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Biomedical subjects

S Goldstein

Publications and source records attributed to S Goldstein.

At least 91 records · Page 5Linked to original sources
PubMed1999

Reduced sarcoplasmic reticulum Ca(2+)-uptake and expression of phospholamban in left ventricular myocardium of dogs with heart failure.

The purpose of this study was to examine the sarcoplasmic reticulum (SR) Ca(2+)-uptake and the expression of phospholamban (PLB) and Ca(2+)-ATPase (CAA) in left ventricular (LV) and right ventricular (RV) myocardium of 6 normal (NL) dogs and 6 dogs with chronic heart failure (HF). In addition, gene expression of PLB and CAA was also examined in LV myocardium of NL and HF dogs. HF (LV ejection fraction 23+/-2%) was produced by multiple sequential intracoronary microembolizations. Oxalate-dependent Ca(2+)-uptake was measured in isolated membrane vesicles. Using specific dog myocardial monoclonal antibody, the expression of CAA, PLB and calsequestrin (CSQ) were measured in sodium dodecyl sulfate extract prepared from LV and RV tissue. Steady-state mRNA levels were determined by Northern hybridization using specific cDNA clones of PLB, CAA, CSQ, and glyceraldehyde-3-phosphate dehydrogenase (GADPH), a house keeping gene. SR Ca(2+)-uptake of NL and HF dogs increased with increasing Ca(2+)concentrations and reached a plateau at 3 microm in both LV and RV. Total capacity (134+/-9 v 224+/-10 nmol(45)Ca/mg protein/10 min, P<0.05) and maximal velocity (15+/-2 v 2 nmol(45)Ca/mg protein/min, P<0.05) of the SR to sequester Ca(2+)was significantly lower in LV myocardium of HF dogs compared to NL, whereas the Hill coefficient and the affinity of the Ca(2+)-pump for Ca(2+)were unchanged. LV tissue levels of the PLB and CAA, normalized to noncollagen protein or to CSQ and the PLB and CAA mRNA levels, normalized to CSQ or GADPH mRNA, were also significantly lower in HF dogs compared to NL. In RV myocardial tissue, no significant differences in total capacity of SR to sequester Ca(2+), maximal velocity of SR Ca(2+)-uptake, the affinity and Hill Coefficient of the Ca(2+)-pump for Ca(2+), or tissue levels of PLB and CAA were observed between NL dogs compared to HF dogs. We conclude that SR Ca(2+)-uptake and SR PLB and CAA protein and gene expression levels are reduced in LV myocardium of dogs with chronic HF. These abnormalities can lead to Ca(2+)-overload and subsequent global LV dysfunction.

Animals↗
PubMed1999

Clinical predictors of heart failure in patients with first acute myocardial infarction.

BACKGROUND: The occurrence of heart failure associated with an acute myocardial infarction has a strong adverse effect on long-term morbidity and mortality. The prediction and prevention of heart failure could influence these adverse events. METHODS AND RESULTS: We studied 483 consecutive patients who had their first acute myocardial infarction and who were admitted within 24 hours of the onset of symptoms. Heart failure was defined as the presence of pulmonary rales or an S3 gallop, or the presence of alveolar or interstitial edema by radiograph. Baseline demographic data, determination of peak creatine phosphokinase level, echocardiographic left ventricular ejection fraction, blood pressure, and pulse were obtained. Heart failure occurred in 41.6% (201 of 483) of the patients. We observed a bimodal occurrence of heart failure with an early occurrence at admission in 4% (20 of 483) followed by a second increase beginning after the fourth day of admission in 39% of the remaining patients (181 of 463). Predictors of early heart failure were older age, diabetes mellitus, or previous cardiac symptoms, whereas the predictors of heart failure after the fourth day included the same demographic predictors in addition to a history of hypertension, male sex, increased peak creatine phosphokinase level and heart rate, and decrease in left ventricular ejection fraction. In-hospital death occurred in 5.3% compared with 1.4% (P =.012) in patients who did and did not have heart failure, respectively. The occurrence of heart failure during hospital admission also adversely affected the 18-month follow-up, with 14.9% deaths in the patients with heart failure and 6.4% in those without heart failure (P =.002). CONCLUSION: Heart failure is frequently associated with acute myocardial infarction and occurs with a bimodal distribution and is associated with increased risk of death during hospitalization and during 18 months of follow-up. Predictors of early heart failure include previous medical conditions and age. The second peak occurrence can be predicted by similar characteristics in addition to increased peak creatine phosphokinase level, decreased left ventricular ejection fraction, and increased heart rate.

Aged↗
PubMed1999

A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: the U.S. ecadotril pilot safety study.

OBJECTIVE: To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. METHODS: Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction </=35%, taking stable doses of angiotensin-converting enzyme inhibitor, diuretics, and optionally digoxin were enrolled in a randomized, double-blind, placebo-controlled dose-escalation study of ecadotril 50 to 400 mg twice daily versus conventional therapy alone. RESULTS: No increases in deaths, serious adverse events, or dropouts from adverse events were observed for the ecadotril group compared with placebo. The serum measures of neurohormonal activation were highly variable. Changes in signs and symptoms of heart failure, New York Heart Association class, and patient self-assessment of symptoms were not observed with ecadotril therapy; however, the study was not designed to detect differences in these parameters. CONCLUSION: In this small pilot study, ecadotril in doses of 50 to 400 mg twice daily was generally well-tolerated and without severe short-term adverse effects in patients with mild to moderate heart failure. Evaluation of the clinical efficacy and long-term safety of ecadotril and other neutral endopeptidase inhibitors in patients with heart failure requires further study.

Adolescent↗
PubMed1999

Metoprolol CR/XL in patients with heart failure: A pilot study examining the tolerability, safety, and effect on left ventricular ejection fraction.

BACKGROUND: This study was designed to investigate the tolerability, safety, and effect on left ventricular function of a new long-acting preparation of metoprolol, metoprolol succinate (CR/XL). METHODS AND RESULTS: Sixty patients were randomly assigned with a 2:1 ratio, drug versus placebo, administered with a gradually increasing dose of 12.5 to 150 mg of blinded medication during an 8-week period and continued for 6 months. The average peak dose achieved was 99 mg and 132 mg in the metoprolol succinate and placebo groups, respectively. The drug was well tolerated and there was no significant difference in drug withdrawals, New York Heart Association class, or quality of life assessment. The increase in left ventricular ejection fraction measure at baseline and 6 months measured by radioisotopic ventriculography was greater in the metoprolol succinate group (27. 5% to 36.3%) than in the placebo group (26% to 27.9%) (P <.015). Examination of serial Holter electrocardiographic recordings indicate that metoprolol succinate therapy was associated with a significant (P <.05) decrease in total ventricular ectopy at 8 weeks of therapy and a decrease in ventricular couplets and nonsustained ventricular tachycardia at 8 through 26 weeks of therapy. No changes were observed in plasma norepinephrine during therapy except a transitory significant (P <.05) increase in N terminal proatrial natriuretic factor at 8 weeks in the metoprolol succinate group. CONCLUSIONS: This study indicates that treatment with metoprolol succinate for a 6-month period is safe and well tolerated and is associated with an increase in left ventricular ejection fraction and a decrease in ventricular ectopic beats.

Double-Blind Method↗
PubMed1999

Effects of exercise training on chronotropic incompetence in patients with heart failure.

OBJECTIVE: To describe the effects of exercise training on chronotropic incompetence in patients with stable heart failure, as measured by their inability to achieve a peak exercise heart rate greater than 85% of maximum. BACKGROUND: Exercise intolerance and chronotropic incompetence are characteristic of patients with heart failure. Exercise training improves exercise capacity in these patients; however, to what extent reversal of chronotropic incompetence contributes to such a response remains uncertain. METHODS: Fifty-one patients undergoing standard medical therapy were randomly assigned to a 24-week exercise training program or a no exercise control group. Twenty-one of 26 patients assigned to the exercise group and 22 of 25 control patients completed the study. Peak oxygen consumption, resting and exercise plasma norepinephrine level, and quality of life (Living With Heart Failure Questionnaire) were assessed. RESULTS: A significant (P <.05) increase in peak heart rate was observed in the exercise group (9 +/- 3 beats/min) when compared with the control group (1 +/- 3 beats/min). Among exercise-trained patients with chronotropic incompetence at baseline (n = 14), the increase in peak heart rate at week 24 was 12 +/- 3 beats/min. Peak oxygen consumption was significantly (P <.05) increased in the exercise group (204 +/- 57 mL/min) versus the control group (72 +/- 33 mL/min). Health-related quality of life was not significantly changed with exercise training. Twenty-four weeks of exercise training induced a greater (P <.05) reduction in plasma norepinephrine at rest and during exercise in patients with a nonischemic cardiomyopathy versus those with ischemic cardiomyopathy. CONCLUSIONS: Exercise training results in an increase in peak heart rate and partial reversal of chronotropic incompetence among patients with stable heart failure. These responses contribute, in part, to the exercise training-induced increase in exercise capacity that occurs in these patients.

Cardiac Output↗
PubMed1999

Kinetics of superoxide-induced exchange among nitroxide antioxidants and their oxidized and reduced forms.

Nitroxide stable radicals generally serve for probing molecular motion in membranes and whole cells, transmembrane potential, intracellular oxygen and pH, and are tested as contrast agents for magnetic resonance imaging. Recently nitroxides were found to protect against oxidative stress. Unlike most low molecular weight antioxidants (LMWA) which are depleted while attenuating oxidative damage, nitroxides can be recycled. In many cases the antioxidative activity of nitroxides is associated with switching between their oxidized and reduced forms. In the present work, superoxide radicals were generated either radiolytically or enzymatically using hypoxanthine/xanthine oxidase. Electron paramagnetic resonance (EPR) spectrometry was used to follow the exchange between the nitroxide radical and its reduced form; whereas, pulse radiolysis was employed to study the kinetics of hydroxylamine oxidation. The results indicate that: a) The rate constant of superoxide reaction with cyclic hydroxylamines is pH-independent and is lower by several orders of magnitude than the rate constant of superoxide reaction with nitroxides; b) The oxidation of hydroxylamine by superoxide is primarily responsible for the non-enzymatic recycling of nitroxides; c) The rate of nitroxides restoration decreases as the pH decreases because nitroxides remove superoxide more efficiently than is hydroxylamine oxidation; d) The hydroxylamine reaction with oxidized nitroxide (comproportionation) might participate in the exchange among the three oxidation states of nitroxide. However, simulation of the time-dependence and pH-dependence of the exchange suggests that such a comproportionation is too slow to affect the rate of non-enzymatic nitroxide restoration. We conclude that the protective activity of nitroxides in vitro can be distinguished from that of common LMWA due to hydroxylamine oxidation by superoxide, which allows nitroxide recycling and enables its catalytic activity.

Antioxidants↗
PubMed1999

The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group.

BACKGROUND: Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate (FP) as the cornerstone of anti-inflammatory therapy for asthma. OBJECTIVE: The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP as compared with increasing the dose of FP. METHODS: In a multicenter, double-blind study conducted over 24-weeks, 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were randomly assigned to receive either salmeterol (42 microg twice daily) or FP 220 microg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures included FEV1, symptom scores, nighttime awakenings, and supplemental albuterol use. Safety was assessed by reported adverse events and asthma exacerbations. RESULTS: The addition of salmeterol resulted in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily (P < .001) while the percent of symptom-free days increased from baseline by 26% of days as compared with 10% of days (P < .001). The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment. CONCLUSIONS: The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinically and statistically superior to increasing the dose of FP.

Adolescent↗
PubMed1999

Effect of *NO on the decomposition of peroxynitrite: reaction of N2O3 with ONOO-.

Nitric oxide reacts slowly with ONOO- (k < 1.3 x 10(-)3 M-1 s-1), and therefore does not affect the stability of peroxynitrite at pH >12. A chain consumption of peroxynitrite by *NO takes place at pH <12 through the reaction of N2O3 with ONOO-, where the former is formed through two initiation steps: (i) autoxidation of *NO, which is the main process in alkaline solutions, and (ii) spontaneous decomposition of peroxynitrite. The effect of *NO on the decomposition of peroxynitrite depends on the rate of the reaction of ONOO- with N2O3 (propagation step) relative to that of the hydrolysis of N2O3 (termination step). Therefore, rapid consumption of peroxynitrite occurs upon increasing the peroxynitrite concentration, decreasing the phosphate concentration, and lowering the pH, as the hydrolysis of N2O3 is base-catalyzed. The rate constant of the reaction of ONOO- with N2O3 has been determined in alkaline solutions to be (3.1 +/- 0.3) x 10(8) M-1 s-1. The decomposition of ONOOH in acidic solutions is hardly affected by *NO, as N2O3 does not react with ONOOH. Under physiological conditions, the reaction of *NO with peroxynitrite cannot give rise to a chain consumption of peroxynitrite as the reaction of N2O3 with the relatively low concentrations of peroxynitrite cannot compete with the hydrolysis of N2O3.

Hydrogen-Ion Concentration↗
PubMed1999

Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration.

The inability to deliver growth factors locally in a transient but sustained manner is a substantial barrier to tissue regeneration. Systems capable of localized plasmid gene delivery for prolonged times may offer lower toxicity and should be well-suited for growth factor therapeutics. We investigated the potency of plasmid gene delivery from genes physically entrapped in a polymer matrix (gene activated matrix) using bone regeneration as the endpoint in vivo. Implantation of gene activated matrices at sites of bone injury was associated with retention and expression of plasmid DNA for at least 6 weeks, and with the induction of centimeters of normal new bone in a stable, reproducible, dose- and time-dependent manner.

Animals↗
PubMed1999

Absence of chaos in Bohmian dynamics.

The Bohm motion for a particle moving on the line in a quantum state that is a superposition of n+1 energy eigenstates is quasiperiodic with n frequencies.

Journal Article↗
PubMed1999

Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure.

The objective of the present study was to determine the effects of early long-term monotherapy with the angiotensin II AT1-receptor antagonist valsartan on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Studies were performed in 30 dogs with moderate HF produced by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction was 30-40%. Two weeks after the last embolization, dogs were randomized to 3 mo of oral therapy with low-dose valsartan (400 mg twice daily, n = 10), to high-dose valsartan (800 mg twice daily, n = 10), or to no treatment at all (control, n = 10). Treatment with valsartan significantly reduced mean aortic pressure and LV end-diastolic pressure compared with control. In untreated dogs, LV ejection fraction decreased (37 +/- 1 vs. 29 +/- 1%, P = 0.001) and end-systolic volume (ESV) and end-diastolic volume (EDV) increased (81 +/- 5 vs. 92 +/- 5 ml, P < 0.001; 51 +/- 3 vs. 65 +/- 3 ml, P = 0.001, respectively) after 3 mo of follow-up compared with those levels before follow-up. In dogs treated for 3 mo with low-dose valsartan, ejection fraction was preserved (37 +/- 1 vs. 38 +/- 2%, pretreatment vs. posttreatment) as was ESV but not EDV. In dogs treated for 3 mo with high-dose valsartan, ejection fraction decreased (35 +/- 1 vs. 31 +/- 2%, P = 0.02) and ESV and EDV increased in a manner comparable to those levels in controls. Valsartan had no significant effects on cardiomyocyte hypertrophy or on the extent of interstitial fibrosis. We conclude that, for dogs with moderate HF, early long-term therapy with the AT1-receptor blocker valsartan decreases preload and afterload but has only limited benefits in attenuating the progression of LV dysfunction and chamber remodeling.

Angiotensin Receptor Antagonists↗
PubMed1999

Apexification & apexogenesis.

When there is pulpal involvement of permanent teeth with incompletely formed roots, techniques for the induction of apical closure should be completed before endodontic therapy is begun. Apexification is a method of inducing a calcified barrier at the apex of a nonvital tooth with incomplete root formation. Apexogenesis refers to a vital pulp therapy procedure performed to encourage physiological development and formation of the root end.

Adolescent↗
PubMed1999

Applications for guided bone regeneration in endodontic surgery.

Regeneration of apical bony defects remains a significant problem in endodontic surgery. When a resorbable membrane is placed over a defect, it acts as a barrier between the defect and the overlying gingival tissue. This barrier membrane provides sufficient time for bone to regenerate while preventing the faster growing connective tissue from invaginating into the area. When new tissue replicates the structure and function of the lost tissue, then apical regeneration has occurred.

Absorbable Implants↗
PubMed1999

The mortality effect of metoprolol CR/XL in patients with heart failure: results of the MERIT-HF Trial.

The study was undertaken to investigate the effect of metoprolol CR/XL on all-cause mortality in patients with heart failure in New York Heart Association (NYHA) class II-IV. In all, 3,991 patients in NYHA class II-IV who were stable on standard medical treatment, including angiotensin-converting enzyme inhibitors, diuretics, and digitalis, were randomized to metoprolol CR/XL or placebo and uptitrated from 12.5 or 25 mg to 200 mg over an 8-week period and were planned to be followed for a period of 2 years. The study was stopped earlier than planned due to the significant benefit achieved with metoprolol CR/XL on all-cause mortality. Treatment with metoprolol CR/XL was associated with a 34% decrease in all-cause mortality, 38% decrease in cardiovascular mortality, 41% decrease in sudden death, and 49% decrease in death due to progressive heart failure. The average dose of metoprolol CR/XL at the end of the study was 159 mg, and 64% of the patients were receiving 200 mg of metoprolol CR/XL. There was no significant difference in the placebo and active treatment group with regard to permanent discontinuation. Treatment of patients in NYHA class II-IV with metoprolol CR/XL is associated with a significant decrease in total mortality.

Adrenergic beta-Antagonists↗
PubMed1999

The SynerGraft valve: a new acellular (nonglutaraldehyde-fixed) tissue heart valve for autologous recellularization first experimental studies before clinical implantation.

The durability of current bioprosthetic heart valves is diminished by glutaraldehyde-associated leaflet calcification or by the associated absence of a cellular component capable of repair of wear-related damage. As a novel tissue engineering approach to improving replacement heart valve durability, we have developed a decellularization process to replace the use of cross-linking to limit xenograft antigenicity. The effectiveness of this process was assessed in a weanling sheep right ventricular outflow tract reconstruction model where valve function, calcification, and recellularization were examined. Porcine aortic valves were decellularized by a process designed to remove all histologically demonstrable leaflet cells. Stentless, bioprosthetic valves were fabricated from acellular tissues, cryopreserved, sterilized, and then implanted as pulmonary valve replacements in 4- to 6-month old female Suffolk sheep. Sheep aortic valves were implanted as allograft control subjects. After 150 days, the grafts were explanted and assessed histologically and by atomic absorption spectrophotometry for calcium content. All valves were hemodynamically functional at explant. Histological examination showed intact leaflets with in-growth of host fibroblastoid cells in all explanted porcine valves and no evidence of calcification. Porcine leaflet calcium content was unchanged over the duration of the implant (1.0+/-1.2 vs 1.5+/-1.8 mg/g dry weight, P = ns). Decellularization can stabilize xenogenic heart valves. Lack of calcification of acellular aortic leaflets suggests that prolonged durability of such valves is attainable without the use of cross-linking agents. The repopulation of the leaflet matrix offers additional promise of durability based on revitalization of the graft in vivo.

Animals↗
PubMed1998

Preliminary animal and clinical experiences using an electromechanical endocardial mapping procedure to distinguish infarcted from healthy myocardium.

BACKGROUND: A catheter-based left ventricular (LV) endocardial mapping procedure using electromagnetic field energy for positioning of the catheter tip was designed to acquire simultaneous measurements of endocardial voltage potentials and myocardial contractility. We investigated such a mapping system to distinguish between infarcted and normal myocardium in an animal infarction model and in patients with coronary artery disease. METHODS AND RESULTS: Measurements of LV endocardial unipolar (UP) and bipolar (BP) voltages and local endocardial shortening were derived from dogs at baseline (n=12), at 24 hours (n=6), and at 3 weeks (n=6) after occlusion of the left anterior descending coronary artery. Also, 12 patients with prior myocardial infarction (MI) and 12 control patients underwent the LV endocardial mapping study for assessment of electromechanical function in infarcted versus healthy myocardial regions. In the canine model, a significant decrease in voltage potentials was noted in the MI zone at 24 hours (UP, 42. 8+/-9.6 to 29.1+/-12.2 mV, P=0.007; BP, 11.6+/-2.3 to 4.9+/-1.2 mV, P<0.0001) and at 3 weeks (UP, 41.0+/-8.9 to 13.9+/-3.9 mV, P<0.0001; BP, 11.2+/-2.8 to 2.4+/-0.4 mV, P<0.0001). No change in voltage was noted in zones remote from MI. In patients with prior MI, the average voltage was 7.2+/-2.7 mV (UP)/1.4+/-0.7 mV (BP) in MI regions, 17.8+/-4.6 mV (UP)/4.5+/-1.1 mV (BP) in healthy zones remote from MI, and 19.7+/-4.4 mV (UP)/5.8+/-1.0 mV (BP) in control patients without prior MI (P<0.001 for MI values versus remote zones or control patients). In the canine model and patients, local endocardial shortening was significantly impaired in MI zones compared with controls. CONCLUSIONS: These preliminary data suggest that infarcted myocardium could be accurately diagnosed and distinguished from healthy myocardium by a reduction in both electrical voltage and mechanical activity. Such a diagnostic electromechanical mapping study might be clinically useful for accurate assessment of myocardial function and viability.

Animals↗
PubMed1998

Upregulation of functional ryanodine receptors during in vitro aging of human diploid fibroblasts.

We demonstrate for the first time that cellular aging in vitro is accompanied by a dramatic elevation in the levels of ryanodine receptor-bearing Ca2+ channels. These channels normally reside within microsomal membranes and gate Ca2+ release from intracellular stores. We therefore measured cytosolic Ca2+ levels in 'young' (30 mean population doublings, MPDs) and 'senescent' (53 to 58 MPDs) human diploid fibroblasts (HDFs). Application of the known ryanodine receptor modulators, caffeine or cyclic adenosine diphosphate-ribose (cADPr), triggered cytosolic Ca2+ signals in both young and senescent cells. The signal magnitude however was significantly greater in senescent compared with young HDFs. In parallel, incubation with a highly specific anti-ryanodine receptor antiserum resulted in specific immunofluorescence only in senescent HDFs. We envisage that elevated levels of functional ryanodine receptors may underlie the defective Ca2+ handling and cellular degeneration that occurs with aging.

Adenosine Diphosphate Ribose↗