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Biomedical subjects

L Rosenfeld

Publications and source records attributed to L Rosenfeld.

At least 37 records · Page 2Linked to original sources
PubMed1996

Initial single-center experience with an advanced third-generation investigational defibrillator.

The CPI PRxII is a recently approved, multitiered implantable cardioverter defibrillator (ICD) that delivers high and low energy biphasic shocks, antitachycardia (ATP) and bradycardia pacing, and stores 2.5 minutes of electrograms from the widely spaced shocking electrodes. The PRxII was implanted in 58 patients at Yale-New Haven Hospital between December 1993 and January 1995. At implant, mean biphasic defibrillation threshold (DFT) in patients with testing to failure was 10 J (1-20). All 36 patients who were candidates for a new transvenous system underwent successful nonthoracotomy implantation. Based on noninvasive predischarge EPS results, 30 patients had > or = 1 VT zone: 21 patients had ATP, 9 others had first shock < or = 5 J. During follow-up, 13 patients had been treated for 379 events (range, 1-127). Of 340 events in a zone with ATP, 97% responded to ATP, 3% required shock. First programmed shock converted all events in a VF zone. Details, including RR intervals, were available for all events in 15 of 17 patients receiving appropriate or inappropriate therapy or diverted shocks. One hundred eleven of 148 available electrograms confirmed VT by morphology, rate, and/or presence of AV dissociation. In nine patients, electrogram data altered therapy through diagnosis of inappropriate or diverted therapy, guidance of detection enhancements, or diagnosis of previously unrecognized VTs. We conclude the PRxII achieves low DFTs that obviate the need for thoracotomy and effectively treats ventricular arrhythmias with ATP and shock, with programming guided by noninvasive electrophysiology. Multiple stored electrograms from widely spaced shocking electrodes greatly enhance diagnostic capabilities, facilitating effective treatment.

Aged↗
PubMed1994

Specific heparin fractions suppress endothelin-1 production in cultured human umbilical vein endothelial cells.

Vascular endothelial cells produce endothelin-1, a peptide with potent vasoconstrictor and mitogenic properties. Heparin suppresses thrombin-stimulated endothelin-1 production in endothelial cells; this is consistent with its reported effect of lowering blood pressure. Since heparin is a heterogeneous mixture of glycosaminoglycans, we examined the effects of different fractions of heparin in suppressing endothelin-1 production in cultured endothelial cells. Heparin fractions differing in size and in antithrombin III affinity were prepared. The results show that the suppressive effect of heparin is independent of these properties of size and antithrombin III affinity. Heparin sulfate suppressed endothelin-1 production to a similar level as heparin. These experiments were conducted in a complete culture medium in the absence of added thrombin. To assess the role of endogenous thrombin in the medium on this process, we tested the effects of hirudin, a specific thrombin inhibitor peptide, on suppression of endothelin-1. Hirudin, like heparin, binds to the anion-binding exosite of thrombin. Hirudin alone, and combined with heparin, suppressed endothelin levels to the same extent as heparin. These experiments demonstrate that the suppressive effect of heparin is the result of its binding to the traces of thrombin in the culture medium, preventing stimulation of endothelin-1 production. This study supports the hypothesis that the functional thrombin receptor may participate in the stimulation of endothelin-1 by thrombin.

Analysis of Variance↗
PubMed1994

Circadian variation of sustained ventricular tachycardia in patients with coronary artery disease and implantable cardioverter-defibrillators.

BACKGROUND: While previous studies using epidemiological data and ambulatory ECG monitoring have shown peak occurrence of sudden death and nonsustained ventricular tachycardia in the morning, none have examined circadian variation of potentially life-threatening ventricular tachycardia (VT), nor has any study observed circadian behavior of any arrhythmias in individuals followed longitudinally. We used the event memory of multiprogrammable implantable cardioverter-defibrillators to evaluate the circadian pattern of sustained VT over time. METHODS AND RESULTS: Data were reviewed from 32 consecutive patients with coronary artery disease and sustained VT who had received the Ventak PRX (CPI, Inc) cardioverter-defibrillator between May 1991 and August 1993 and had experienced at least one episode of VT terminated by their device. Mean follow-up was 14 +/- 7 months. Among the 2558 episodes recorded by the device logs, VT occurrence peaked between 6 AM and noon (P = .007 by ANOVA among four 6-hour time periods). Harmonic regression revealed a morning peak at 9 AM (P < .01). This morning peak occurred in patients with both frequent and infrequent events. Among 21 patients who experienced more than four VT events, 8 (38%) had an AM peak of VT occurrence (> 35% of VT between 6 AM and noon). Neither age, ejection fraction, event frequency, presenting arrhythmia, nor drug therapy distinguished patients who displayed the AM VT peak. CONCLUSIONS: In patients with coronary artery disease, sustained VT displays circadian variation with peak frequency in the morning, similar to that for sudden death. Individual patients who display specific patterns of circadian variation over time can be identified using defibrillator logs. Investigation of circadian variation of other phenomena to elucidate mechanisms of VT should focus on these patients.

Aged↗
PubMed1992

Heparin enhances active site-dependent binding of tissue-type plasminogen activator to endothelial cells.

Human umbilical vein endothelial cells (HUVEC) in culture express two classes of binding sites for tissue-type plasminogen activator (t-PA). The high-affinity binding site has been identified as PA inhibitor type 1 (PAI-1), which binds to the catalytic portion of the molecule, while the second site binds t-PA through an active-site independent domain. Because recombinant t-PA (rt-PA) is often administered concomitantly with heparin, we investigated the effects of heparin on rt-PA binding to HUVEC. Preincubation of HUVEC with heparin at 4 degrees C increased the binding of radiolabeled rt-PA in a time- and dose-dependent manner. One-half maximal increase in binding was observed within 10 minutes of heparin addition. When HUVEC were preincubated with optimal concentrations (5 U/mL) of heparin for 4 hours at 4 degrees C, a 2.5- +/- 0.2-fold increase in specific binding was observed (mean +/- SEM, n = 12, P less than .01). Other highly sulfated glycosaminoglycans and fucoidan (a sulfated polymer of fucose) stimulated rt-PA binding as well, whereas glycosaminoglycans with lower sulfate content than heparin did not. Several results suggested that heparin increased the binding of rt-PA to "cell-associated" PAI-1. First, only active-site-dependent binding was enhanced by heparin, whereas binding of active-site blocked rt-PA was not affected. Second, extracts from HUVEC preincubated with heparin contained increased amounts of rt-PA-PAI-1 complexes as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Third, antibodies to PAI-1 blocked the increased binding entirely. HUVEC preincubated with heparin also bound increased amounts of enzymatically active radiolabeled urokinase-type PAs. However, HUVEC preincubated with heparin did not express increased amounts of immunoreactive PAI-1. Therefore, heparin, at therapeutic concentrations, may enhance or stabilize the association of PAs with endothelial cell-associated PAI-1.

Binding Sites↗
PubMed1991

Comparison of the separation of bovine heparin by strong anion exchange and by gel filtration chromatography.

Heparin has been fractionated by strong anion exchange chromatography followed by elution of the pools on a gel filtration column. This resulted in the expected inverse relationship in the elution order for the pools run by the two methods. Also chromatography of heparin was performed in the reverse order: gel filtration first, followed by anion exchange of the pools. For this order of separation four of the five gel filtration pools of different molecular weights eluted at a similar LiCl concentration. The specific activities of different pools of heparin were evaluated using a colorimetric microwell kinetics assay using antithrombin and thrombin. For the pools separated by ion exchange first, there was an exponential increase of specific activity with increasing molecular weight for all pools. For the pools isolated by gel filtration first, the specific activities became level after an initial increase in relation to molecular weight. Thus, unique pools of heparin species are being isolated by different modes of chromatography.

Animals↗
PubMed1991

Interaction of fibronectin with heparin in model extracellular matrices: role of arginine residues and sulfate groups.

The interaction of heparin with the NH2-terminal domain of human plasma fibronectin was studied by using matrix-driven translocation, an assay for the adhesion of extracellular macromolecules with cell or particle surfaces within artificial collagen matrices. Partial desulfation of heparin rendered it ineffective in competitively inhibiting the interaction of the fibronectin NH2-terminal domain with heparin-coated particles, suggesting a role for sulfate groups of heparin in the interaction. Analysis of the fibronectin domain in terms of its primary structure, its proposed organization into "type I modules", and its hydrophilic and flexible segments led to the identification of several arginine-containing sites of potential interaction with the sulfate groups of heparin. Modification of increasing numbers of arginine side chains with 1,2-cyclohexanedione under mild conditions eventually led to decreases in translocation-promoting activity, and of heparin binding capacity as measured in a gel-shift assay, but the major portions of these functions were retained even when the four most accessible arginines (attributed to sites in and adjacent to the large loops of the type I modules) were modified. With the modification of additional arginines (attributed to sites in the small loops), both functions were lost. The peptide Gly-Arg-Gly, corresponding to a repeated determinant at the tips of two small loops, inhibited translocation, but arginine alone did not. Cleavage of the large loops by CNBr also led to loss of translocation-promoting activity. The correspondence between the molecular determinants of matrix-driven translocation and those previously found for mesenchymal morphogenesis indicates the utility of this system in the analysis of adhesive interactions of biological importance.

Amino Acid Sequence↗
PubMed1990

Characterization of human endothelial cell urokinase-type plasminogen activator receptor protein and messenger RNA.

Human umbilical vein endothelial cells in culture (HUVEC) express receptors for urokinase-type plasminogen activators (u-PA). The immunochemical nature of this receptor and its relationship to u-PA receptors expressed by other cell types is unknown. Cross-linking active site-blocked u-PA to HUVEC lead to an increase in its apparent molecular mass by approximately 40 Kd. The predominant u-PA binding protein isolated from whole cell detergent extracts migrated with a molecular mass of approximately 36 Kd using affinity chromatography. In contrast, when only cell surface proteins were radiolabeled before extraction, the predominant labeled u-PA binding protein isolated migrated with a molecular mass of approximately 46 Kd. Several pieces of evidence suggested that the difference in molecular mass between these two u-PA binding proteins resulted from glycosylation of a single receptor protein. First, a polyclonal antibody against u-PA receptor isolated from phorbol myristate acetate (PMA) stimulated U-937 cells reacted with both the 36- and 46-Kd proteins on Western blotting. Second, the size of the unmodified receptor was estimated by amplifying a full-length cDNA for u-PA receptor from an endothelial cell cDNA library using the polymerase chain reaction (PCR) and oligonucleotide primers corresponding to the DNA sequence of the receptor cloned from transformed human fibroblasts (Roldan et al, EMBO J 9:467, 1990). The size of the cDNA (approximately 1,054 base pairs, bp) and the presence of a single 1.4-kilobase (Kb) mRNA transcript on Northern blot analysis predict an unglycosylated receptor protein of approximately 35 Kd. Third, synthesis of 35S-labeled 46-Kd cell surface receptor protein was inhibited when the cells were grown in the presence of tunicamycin, while the synthesis of the 36-Kd species was unaffected. Moreover, the apparent molecular mass of purified surface-labeled receptor (approximately 46 Kd) was reduced by N-glycanase. These studies suggest that the u-PA receptor on the surface of HUVEC is a glycoprotein derived from a protein of approximately 35 Kd which is similar immunologically to u-PA receptors on other cell types.

Base Sequence↗
PubMed1990

Interaction of single-chain urokinase-type plasminogen activator with human endothelial cells.

The interaction of urokinase-type plasminogen activators with receptors on the surface of endothelial cells may play an important role in the regulation of fibrinolysis and cell migration. Therefore, we investigated whether human umbilical vein endothelial cells (HUVEC) express receptors for single-chain urokinase (scu-PA) on the cell surface and examined the effect of such binding on plasminogen activator activity. Binding of 125I-labeled scu-PA to HUVEC, performed at 4 degrees C, was saturable, reversible, and specific (k+1 4 +/- 1 X 10(6) min-1 M-1, k-1 6.2 +/- 1.4 X 10(-3) min-1, Kd 2.8 +/- 0.1 nM; Bmax 2.2 +/- 0.1 X 10(5) sites/cell; mean +/- S.E.). Binding of radiolabeled scu-PA was inhibited by both natural and recombinant wild-type scu-PA, high molecular weight two-chain u-PA (tcu-PA), catalytic site-inactivated tcu-PA, an amino-terminal fragment of u-PA (amino acids 1-143), and a smaller peptide (amino acids 4-42) corresponding primarily to the epidermal growth factor-like domain. Binding was not inhibited by low molecular weight urokinase or by a recombinant scu-PA missing amino acids 9-45. Cell-bound scu-PA migrated at its native molecular mass on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the presence of plasminogen, scu-PA bound to endothelial cells generated greater plasmin activity than did scu-PA in the absence of cells. In contrast, when tcu-PA was added directly to HUVEC, sodium dodecyl sulfate-stable complexes formed with cell or matrix-associated plasminogen activator inhibitors with a loss of plasminogen activator activity. These studies suggest that endothelial cells in culture express high affinity binding sites for the epidermal growth factor domain of scu-PA. Interaction of scu-PA with these receptors may permit plasminogen activator activity to be expressed at discrete sites on the endothelial cell membrane.

Binding, Competitive↗
PubMed1989

Lipoprotein analysis. Early methods in the diagnosis of atherosclerosis.

Before 1950, there was no clear perception of the interrelationship of serum lipids, atherosclerosis, and coronary heart disease. Since then, research laboratories have made conflicting claims for the most useful measurement of the serum lipid levels in detecting and managing coronary heart disease. Emphasis has been placed in turn on the measurement of levels of serum cholesterol, lipoproteins, triglycerides, and, currently, cholesterol and lipoproteins again. Physical separation and characterization of serum lipoproteins by ultracentrifugation and electrophoresis resulted in two classification systems for lipoproteins based on hydrated density and electrophoretic mobility, respectively. Two operational by-products were the atherogenic index, an empirical formula supposed to correlate with coronary heart disease, and a phenotype system for classification of the lipoproteinemias. Current National Heart, Lung, and Blood Institute criteria for atherosclerosis risk implicate elevated levels of cholesterol and low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein cholesterol. Although triglycerides are closely associated with cholesterol in lipoprotein molecules and are positively associated with cardiovascular disease, there is no strong evidence of elevated levels of plasma triglycerides as an independent risk factor in coronary heart disease. Elevated levels of triglycerides can help identify persons with increased risk of cardiovascular disease from other causes, but screening for hypertriglyceridemia is not recommended. Apolipoproteins and lipoprotein Lp(a) are briefly discussed.

Arteriosclerosis↗
PubMed1989

Hodgkin's disease: origin of an eponym--and one that got away.

Hodgkin's disease, the syndrome of enlarged lymph nodes associated with enlarged spleen, was described in 1832 on the basis of the gross appearance of the affected parts. The eponym entered the medical literature after repeated attempts by Dr. Samuel Wilks to credit Thomas Hodgkin with the priority of discovery. Today, this malady, also known by many other names, is recognized by microscopic examination of histological features. Hodgkin also described retroversion of the aortic valves with insufficiency in 1827 but Dr. Dominic Corrigan, whose report appeared in 1832, was credited with the eponym, despite efforts again by Wilks on behalf of Hodgkin.

History, 18th Century↗
PubMed1989

Martin Robison Delany (1812-1885): physician, black separatist, explorer, soldier.

Martin Robison Delany's great contribution to American life and black history stems from his defiant blackness. He was America's first "Black Nationalist" and the intense embodiment of black pride. Ever changing in his career, he always identified with the black experience and its place in history. In an active life he was doctor, dentist, orator, editor, publisher, Harvard medical student, explorer, dabbler in Central American politics, army officer, and Reconstruction office seeker.

Black or African American↗
PubMed1988

Location of specific oligosaccharides in heparin in terms of their distance from the protein linkage region in the native proteoglycan.

Studies were conducted to define the location of components and sequences in heparin with respect to their distance from the peptide linkage in the native proteoglycan. A purified heparin-oligopeptide was linked via its amino terminus to a matrix containing an azo bond and an activated carboxyl group. The polysaccharide chain was maximally degraded, either with heparinase or nitrous acid, and the soluble products were removed. The heparin-oligopeptide fragments that remained on the matrix were released by reductive cleavage of the azo linkage and characterized. The fragments, as well as heparin released without prior degradation, contained serine and glycine as the principal amino acids; the ratio of galactose to xylose was 2:1. The ratio of glucosamine to serine of 33:1 in the undegraded heparin was reduced to 6:1 and 1:1 in the heparinase-treated and nitrous acid-treated products, respectively. The undegraded sample and the fragments contained phosphate in equivalent amounts, demonstrating its presence in the heparin-protein linkage region. The heparin-oligopeptide preparation was also fractionated by gel filtration and high and low molecular weight fractions thus obtained were each linked to the insoluble matrix. The products that were subsequently released were subfractionated on a molecular weight-calibrated column of Sephadex G-200, and eluates were assayed for activity in promoting the neutralization of thrombin and factor Xa by antithrombin. The results revealed a sharp decrease in specific activity in heparin-oligopeptide fractions below Mr = 15,000 indicating that the anticoagulant-conferring segment is located at about 20 disaccharide units away from the peptide linkage region.

Amino Acids↗