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Steven W Graves - One of the best experts on this subject based on the ideXlab platform.

  • association of cord blood Digitalis Like Factor and necrotizing enterocolitis
    American Journal of Obstetrics and Gynecology, 2014
    Co-Authors: Steven W Graves, Michael Esplin, Paula Mcgee, Dwight J Rouse, Kenneth J Leveno, Brian M Mercer, Jay D Iams, Ronald J Wapner, Yoram Sorokin
    Abstract:

    Objective Endogenous digoxin-Like Factor (EDLF) has been linked to vasoconstriction, altered membrane transport, and apoptosis. Our objective was to determine whether increased EDLF in the cord sera of preterm infants was associated with an increased incidence of necrotizing enterocolitis (NEC). Study Design Cord sera from pregnant women enrolled in a randomized trial of MgSO 4 for fetal neuroprotection were analyzed for EDLF using a red cell Rb + uptake assay in which the inhibition of sodium pump-mediated Rb + transport was used as a functional assay of EDLF. Specimens were assayed blinded to neonatal outcome. Cases (NEC, n = 25) and controls (neonates not developing stage 2 or 3 NEC, n = 24) were matched by study center and gestational age. None of the women had preeclampsia. Cases and controls were compared using the Wilcoxon test for continuous and the Fisher exact test for categorical variables. A conditional logistic regression analysis was used to assess the odds of case vs control by EDLF level. Results Cases and controls were not significantly different for gestational age, race, maternal steroid use, premature rupture of membranes, or MgSO 4 treatment. In logistic models adjusted for treatment group, race, premature rupture of membranes, and gestational age, cord sera EDLF was significantly associated with development of NEC ( P  = .023). Conclusion These data demonstrated an association between cord sera EDLF and NEC.

  • Association of cord blood Digitalis-Like Factor and necrotizing enterocolitis.
    American journal of obstetrics and gynecology, 2013
    Co-Authors: Steven W Graves, Michael Esplin, Paula Mcgee, Dwight J Rouse, Kenneth J Leveno, Brian M Mercer, Jay D Iams, Ronald J Wapner, Yoram Sorokin, John M Thorp
    Abstract:

    Endogenous digoxin-Like Factor (EDLF) has been linked to vasoconstriction, altered membrane transport, and apoptosis. Our objective was to determine whether increased EDLF in the cord sera of preterm infants was associated with an increased incidence of necrotizing enterocolitis (NEC). Cord sera from pregnant women enrolled in a randomized trial of MgSO4 for fetal neuroprotection were analyzed for EDLF using a red cell Rb(+) uptake assay in which the inhibition of sodium pump-mediated Rb(+) transport was used as a functional assay of EDLF. Specimens were assayed blinded to neonatal outcome. Cases (NEC, n = 25) and controls (neonates not developing stage 2 or 3 NEC, n = 24) were matched by study center and gestational age. None of the women had preeclampsia. Cases and controls were compared using the Wilcoxon test for continuous and the Fisher exact test for categorical variables. A conditional logistic regression analysis was used to assess the odds of case vs control by EDLF level. Cases and controls were not significantly different for gestational age, race, maternal steroid use, premature rupture of membranes, or MgSO4 treatment. In logistic models adjusted for treatment group, race, premature rupture of membranes, and gestational age, cord sera EDLF was significantly associated with development of NEC (P = .023). These data demonstrated an association between cord sera EDLF and NEC. Copyright © 2014 Mosby, Inc. All rights reserved.

  • digoxin antibody fragment antigen binding fab treatment of preeclampsia in women with endogenous Digitalis Like Factor a secondary analysis of the deep trial
    American Journal of Obstetrics and Gynecology, 2013
    Co-Authors: Moana Hopoatesitake, Vardaman M Buckalew, D Adair, Donna Johnson, David F Lewis, Christopher Robinson, George R Saade, Steven W Graves
    Abstract:

    Objective Endogenous Digitalis-Like Factors (EDLFs) are elevated in women with preeclampsia, and the use of an anti-digoxin antibody Fab (DIF) in women with preeclampsia who were remote from term reduced maternal blood pressure and preserved renal function. The objective was to determine whether DIF treatment in women with severe preeclampsia in association with positive EDLFs in maternal serum improves maternal-perinatal outcomes. Study Design This was a planned secondary analysis from a randomized, placebo-controlled, double-blind study of DIF in women with severe preeclampsia with positive EDLF status that was managed expectantly between 23 weeks 5 days and 34 weeks' gestation (19 women received placebo, and 17 women received DIF). Primary outcome variables were a change in creatinine clearance and the use of antihypertensives. Secondary outcomes were maternal and perinatal complications. Results Women with positive EDLFs who received DIF had an attenuated decline in creatinine clearance from baseline compared with placebo (–4.5 ± 12.9 vs –53.2 ± 12.6 mL/min; P  = .005). In this same group, the use of antihypertensives (the other primary outcome) was lower but not significantly so (41% vs 63%; P  = .12). However, women who were treated with DIF had a lower rate of pulmonary edema (1/17 vs 6/19 women; P  = .035) and lower rates of neonatal intraventricular hemorrhage (DIF: 0/17 women vs placebo: 5/19 women; P  = .015). Conclusion In women with severe preeclampsia who were remote from term who were EDLF positive, the use of DIF was associated with improved maternal and neonatal outcome. These findings suggest the need for a large multicenter trial that would evaluate the benefits of DIF in the treatment of women with severe preeclampsia who are remote from term and with positive EDLF status.

  • Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous Digitalis-Like Factor: a secondary analysis of the DEEP Trial.
    American journal of obstetrics and gynecology, 2013
    Co-Authors: Moana Hopoate-sitake, Vardaman M Buckalew, C. David Adair, David F Lewis, George R Saade, Donna D Johnson, Christopher J Robinson, Steven W Graves
    Abstract:

    Endogenous Digitalis-Like Factors (EDLFs) are elevated in women with preeclampsia, and the use of an anti-digoxin antibody Fab (DIF) in women with preeclampsia who were remote from term reduced maternal blood pressure and preserved renal function. The objective was to determine whether DIF treatment in women with severe preeclampsia in association with positive EDLFs in maternal serum improves maternal-perinatal outcomes. This was a planned secondary analysis from a randomized, placebo-controlled, double-blind study of DIF in women with severe preeclampsia with positive EDLF status that was managed expectantly between 23 weeks 5 days and 34 weeks' gestation (19 women received placebo, and 17 women received DIF). Primary outcome variables were a change in creatinine clearance and the use of antihypertensives. Secondary outcomes were maternal and perinatal complications. Women with positive EDLFs who received DIF had an attenuated decline in creatinine clearance from baseline compared with placebo (-4.5 ± 12.9 vs -53.2 ± 12.6 mL/min; P = .005). In this same group, the use of antihypertensives (the other primary outcome) was lower but not significantly so (41% vs 63%; P = .12). However, women who were treated with DIF had a lower rate of pulmonary edema (1/17 vs 6/19 women; P = .035) and lower rates of neonatal intraventricular hemorrhage (DIF: 0/17 women vs placebo: 5/19 women; P = .015). In women with severe preeclampsia who were remote from term who were EDLF positive, the use of DIF was associated with improved maternal and neonatal outcome. These findings suggest the need for a large multicenter trial that would evaluate the benefits of DIF in the treatment of women with severe preeclampsia who are remote from term and with positive EDLF status. Copyright © 2013 Mosby, Inc. All rights reserved.

  • 188 association of cord blood Digitalis Like Factor and necrotizing enterocolitis in the neonate
    American Journal of Obstetrics and Gynecology, 2013
    Co-Authors: Steven W Graves, Sean Esplin
    Abstract:

    MRI findings at 6 weeks of life (cases) were compared to those with normal MRI findings following whole body cooling (controls). Glucose levels were obtained from their cord blood. ELISA-Like colorimetric tests were performed at standard conditions. Maternal demographics, antepartum and intrapartum complications were compared. Standard statistics including Ttests, chi-square and logistic regression were performed using STATA version 11. Power calculations were performed. Sensitivity and specificity were calculated. RESULTS: Thirty one infants were identified; 19 with normal MRI and 12 with abnormal MRI findings. The neonates with abnormal MRIs had a median gestational age (GA) of 39.0 wks (SD 1.40), mean birthweight 3325g (SD 683.6) and mean cord pH of 6.92 (SD 0.05). The neonates with normal MRIs had a median GA of 39.26 wks (SD 1.73), mean birthweight of 3403g (SD 133.6) and mean cord pH of 6.96 (SD 0.03). Logistic regression modeling revealed an odds ratio 0.64 (95% CI 0.0006-0.625) for abnormal MRI findings associated with glucose above 85 mg/dL (even after controlling for confounders) with a sensitivity of 92% and specificity of 63%. CONCLUSION: Cord glucose above 85 mg/dL in term encephalopathic neonates who qualified for whole body cooling is associated with improved MRI findings. Cord blood glucose may prove to be an additional risk stratification tool for encephalopathic neonates.

Norman K Hollenberg - One of the best experts on this subject based on the ideXlab platform.

  • application of supercritical fluid chromatography to characterize a labile Digitalis Like Factor
    Hypertension, 2000
    Co-Authors: Steven W Graves, Karen E Markides, Norman K Hollenberg
    Abstract:

    Abstract —A sodium pump inhibitor (Digitalis-Like Factor), isolated from the peritoneal dialysate of volume-expanded, hypertensive patients with kidney failure who were treated with this dialysis modality, was further purified and characterized by means of supercritical fluid chromatography, a separation technique whose application to very-low-concentration biomolecules is new. Previous studies suggested that after high-performance liquid chromatography (HPLC) purification, this inhibitor was the only Factor correlated with volume status and blood pressure in these patients. When this same HPLC fraction was furthered purified on 2-dimensional supercritical fluid chromatography, a single peak coeluted with [Na,K]ATPase inhibitory activity. When split specimens were used, there was a strict correlation between the peak area, measured by flame ionization detection, and activity (n=10, R =0.98, P =0.00001). Inhibitory activity after supercritical fluid chromatography was still correlated with the degree of volume expansion of donor patients ( P =0.01). After HPLC purification, this volume-sensitive inhibitor was chemically labile. With further purification on supercritical fluid chromatography, the active peak was still labile with comparable half-life. Supercritical fluid chromatography coupled with flame ionization detection provided an estimate of the amount of the inhibitor present. Again using split specimens, we determined that the labile Digitalis-Like Factor was ≈30-fold more effective than ouabain in inhibiting renal [Na,K]ATPase activity and ≥500 times more effective than ouabain in causing vascular smooth muscle contraction. The data suggest that we have purified to homogeneity a labile Digitalis-Like Factor that is readily distinguished from ouabain or bufalin, based on chromatographic characteristics, chemical lability, and a much lower effective concentration for its biological activity.

  • Sodium Pump Inhibition and Regional Expression of Sodium Pump α-Isoforms in Lens
    Hypertension, 1999
    Co-Authors: Norman K Hollenberg, Steven W Graves
    Abstract:

    Abstract —Both hypertension and cataract formation have been associated with reductions in sodium pump activity, possibly as a result of an endogenous inhibitor. The objective of the present study was to answer 4 closely related questions: (1) Is the lens sodium pump effectively inhibited by a labile, Digitalis-Like Factor we have identified in the peritoneal dialysate from hypertensive patients in end-stage renal failure? (2) How does that inhibition compare to that induced by ouabain? (3) Does sodium pump isoform distribution determine the degree of lens sodium pump inhibition? (This question was precipitated by the unanticipated finding that the labile DLF was more effective in inhibiting lens sodium pump than was anticipated.) (4) Is sodium pump activity altered in lens in response to increased salt intake, a maneuver known to increase endogenous Digitalis-Like Factor? We found that whereas ouabain produced equivalent or significantly less inhibition of lens Na + ,K + -ATPase from calf or rabbit, respectively, compared with brain, labile Digitalis-Like Factor preferentially inhibited lens compared with brain. Analysis of whole-lens preparations from rabbit, calf, and normal human lens revealed substantial α2- and α3-isoforms of the sodium pump but little α1-isoform. Ouabain inhibition of whole-lens Na + ,K + -ATPase from rabbit and calf were comparable: for rabbit lens, K i =5.2×10 −7 mol/L; for calf lens, K i =1.0×10 −6 mol/L. Limited quantities of labile Digitalis-Like Factor prohibited similar determinations; however, its concentration-activity profile paralleled that of ouabain. Na + ,K + -ATPase activity, measured in the 3 major anatomic regions of lens and normalized to nucleus, was greatest in epithelium (56.9±17.9) compared with cortex (5.8±1.4) and nucleus (1.0±0.0; P =0.01). Immunohistochemistry of rabbit lens found abundant α2- and α3-isoforms in epithelium and limited α3 but undetectable α1 in cortex and nucleus. Finally, rats randomized to a high Na diet showed significantly reduced lens Na + ,K + -ATPase activity compared with those on a low Na diet, consistent with the effects of a sodium pump inhibitor. In conclusion, the present study suggests that Digitalis-Like Factor may provide a link between hypertension and cataract formation.

  • specificity of the vascular smooth muscle contractile response to a labile Digitalis Like Factor in peritoneal dialysate the influence of potassium
    American Journal of Hypertension, 1997
    Co-Authors: Piotr A Soszynski, Steven W Graves, Allison Ensign, Norman K Hollenberg
    Abstract:

    Abstract Although multiple lines of evidence have suggested that a circulating endogenous Digitalis-Like Factor (DLF) might contribute to the pathogenesis of sodium-sensitive hypertension, the subject remains controversial. This study was designed to compare the influence of potassium on vascular responses to an endogenous DLF isolated from peritoneal dialysate (PD) in volume-expanded patients with other sodium pump inhibitors, such as ouabain and bufalin, and the influence of serotonin as an index of specificity. An increase in bath potassium (K+) concentration from 2.7 to 10 mmol/L relaxed bovine facial artery precontracted with serotonin, but induced a secondary paradoxical contractile response in vascular-smooth muscle (VSM) precontracted with ouabain, bufalin, or the endogenous DLF from PD. There was a strong correlation between the primary contraction induced by each sodium pump inhibitor, and the magnitude of the paradoxical secondary contractile response. The increase in potassium concentration did not influence ouabain binding in the 20 min required for the experimental protocol, although binding was decreased after 120 min. The findings indicate that the VSM contractile response induced by the agent isolated from PD reflects VSM sodium pump inhibition, supporting its candidacy as a circulating regulator of the sodium pump.

  • sodium pump isoform specificity for the Digitalis Like Factor isolated from human peritoneal dialysate
    Hypertension, 1997
    Co-Authors: Norman K Hollenberg, Deborah A Price, Steven W Graves
    Abstract:

    We have isolated a labile, specific sodium pump inhibitor or Digitalis-Like Factor from the peritoneal dialysate of volume-expanded renal failure patients whose levels correlated closely with volume status and blood pressure. This study characterizes the inhibitory profile of this agent compared with that of ouabain against the three α-isoforms of the sodium pump. We prepared microsomal Na,K-ATPase from rat tissues representing the highest proportion of one of the α-isoforms. Both Northern and Western blot analyses confirmed that kidney had predominantly the α1-isoform, skeletal muscle the α2-isoform, and fetal brain the α3-isoform. Ouabain (5×10−6 mol/L) produced little inhibition of kidney Na,K-ATPase (3.4±2.0%) but significant inhibition of skeletal muscle (37.2±3.7%, P <.001) and fetal brain (38.8±3.5%, P <.001) activity. In contrast, the labile Digitalis-Like Factor, causing comparable inhibition of fetal brain Na,K-ATPase activity (33.3±4.7%), produced markedly greater inhibition of kidney (42.5±5.6%, P <.001) and moderately greater inhibition of skeletal muscle pump activity (57.7±6.3%, P <.05). In addition, the labile Digitalis-Like Factor produced a marked concentration-dependent inhibition of the α2- and α3-isoforms ( r =.79, P =.00005). Experiments combining the labile Digitalis-Like Factor and ouabain confirmed that Digitalis-Like Factor, unLike ouabain, was an effective inhibitor of all three isoforms in rat, in particular α2. The different pattern of isoform sensitivity displayed by the labile Digitalis-Like Factor and ouabain further differentiates the two agents and raises some interesting possibilities about the functional implications of the endogenous Factor.

  • Sodium Pump Isoform Specificity for the Digitalis-Like Factor Isolated From Human Peritoneal Dialysate
    Hypertension, 1997
    Co-Authors: Norman K Hollenberg, Deborah A Price, Steven W Graves
    Abstract:

    We have isolated a labile, specific sodium pump inhibitor or Digitalis-Like Factor from the peritoneal dialysate of volume-expanded renal failure patients whose levels correlated closely with volume status and blood pressure. This study characterizes the inhibitory profile of this agent compared with that of ouabain against the three α-isoforms of the sodium pump. We prepared microsomal Na,K-ATPase from rat tissues representing the highest proportion of one of the α-isoforms. Both Northern and Western blot analyses confirmed that kidney had predominantly the α1-isoform, skeletal muscle the α2-isoform, and fetal brain the α3-isoform. Ouabain (5×10−6 mol/L) produced little inhibition of kidney Na,K-ATPase (3.4±2.0%) but significant inhibition of skeletal muscle (37.2±3.7%, P

Toshio Nishikawa - One of the best experts on this subject based on the ideXlab platform.

  • de novo synthesis of possible candidates for the inagami tamura endogenous Digitalis Like Factor
    Journal of Organic Chemistry, 2017
    Co-Authors: Atsuo Nakazaki, Keiko Hashimoto, Ai Ikeda, Takahiro Shibata, Toshio Nishikawa
    Abstract:

    De novo synthesis of possible candidates for the Inagami–Tamura endogenous Digitalis-Like Factor (EDLF) was achieved to validate a previously proposed structure. Our synthetic approach involves a highly regio- and diastereoselective Mizoroki–Heck reaction and a Friedel–Crafts-type cyclodehydration to construct steroidal tetracycle 14 as a versatile common intermediate leading to seven 2,14β-dihydroxyestradiol analogues 1a–c, 2a–c, and 3 as possible candidates. By comparing the potency of inhibitory activity against Na+/K+-ATPase between the synthesized candidates and the EDLF, it was found that the proposed structure is not Likely to be a true structure of the Inagami–Tamura EDLF.

  • De Novo Synthesis of Possible Candidates for the Inagami–Tamura Endogenous Digitalis-Like Factor
    Journal of Organic Chemistry, 2017
    Co-Authors: Atsuo Nakazaki, Keiko Hashimoto, Ai Ikeda, Takahiro Shibata, Toshio Nishikawa
    Abstract:

    De novo synthesis of possible candidates for the Inagami–Tamura endogenous Digitalis-Like Factor (EDLF) was achieved to validate a previously proposed structure. Our synthetic approach involves a highly regio- and diastereoselective Mizoroki–Heck reaction and a Friedel–Crafts-type cyclodehydration to construct steroidal tetracycle 14 as a versatile common intermediate leading to seven 2,14β-dihydroxyestradiol analogues 1a–c, 2a–c, and 3 as possible candidates. By comparing the potency of inhibitory activity against Na+/K+-ATPase between the synthesized candidates and the EDLF, it was found that the proposed structure is not Likely to be a true structure of the Inagami–Tamura EDLF.

Kaoru Yamada - One of the best experts on this subject based on the ideXlab platform.

  • effect of endogenous Digitalis Like Factor on endothelin secretion from bovine endothelial cells
    Journal of Cardiovascular Pharmacology, 1991
    Co-Authors: Kaoru Yamada, Atsuo Goto, T Sugimoto
    Abstract:

    We have recently isolated two endogenous Digitalis-Like Factors (EDLFs) from human urine. The polar EDLF (ouabain-displacing compound 1; ODC-1) fulfills the criteria for the putative natriuretic and vasoactive Digitalis-Like Factor. In this study, we examined the effects of ODC-1 and ouabain on endothelin-1 (ET-1) secretion from cultured endothelial cells. ODC-1 was partially purified from human urine with use of reverse-phase HPLC based on the inhibitory effects on [ 3 H]ouabain binding to intact human erythrocytes

  • endogenous Digitalis Like Factor as a stimulator of endothelin secretion from endothelial cells
    Biochemical and Biophysical Research Communications, 1990
    Co-Authors: Kaoru Yamada, Atsuo Goto, Tsuneaki Sugimoto
    Abstract:

    Summary Effects of human urine-derived endogenous Digitalis-Like Factor (EDLF) and ouabain on endothelin (ET) secretion were examined in cultured endothelial cells. ET was secreted in a linear fashion over 5 hours from bovine pulmonary artery endothelium into serum-free medium. EDLF stimulated ET secretion in a dose-dependent manner. In contrast, ouabain did not affect ET secretion at the concentration of 10−9–10−5M. These results indicate that human urine-derived EDLF is distinct from plant-derived ouabain and act as a stimulator of ET secretion by endothelial cells.

  • Digitalis-Like activity in human plasma: Relation to blood pressure and sodium balance
    The American Journal of Medicine, 1990
    Co-Authors: Atsuo Goto, Kaoru Yamada, Masao Ishii, Tsuneaki Sugimoto
    Abstract:

    Abstract purpose : On the assumption that renal tubular cells are more important as the target cells for a natriuretic Factor than blood cells, we used a well-characterized cultured renal tubular cell line, Madin-Darby canine kidney (MDCK) cells, to monitor the circulating Digitalis-Like Factor in human plasma and examine its role in the regulation of blood pressure and sodium balance. subjects and methods : We investigated the effects of plasma on binding of radioactive ouabain to monolayered MDCK cells in order to determine the level of a circulating Digitalis-Like Factor. First, we measured specific 3H-ouabain binding to MDCK cells in the presence of plasma from 71 outpatients (34 normotensive subjects and 37 hypertensive patients) after incubation for 4 hours. Second, we measured specific 3H-ouabain binding after incubation of cells with plasma from 16 hospitalized subjects (eight normotensive subjects and eight hypertensive patients) receiving low and high sodium diets. results : In Study 1, ouabain binding was lower by 30% with plasma from hypertensive patients than with plasma from normotensive subjects (p conclusions : These findings suggest that a circulating Digitalis-Like Factor, which may act on renal tubular cells as the ouabain-displacing compound, is increased in patients with essential hypertension and also demonstrate that plasma levels may be influenced by changes in dietary sodium intake.

Tsuneaki Sugimoto - One of the best experts on this subject based on the ideXlab platform.

  • endogenous Digitalis Like Factor as a stimulator of endothelin secretion from endothelial cells
    Biochemical and Biophysical Research Communications, 1990
    Co-Authors: Kaoru Yamada, Atsuo Goto, Tsuneaki Sugimoto
    Abstract:

    Summary Effects of human urine-derived endogenous Digitalis-Like Factor (EDLF) and ouabain on endothelin (ET) secretion were examined in cultured endothelial cells. ET was secreted in a linear fashion over 5 hours from bovine pulmonary artery endothelium into serum-free medium. EDLF stimulated ET secretion in a dose-dependent manner. In contrast, ouabain did not affect ET secretion at the concentration of 10−9–10−5M. These results indicate that human urine-derived EDLF is distinct from plant-derived ouabain and act as a stimulator of ET secretion by endothelial cells.

  • Digitalis-Like activity in human plasma: Relation to blood pressure and sodium balance
    The American Journal of Medicine, 1990
    Co-Authors: Atsuo Goto, Kaoru Yamada, Masao Ishii, Tsuneaki Sugimoto
    Abstract:

    Abstract purpose : On the assumption that renal tubular cells are more important as the target cells for a natriuretic Factor than blood cells, we used a well-characterized cultured renal tubular cell line, Madin-Darby canine kidney (MDCK) cells, to monitor the circulating Digitalis-Like Factor in human plasma and examine its role in the regulation of blood pressure and sodium balance. subjects and methods : We investigated the effects of plasma on binding of radioactive ouabain to monolayered MDCK cells in order to determine the level of a circulating Digitalis-Like Factor. First, we measured specific 3H-ouabain binding to MDCK cells in the presence of plasma from 71 outpatients (34 normotensive subjects and 37 hypertensive patients) after incubation for 4 hours. Second, we measured specific 3H-ouabain binding after incubation of cells with plasma from 16 hospitalized subjects (eight normotensive subjects and eight hypertensive patients) receiving low and high sodium diets. results : In Study 1, ouabain binding was lower by 30% with plasma from hypertensive patients than with plasma from normotensive subjects (p conclusions : These findings suggest that a circulating Digitalis-Like Factor, which may act on renal tubular cells as the ouabain-displacing compound, is increased in patients with essential hypertension and also demonstrate that plasma levels may be influenced by changes in dietary sodium intake.