. With the exception of sera, where alpha 2-PEG was undetectable using rocket immunoelectrophoresis, estimates of alpha 2-PEG levels in these compartments, measured by rocket immunoelectrophoretic and RIA assays were comparable, although for seminal plasma 2.5-fold higher estimates were obtained by RIA. Detectable levels of alpha 2-PEG were obtained in 253 of 275 (92%) pregnancy sera tested. During pregnancy, peak levels were detected between weeks 6 and 11 but these represented only 2% of the levels detected in amniotic fluid. These observations support evidence from in vitro studies that alpha 2-PEG is a product of the secretory glandular epithelium, a tissue prominent in the first trimester and whose principal secretory route during pregnancy is into the amniotic fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Amniotic Fluid↗

PubMed1987

Pregnancy-associated endometrial alpha 2-globulin, the major secretory protein of the luteal phase and first trimester pregnancy endometrium, is not glycosylated prolactin but related to beta-lactoglobulins.

We previously reported that the major secretory protein of the endometrium during the first trimester of pregnancy, pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), also represented the major secretory protein during the mid- to late luteal phase. Recently, the major secretory endometrial protein during the luteal phase of the menstrual cycle was identified as glycosylated PRL (G-PRL). Although certain properties of alpha 2-PEG resemble G-PRL, in this study G-PRL was demonstrated to be immunochemically distinct from alpha 2-PEG, and deglycosylation of alpha 2-PEG produced a protein unrelated to PRL. The sequence of the 38 N-terminal amnio acid residues of alpha 2-PEG was determined by a gas phase sequenator. A sequence of Met-Asp-Ileu-Pro-Gln-Thr-Lys-Gln-Asp-Leu-Glu-Leu-Pro-Lys-Leu-Ala-G ly-Lys-Trp- His-Ser-Met-Ala-Met-Ala-Thr-Asn-?-Ileu-Ser-Leu-Met-Ala-Thr-Leu-Lys -Ala-Pro was obtained which was unique and unrelated to that of PRL. However, sequence homology between alpha 2-PEG and the major milk whey protein beta-lactoglobulin of the horse was demonstrated. The data indicate that alpha 2-PEG is a unique protein and is a human homolog of the beta-lactoglobulin family.

Amino Acid Sequence↗

PubMed1987

Immunochemical detection, physicochemical characterization and levels of pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG) in seminal plasma of men.

Pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein of the human uterine endometrium during the luteal phase of the menstrual cycle and early first trimester of pregnancy, has been detected by immunochemical techniques in seminal plasma. Biochemical analysis and immunoblotting has verified that immunoreactive alpha 2-PEG in seminal plasma exhibits properties identical to those of endometrial alpha 2-PEG, i.e. Concanavalin A-binding dimeric glycoprotein of native Mr 56,000, subunit Mr 28,000, average pI 4.7 and of alpha 2-mobility. Concentration of alpha 2-PEG in seminal plasma was 22.13 +/- 2.82 micrograms/ml (mean +/- s.e.m., n = 110) which compared to 12.02 +/- 1.65 micrograms/ml (mean +/- s.e.m., n = 48) found in amniotic fluid at 11-20 weeks of pregnancy, to 4.29 +/- 1.66 micrograms/ml (mean +/- s.e.m., n = 15) in uterine luminal fluid in women during the luteal phase and to 0.245 +/- 0.025 micrograms/ml (mean +/- s.e.m., n = 10) in sera at 10 weeks of pregnancy. This distribution is very different from that observed for pregnancy-associated placentally-derived serum proteins detected in seminal plasma. The source of alpha 2-PEG in seminal plasma is unknown but is unlikely to be the testis because of the normal levels observed in vasectomized men. In the endometrium alpha 2-PEG synthesis and secretion appears to be related to progesterone-dependent differentiation of the glandular epithelium. Therefore these observations suggest that a different mechanism of regulation of the gene for alpha 2-PEG operates in the male reproductive tract.

Chromatography↗

PubMed1987

Distributions of genetic markers in United States populations: II. Isoenzyme systems.

All published and unpublished population frequency data that could be located for U.S. populations is tabulated and presented for the isoenzyme systems phosphoglucomutase, esterase D, adenylate kinase, acid phosphatase, glyoxalase I, adenosine deaminase, 6-phosphogluconate dehydrogenase, glutamic-pyruvic transaminase, carbonic anhydrase II, and glucose-6-phosphate dehydrogenase. Results obtained by combining data for comparable racial/ethnic groups are also presented. The results obtained with combined data may give better information on frequencies for the U.S. population at large than is obtainable from studies conducted in restricted geographic areas.

Black People↗

PubMed1987

Distributions of genetic markers in United States populations: I. Blood group and secretor systems.

All published and unpublished population frequency data that could be located for U.S. populations are tabulated and presented for the blood group and secretor systems. Results obtained by combining data for comparable racial/ethnic groups are also presented. The results obtained with combined data may give better information on frequencies for the U.S. population at large than is obtainable from studies conducted in restricted geographic areas.

Blood Group Antigens↗

PubMed1987

Distributions of genetic markers in United States populations: III. Serum group systems and hemoglobin variants.

All published and unpublished population frequency data that could be located for U.S. populations are tabulated and presented for the serum group systems haptoglobin (alpha-chain), group specific component, and transferrin and for the common beta-chain variants of hemoglobin. Results obtained by combining data for comparable racial/ethnic groups are also presented. Some evidence is presented to indicate that the results obtained from the combined data may give better information on frequencies for the U.S. population at large than is obtainable from studies conducted in restricted geographic areas.

Black People↗

PubMed1986

Humoral immune responses in murine pregnancy. V. Relationship to the differential immunogenicity of placental and fetal tissues.

The nature of the humoral immune response induced in virgin female mice by injections of F1 placental and fetal tissues has been examined and compared to that induced by immunization with F1 adult spleen cells and by multiple allogeneic pregnancy. In a 'responder' strain mouse, as defined by the ability of multiple allogeneic pregnancy to elicit an anti-paternal humoral immune response, both F1 placental and fetal tissues induced the formation of alloantibodies primarily of the IgG1 sub-class, similar to those induced by allogeneic pregnancy, but different from those elicited by adult spleen cells. However, only the placental tissues induced alloantibodies possessing all the characteristics of those appearing in multiparous allogeneic pregnancy. In contrast, the alloantibodies induced by the injected fetal tissue possessed complement-dependent cytotoxic activity, indicating that the inability of pregnancy-induced alloantibodies to mediate cytotoxicity may not be related to their restriction to the IgG1 sub-class. In a 'non-responder' mouse strain, where multiple allogeneic pregnancy does not lead to a maternal alloantibody response, F1 placental tissues, in contrast to fetal and adult tissues, failed to induce a humoral immune response. Injection of F1 placental tissue therefore elicits responses that mimic both the properties and the strain-dependent distribution of the alloantibodies identified in normal murine pregnancy. This implies that the immunogenic stimulus in pregnancy emanates from the placental rather than the fetal compartment of the allogeneic conceptus.

Animals↗

PubMed1986

Novel 1,3-bis(aryloxy)propanes as leukotriene D4 antagonists.

The synthesis and structure-activity relationships of a number of 1,3-bis(aryloxy)propanes, which are in vivo antagonists of LTD4 in the guinea pig, are described. One of these compounds, 4 (Wy-44,329), was not only approximately equipotent with the standard 1 (FPL 55712) in the LTC4 (ID50 = 0.17 and 0.23 mg/kg iv, respectively) and LTD4 (ID50 = 0.11 and 0.15 mg/kg iv, respectively) challenge models but also possessed greater potency in the ovalbumin challenge model (ID50 = 0.47 mg/kg and 4.1 mg/kg iv, respectively) and a longer duration of action. This compound was a competitive LTD4 antagonist on guinea pig ileum (pA2 = 9.4) and possessed mediator release (rat PCA, ID50 = 0.26 mg/kg iv) and 5-lipoxygenase (IC50 = 32 microM vs. 5-HETE) inhibitory activities.

Animals↗

PubMed1986

Secretory endometrial and decidual proteins: studies and clinical significance of a maternally derived group of pregnancy-associated serum proteins.

In contrast to our ability to monitor placental function during pregnancy, due to the availability of a range of placentally derived secretory products such as HCG, HPL, SP1, PAPP-A, etc. the equivalent monitoring of the endometrial function in implantation and pregnancy has been impaired by a lack of equivalent endometrial products. Decidual diamine oxidase and prolactin have been extensively characterized but each have clinical drawbacks and may indeed be minor products of the endometrium. Recent developments in the characterization of the major secretory protein products of the endometrium, and a re-assessment of the origin of a number of placental proteins, radically alter our ability to monitor endometrial function, offer a new clinical window on pregnancy and might provide new knowledge on the extent of feto-maternal dialogue at implantation and during pregnancy. In this review, aspects of many scientific studies, and the function and possible clinical significance of these endometrial and decidual protein products are assessed.

Animals↗

PubMed1986

Purification of human secretory pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG) from cytosol of first trimester pregnancy endometrium.

Pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein as assessed by in-vitro synthesis and secretion by the endometrium during the luteal phase of the menstrual cycle and early first trimester of pregnancy, has been purified from the cytosolic fraction of pregnancy endometrium. The purification schedule involved anion exchange chromatography (DE52), gel filtration (Sephacryl S-200), concanavalin A-Sepharose, chromatofocusing and negative immunoaffinity chromatography. On anion exchange chromatography alpha 2-PEG eluted at 0.11 M NaCl, on Sephacryl S-200 with an apparent Mr of 56 K, it bound to concanavalin A and eluted from a chromatofocusing column at a pH of 4.6. alpha 2-PEG was isolated with 98% purity, as assessed by one-dimensional sodium dodecyl sulphate (SDS)-gradient polyacrylamide gel electrophoresis (subunit Mr under reducing conditions 28 K), and a yield of 0.11 mg per g wet weight tissue. This purified alpha 2-PEG should enable in-vitro assessment of the function of this unique protein in implantation and pregnancy and provide antigenic material for the development of a radioimmunoassay.

Chromatography, Affinity↗

PubMed1986

Amniotic fluid concentrations of secreted pregnancy-associated endometrial alpha 1- and alpha 2-globulins (alpha 1- and alpha 2-PEG).

The levels of pregnancy-associated endometrial alpha 1- and alpha 2-globulins (alpha 1- and alpha 2-PEG), the two major proteins synthesized and secreted by the endometrium in vitro, have been assayed in 210 amniotic fluid specimens obtained at termination of pregnancy or by amniocentesis, or at delivery. alpha 1-PEG was undetectable until week 10 and thereafter rose to peak levels between weeks 20 and 24. Levels fell 15-fold by week 35 but substantial amounts were still present at parturition. alpha 2-PEG was present at highest levels during early pregnancy, at weeks 6-15, but thereafter levels rapidly fell until during weeks 31-42 alpha 2-PEG was detectable in only 3 of 25 specimens. During weeks 15-20, when alpha 2-PEG levels fell and alpha 1-PEG levels rose, a high correlation was observed between the week of gestation and the log of the ratios of the concentration of these proteins. These observations provide the opportunity to assess the role of endometrial and decidual dysfunction in the aetiology of pregnancy disorders.

Amniotic Fluid↗

PubMed1986

Protein synthesis and secretion by the human endometrium during the menstrual cycle and the effect of progesterone in vitro.

To identify markers of endometrial differentiation specimens of endometrium from the menstrual cycle were incubated in vitro with [35S]methionine, in the absence or presence of progesterone, and protein synthesis and secretion were studied by fluorographic analysis of one dimensional SDS/gradient polyacrylamide gels. Changes were demonstrated in the rate of synthesis and secretion of a number of endometrial proteins (EP) during the cycle and in response to progesterone. Endometrial proteins were classified into three groups: Group I-synthesized and secreted throughout the menstrual cycle and unaffected by progesterone exposure; Group II-synthesis and secretion associated with histological type of endometrium and unaffected by progesterone exposure, e.g. EP 13 (Mr 33,000) with proliferative, EP 15 (Mr 28,000) with secretory and EP 14 (Mr 32,000) with late secretory endometrium; Group III-synthesis and secretion regulated by progesterone exposure irrespective of source of endometrium, e.g. EP 9 (Mr 54,000) and 11 (Mr 45,000). The Group II proteins EP 14 and 15 were also the major secretory protein products of endometrium from first and second trimester pregnancy respectively, the native forms referred to as pregnancy-associated endometrial alpha 1- and alpha 2-globulins (alpha 1- and alpha 2-PEG). We conclude that EP 15 (alpha 2-PEG) represents a human analogue of uteroglobin.

Electrophoresis, Polyacrylamide Gel↗

PubMed1986

Detection and immunohistochemical localization of alpha 1-pregnancy-associated protein (alpha 1-PAP) in rats.

A protein exhibiting immunochemical cross-reactivity with the murine alpha 1-pregnancy-associated protein (alpha 1-PAP) has been detected in the sera of female rats. The protein has an alpha 1-electrophoretic mobility, an estimated molecular weight of 150,000 and is readily detectable in the sera of nonpregnant female rats of each strain examined. During pregnancy, the serum concentration increases up to five-fold, reaching maximal levels at the same gestational stage as alpha 1-PAP in the mouse. Immunohistochemical studies revealed a staining pattern for the rat protein similar to that seen for alpha 1-PAP in the mouse, with positive cells being observed in lumbar lymph nodes, the lamina propria of gut mucosa, Peyer's patches, intracellularly in some hepatocytes and, during pregnancy, also in the placenta and metrial gland. On the basis of these immunochemical, physicochemical and immunohistochemical findings, it is proposed that the protein detected in rat sera represents the analogue of the murine alpha 1-PAP, and that the rat strains examined more closely resemble high endogenous alpha 1-PAP-producer mouse strains. It is proposed that alpha 1-PAP, and a number of other rodent pregnancy proteins recently described, may be used in functional studies of human alpha 2-PAG.

Animals↗

PubMed1985

Immunohistochemical localization of murine alpha 1-pregnancy-associated protein (alpha 1-PAP) in pregnant mice: relationship between serum alpha 1-PAP levels and incidence of positive cells.

Using an electroimmunoassay, the murine pregnancy-associated protein alpha 1-PAP was detected in the sera of virgin MF1 but not C57BL/10 female mice. During pregnancy, alpha 1-PAP levels rose in both strains, although concentrations were higher in the latter and in both fell towards term. Using the unlabelled peroxidase anti-peroxidase (PAP) staining procedure, alpha 1-PAP was detected within mononuclear leukocytes, the majority resembling macrophages, in the small and large intestinal mucosae, Peyer's patches and hepatocytes of virgin MF1 but not C57BL/10 females. During pregnancy, alpha 1-PAP positive cells were observed in each of these sites and in the decidua and placenta of both strains. Quantitative studies revealed that the incidence of alpha 1-PAP positive cells in the gut and associated lymphoid tissues reflected the circulating levels of the protein. In the placenta, the frequency and intensity of alpha 1-PAP positive staining was also reduced towards parturition. In contrast, hepatocyte staining remained constant throughout gestation in both strains. Our observations suggest that there may be at least two types of alpha 1-PAP synthesis operative and that circulating levels of the protein in female mice are influenced by strain, pregnancy and stage of gestation. These findings are discussed in relation to the cell types involved, their contribution to serum levels and the possible role of alpha 1-PAP in fetal allograft survival.

Animals↗

PubMed1985

Protein synthesis and secretion by the human endometrium and decidua during early pregnancy.

To investigate the role of the endometrium in sustaining early pregnancy, specimens of endometrium from early pregnancy were incubated in vitro with radiolabelled amino acids, and protein synthesis and secretion were studied by subsequent fluorographic analysis of one-and two-dimensional polyacrylamide gels. Seventeen secreted endometrial proteins (EP) were identified. Changes were demonstrated in the rate of synthesis and/or secretion of a number of these proteins during early pregnancy. Two proteins, EP 14 and EP 15, are the principal secretory proteins of pregnancy endometrium. EP 14 (subunit mol. wt 32 000) is associated with decidualized endometrium and its rate of synthesis/secretion increases during early pregnancy. EP 15 (subunit mol. wt 28 000) is also synthesized and secreted by the secretory endometrium during the menstrual cycle, and during early pregnancy, but its secretion declines to undetectable levels by week 15-16. These proteins may provide useful markers of endometrial function and differentiation during the menstrual cycle and pregnancy.

Cytosol↗

PubMed1985

Immunochemical detection and characterization of pregnancy-associated endometrial alpha 1- and alpha 2-globulins secreted by human endometrium and decidua.

Antisera raised against the soluble antigens of the endometrium of early pregnancy detected two antigenic proteins of alpha 1 and alpha 2 mobility in extracts of this tissue and were termed antigens A and B. Neither antigen was detected in pregnancy sera or extracts of proliferative endometrium, but antigen B was detected in extracts of secretory endometrium and both were present in amniotic fluid and medium from in-vitro incubations of pregnancy endometrium. Fractionation of radiolabelled medium on ion-exchange chromatography demonstrated that antigens A and B co-eluted with the proteins from which EP14 and EP15 were derived and which were the major secretory polypeptides of pregnancy endometrium in vitro. Further biochemical purification revealed that EP14 (Mr 32 000) was derived from a protein of native molecular weight 36 000 which existed in two forms, whereas EP15 (Mr 28 000) was derived from a dimeric glycoprotein of native molecular weight 56 000. Immunochemical studies demonstrated that antigens A and B are identical to these two secretory proteins and have been termed pregnancy-associated endometrial alpha 1- and alpha 2-globulins (alpha 1- and alpha 2-PEG).

Alpha-Globulins↗