Activation of the coagulation system in women with mitral stenosis and sinus rhythm.
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Adult↗
Biomedical subjects
S Goldstein
Publications and source records attributed to S Goldstein.
Telomere length predicts replicative capacity of human fibroblasts.
When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.
Base Sequence↗
A novel gene encoding a smooth muscle protein is overexpressed in senescent human fibroblasts.
In order to identify genes that may be causally involved in replicative senescence, we have isolated several gene sequences that are overexpressed in senescent human fibroblasts by differential screening of a cDNA library derived from mRNA of a subject with Werner syndrome of premature aging (Murano, S., et al., Molec. Cell. Biol., 3905-3914, 1991). Herein, we describe the sequence and expression of one of these genes, WS3-10, which encodes a novel human cytoplasmic protein of 22.5 kilodaltons. The steady-state mRNA levels of WS3-10 mRNA were higher in WS and late-passage normal cells compared to early-passage normal cells following serum depletion and subsequent repletion. Computer analysis showed similarities between WS3-10 and certain proteins in other species, indicating that WS3-10 represents the human homolog of a smooth muscle protein involved in calcium interactions that may contribute to replicative senescence.
Amino Acid Sequence↗
Circadian variation in platelet function in healthy volunteers.
Circadian variation in hemostatic factors may contribute to a higher frequency of cardiac events observed in the morning and with activity. Diurnal changes in these factors were investigated by measuring in vitro platelet aggregability in response to epinephrine and adenosine diphosphate together with beta-thromboglobulin and platelet factor 4 as indexes of in vivo platelet activation. Activation of coagulation was measured by thrombin-antithrombin III complexes and D-Dimers. Tests were performed in 9 normal healthy subjects. Circadian changes occurred in beta-thromboglobulin (p less than 0.05) and platelet factor 4 (p less than 0.06). Plasma levels of beta-thromboglobulin and platelet factor 4 were lowest with patients supine and resting at 7 and 8 A.M., and increased with activity, with peak levels achieved at 3 P.M. (p less than 0.01). Thrombin-antithrombin III complexes (p = 0.44), D-Dimer (p = 0.36) and in vitro platelet aggregability to adenosine diphosphate (p = 0.20) did not show diurnal variation. There was a trend toward circadian variation in vitro platelet aggregability to epinephrine, but these changes did not achieve statistical significance (p = 0.16). Circadian changes of in vivo release of beta-thromboglobulin and platelet factor 4 correlated to patient activity and not to the morning peaks in ischemic events. These data indicate that changes in platelet function and not in coagulation have a diurnal occurrence.
Adenosine Diphosphate↗
Inactivated whole-virus vaccine derived from a proviral DNA clone of simian immunodeficiency virus induces high levels of neutralizing antibodies and confers protection against heterologous challenge.
We tested the ability of macaques vaccinated with inactivated whole simian immunodeficiency virus (SIV) to resist challenge with either homologous or heterologous cell-free uncloned SIV administered by the intravenous route. The vaccine virus was derived from a proviral DNA clone and thus was considered genetically homogeneous. Sixteen macaques received either hepatitis B surface antigen (n = 6) or the inactivated whole-SIV vaccine (n = 10) at weeks 0, 4, and 49 of the study. All SIV vaccine recipients developed high levels of homologous and heterologous neutralizing antibodies in response to vaccination. At the time of challenge (week 53), vaccinees were further stratified to receive either homologous (n = 10) or heterologous (n = 6) uncloned live SIV. The envelope glycoproteins of the homologous and heterologous challenge viruses were 94% and 81% identical to the vaccine virus, respectively. Regardless of challenge inoculum, all vaccinees in the control group (hepatitis B surface antigen) became infected, whereas all SIV vaccinees were protected against detectable infection. These data support the concept that an efficacious vaccine for HIV might be possible, and suggest that genetic variation of HIV might not be an insurmountable obstacle for vaccine development.
Animals↗
Neurologic and neuropsychological manifestations of human immunodeficiency virus infection in intravenous drug users without acquired immunodeficiency syndrome. Relationship to head injury.
We examined 99 human immunodeficiency virus (HIV)-negative and 122 HIV-positive intravenous drug users (IVDUs) without acquired immunodeficiency syndrome (AIDS) to determine whether HIV-positive IVDUs had more neurologic and neuropsychological impairment than their HIV-negative counterparts. Controlling for age, education, drug use, history of head injury, and interactions between head injury and HIV status and drug use, HIV-positive subjects had more extrapyramidal signs and frontal release signs. These findings persisted when asymptomatic HIV-positive subjects without systemic signs of infection and HIV-negative subjects were compared. Neurologic findings were more severe in those with more systemic illness. Among those reporting a history of head injury with loss of consciousness, neuropsychological performance was significantly worse in the HIV-positive subjects, and this increased with severity of illness. This was not true in the group without head injury, suggesting an interaction between history of head injury and the seropositive state. No relationship was noted between head injury and either drug use or HIV state. Therefore, subtle neurologic and neuropsychological abnormalities may precede clinical evidence of AIDS in IVDUs and may be more evident in those with head injury.
Adult↗
Left ventricular shape: a factor in the etiology of functional mitral regurgitation in heart failure.
The relationship between left ventricular (LV) shape and functional mitral regurgitation (MR) was examined in 18 dogs with long-standing heart failure produced by multiple sequential intracoronary microembolizations. Global LV shape changes were evaluated from angiographic silhouettes obtained at baseline (before embolization) and during heart failure. LV shape changes at end systole and end diastole were quantitated based upon the ratio of the major-to-minor axis and the sphericity index. Among the 18 dogs studied, 11 developed 1+ to 3+ MR during heart failure and seven did not. There was no difference among the two groups with respect to hemodynamics, LV ejection fraction, chamber volume, and regional wall motion. A significant difference, however, was observed between the two groups with respect to the global indexes of LV shape. In dogs with MR, the end-systolic major-to-minor axis ratio decreased 29 +/- 3% between baseline and heart failure compared with only a 16 +/- 3% decrease in dogs without MR (p less than 0.01). In dogs with MR, the end-systolic sphericity index increased 72 +/- 11% between baseline and heart failure compared with an increase of only 30 +/- 5% in dogs without MR (p less than 0.02). Significant and directionally similar differences were observed during end diastole. These data indicate that in heart failure functional MR is associated with a more spherical LV and is not the result of simple LV chamber enlargement. Shape changes of the LV that occur in heart failure may be an important determinant of functional MR.
Animals↗
Mitochondrial abnormalities in myocardium of dogs with chronic heart failure.
The number, size and structural integrity of mitochondria (MIT) were evaluated in the myocardium of 12 dogs with chronic heart failure (CHF) produced by sequential intracoronary microembolizations (EMB). Tissue specimens for transmission electron microscopy were obtained from the left ventricular (LV) free wall, septum and right ventricular free wall 3 to 4 months after the last EMB. Comparisons were made with samples obtained from identical sites in 9 control dogs. In dogs with CHF, LV ejection fraction decreased from 61 +/- 1% at baseline (prior to EMB) to 22 +/- 2% 3 to 4 months after the last EMB (P < 0.01) while plasma norepinephrine (PNE) concentration increased from 364 +/- 12 pg/ml to 837 +/- 150 pg/ml (P < 0.01). The number of MIT in an area of 100 square sarcomeres was greater in CHF dogs compared to controls (92 +/- 5 vs 64 +/- 2) (P < 0.001); whereas the average size of MIT was smaller (0.53 +/- 0.03 vs. 0.78 +/- 0.04 microm2) (P < 0.001). Injury ranging in severity from matrix depletion to myelinization and membrane disruption was present in 27 +/- 4% of MIT of CHF dogs compared to only 3 +/- 1% of MIT of controls (P < 0.001). MIT abnormalities were present to the same extent in all three regions of the heart. The severity of MIT injury, assessed on the basis of an injury index, was significantly higher in CHF dogs with PNE > or = 600 pg/ml (0.64 +/- 0.07) compared to CHF dogs with PNE < 600 pg/ml (0.32 +/- 0.08) (P < 0.01). Among CHF dogs, the MIT injury index was linearly related to PNE concentration (r = 0.57, P < 0.05), LV ejection fraction (r = 0.57, P < 0.05) and LV end-diastolic pressure (r = 0.57, P < 0.05). These data indicate that profound MIT abnormalities are present in the myocardium of dogs with CHF and are related to PNE concentration and to the severity of LV dysfunction.
Animals↗
Myocardial beta adrenoceptor and voltage sensitive calcium channel changes in a canine model of chronic heart failure.
Effects of chronic heart failure upon receptor binding and cardiac function were studied in mongrel dogs. Heart failure was induced by three to seven, graded, sequential, intracoronary microembolizations performed 1 to 3 weeks apart. Depressed systolic and diastolic left ventricular function, reduced cardiac output, increased systemic vascular resistance, increased plasma norepinephrine concentration, left ventricular hypertrophy, and dilation were associated with the development of heart failure in this model. Three months after the last embolization, the density and affinity of myocardial beta adrenoceptors and voltage sensitive calcium channels were quantified by analyzing saturation isotherms of specific radioligand binding. [3H]Dihydroalprenolol and [3H]nitrendipine bound specifically and with high affinity to cardiac beta adrenoceptors and calcium channels, respectively. Scatchard transformation of the specific binding of these radioligands in membranes prepared following intracoronary embolization demonstrated a 47% decrease in the density of [3H]dihydroalprenolol binding sites (605 +/- 20 fmol/mg, normal, vs. 323 +/- 18 fmol/mg, failed; P < 0.05) and a 20% decrease in [3H]nitredipine binding sites (371 +/- 11 fmol/mg, normal, vs. 298 +/- 17 fmol/mg, failed; P < 0.05). The binding equilibrium dissociation constants for [3H]dihydroalprenolol and [3H]nitrendipine were not significantly different between normal and failed myocardium. There was no difference in the sialic acid content in the sarcolemmal membranes prepared from normal and failed dog hearts (31.07 +/- 0.76 nmol/mg, normal, vs. 30.58 +/- 5.25 nmol/mg, failed). This is inconsistent with the selective purification of membranes utilized in these radioligand binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Early revascularization improves survival in cardiogenic shock complicating acute myocardial infarction.
The effects of coronary revascularization by percutaneous transluminal coronary angioplasty or coronary bypass grafting, or both, on survival were evaluated in 81 patients with cardiogenic shock complicating acute myocardial infarction. Thirty-two patients had successful revascularization and 49 patients had unsuccessful or no revascularization. Revascularization was achieved by coronary angioplasty in 22 patients, coronary bypass surgery in 2 and angioplasty followed by bypass surgery in 8. No significant differences were noted between the two groups with regard to baseline clinical or hemodynamic variables. Intraaortic balloon counterpulsation was employed in 27 (84%) of the 32 patients in the group with revascularization and in 19 (39%) of the 49 patients without revascularization (p = 0.0006). The in-hospital survival was significantly better in the patients with--18 (56%) of 32--than in the patients without revascularization--4 (8%) of 49 (p less than 0.0001). At a mean follow-up period of 21 +/- 15 months, this survival difference persisted--16 (50%) of 32 patients with revascularization survived versus 1 (2%) of 49 patients without revascularization (p less than 0.0001). The mean time from the onset of shock to revascularization differed significantly between survivors (12.4 +/- 15 h) and nonsurvivors (58.5 +/- 93 h) in the group with revascularization (p = 0.0004). In the revascularization group, the in-hospital survival rate was 77% (17 of 22) when revascularization was performed within 24 h but only 10% (1 of 10) when it was performed after 24 h (p = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Mechanism of functional mitral regurgitation during acute myocardial ischemia.
The mechanism and temporal manifestation of functional mitral regurgitation after acute myocardial ischemia were examined in eight dogs. Regional ischemia was produced by selective microembolization of the left circumflex coronary artery. Mitral regurgitation and regional left ventricular wall motion abnormalities were evaluated with use of Doppler color flow mapping and two-dimensional echocardiography, respectively. Measurements were made at baseline (before embolization) and were repeated at 30 min and 3 weeks after embolization. Mitral regurgitation developed in all dogs 30 min after embolization and completely subsided 3 weeks later. There was no evidence of mitral valve prolapse, mitral anulus dilation or left ventricular segmental dyskinesia at any time during the study. Regional wall motion analysis showed only hypokinesia of the left ventricular segment overlying the papillary muscle at 30 min with subsequent normalization of the segment at 3 weeks. Mitral regurgitation was accompanied by an increase of the end-systolic distance between the mitral anulus plane and the point of coaptation of the mitral leaflets. This distance was 0.5 +/- 0.1 cm at baseline, increased to 0.9 +/- 0.1 cm 30 min after the embolization (p less than 0.001) and returned to near baseline (0.6 +/- 0.1 cm) 3 weeks after the embolization. These data indicate that mitral valve prolapse, mitral anulus dilation and regional left ventricular dyskinesia are not necessary conditions for the development of functional mitral regurgitation after acute myocardial ischemia. Instead, hypokinesia of the ventricular segment overlying the papillary muscle and leading to retraction of the mitral leaflets toward the apex appears to be a sufficient condition for incomplete leaflet coaptation.
Animals↗
Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure.
OBJECTIVES: The aim of this study was to examine the temporal association between the onset of functional mitral regurgitation and the development of changes in left ventricular shape, chamber enlargement, mitral anulus dilation and regional wall motion abnormalities during the course of evolving heart failure. BACKGROUND: Despite extensive characterization, the exact etiology of functional mitral regurgitation in patients with chronic heart failure remains unknown. METHODS: Heart failure was produced in seven dogs by multiple sequential intracoronary microembolizations. Serial changes in left ventricular chamber volume and shape were evaluated from ventriculograms. Changes in mitral anulus diameter and ventricular regional wall motion abnormalities were evaluated echocardiographically. The presence and severity of mitral regurgitation were determined with Doppler color flow mapping. Measurements were obtained at baseline and then biweekly until mitral regurgitation was first observed. RESULTS: No dog had mitral regurgitation at baseline but all developed mild to moderate regurgitation 12 +/- 1 weeks after the first embolization. The onset of mitral regurgitation was not associated with an increase in left ventricular end-diastolic volume relative to baseline (58 +/- 3 vs. 62 +/- 3 ml), mitral anulus diameter (2.4 +/- 0.1 vs. 2.4 +/- 0.1 cm) or wall motion abnormalities of left ventricular wall segments overlying the papillary muscles. In contrast, the onset of mitral regurgitation was accompanied by significant changes in global left ventricular shape evidenced by increased end-systolic chamber sphericity index (0.22 +/- 0.02 vs. 0.30 +/- 0.01) (p < 0.01) and decreased end-systolic major axis/minor axis ratio (1.71 +/- 0.05 vs. 1.43 +/- 0.04) (p < 0.001). CONCLUSIONS: These data indicate that transformation of left ventricular shape (increased chamber sphericity) is the most likely substrate for the development of functional mitral regurgitation.
Angiography↗
23rd Bethesda conference: access to cardiovascular care. Task Force 3: The role of the cardiovascular specialist.
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American Heart Association↗
The stability of neuropsychological test performance in a group of parenteral drug users.
The stability of neuropsychological performance in a sample of drug abusers was investigated for a wide range of neuropsychological tests, using a test-retest paradigm with 16 parenteral drug users. The battery administered included tests of general intellectual function, abstract reasoning, verbal memory, language, attention, visuospatial ability, set switching, speeded performance, and manipulative dexterity. Stability coefficients were of a moderate to high magnitude for most of the tests and were comparable to coefficients found in other studies of non-drug-users. Two exceptions, however, were the Selective Reminding Test and the Perdue Pegboard. Possible reasons for instability with these two tests are discussed. It is concluded that neuropsychological investigations of drug abusers can yield consistent and reliable data, although further studies should employ alternative and/or supplementary measures of verbal memory and motor function.
Adult↗
Radiation-induced generation of chlorine derivatives in N2O-saturated phosphate buffered saline: toxic effects on Escherichia coli cells.
The radiolysis of aqueous chloride solutions has been investigated using pulse and steady-state methods. We have found a correlation between the yields of Cl2- and HOCl formed in pulse-irradiated N2O-saturated solutions. The yields increased with the increasing concentrations of Cl- and phosphate. Phosphate enhanced the yield of Cl2- in neutral solutions because of a proton transfer from H2PO4- to HOCl- with a rate constant of (2.6 +/- 0.5) x 10(8) M-1s-1. HOCl could not be detected in pulse-irradiated He or air-saturated, phosphate-buffered saline (PBS) solutions or in gamma-irradiated N2O, He, or air-saturated PBS solutions. The results are discussed in light of previously suggested mechanisms for the formation and decay of Cl2-. Pulse-irradiated N2O-saturated PBS solutions have a lethal effect on Escherichia coli cells, which is proportional to the amount of HOCl in the solutions. Gamma-irradiation of cells in N2O-saturated PBS solution also raises the radiosensitivity of the cells, although HOCl does not accumulate in this system. The effects of the radiation-induced toxic products on E. coli cells are similar to the effects of NaOCl. The cell membrane is probably the site of physiological injury induced by the radiation products.
Adenosine Triphosphate↗
Inactivated whole SIV vaccine in macaques: evaluation of protective efficacy against challenge with cell-free virus or infected cells.
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Animals↗
Spontaneous and inducible ventricular arrhythmias in a canine model of chronic heart failure: relation to haemodynamics and sympathoadrenergic activation.
The relationship between the incidence, frequency and complexity of spontaneous ventricular arrhythmias and the extent of haemodynamic compromise and sympathoadrenergic hyperactivity was evaluated in a canine model of chronic heart failure produced by multiple sequential intracoronary microembolizations. Ambulatory ECG Holter monitoring recorded during chronic heart failure in 18 dogs revealed spontaneous ventricular arrhythmias ranging from single ventricular premature beats (VPBs) to non-sustained episodes of ventricular tachycardia (VT). Single VPBs were present in 94% of dogs, couplets in 67%, triplets in 28% and spontaneous episodes of non-sustained VT in 33%. Dogs with > 28 VPBs.h-1 (n = 9) had a markedly higher plasma norepinephrine (PNE) concentration (1001 +/- 185 vs 561 +/- 31 pg.ml-1) (P < 0.03), and a higher pulmonary artery wedge pressure (PAWP) (18 +/- 2 vs 12 +/- 1 mmHg) (P < 0.03) than dogs with < or = 28 VPBs.h-1 (n = 9). Dogs that developed spontaneous episodes of VT also had significantly higher PNE levels (1119 +/- 247 pg.ml-1) compared to dogs that did not develop VT (612 +/- 64 pg.ml-1) (P < 0.02). Programmed ventricular stimulation performed in seven of 18 dogs resulted in the development of sustained monomorphic VT in three and ventricular fibrillation in three dogs each (43%, 43%). Dogs with inducible sustained monomorphic VT had a significantly higher number of ambient arrhythmias and higher PAWP compared to dogs that did not develop sustained VT. The observed complexity, frequency and incidence of spontaneous and inducible ventricular arrhythmias in this canine model are similar to those described in patients with chronic heart failure.
Animals↗
Left ventricular shape changes during the course of evolving heart failure.
The temporal relationship between left ventricular (LV) shape changes and the development of LV dysfunction, dilation, and sympathoadrenergic hyperactivity was examined in 10 dogs with chronic heart failure produced by multiple sequential intracoronary microembolizations. LV shape was quantitated from serial ventriculograms based on the ratio of the major to minor axis at end systole and end diastole. Measurements were made at baseline (before embolizations) and were repeated at 2, 8, and 16 wk after the last embolization. A significant increase of LV sphericity was present at 2 wk, with only minimal changes occurring thereafter. Despite the tendency for LV shape changes to plateau between 2 and 16 wk, LV ejection fraction continued to decline (31 +/- 1 vs. 20 +/- 2%; P less than 0.001), and LV end-diastolic volume continued to increase (86 +/- 6 vs. 103 +/- 9 ml; P less than 0.01) as did plasma norepinephrine concentration (456 +/- 30 vs. 868 +/- 172 pg/ml; P less than 0.02). These data indicate that in the course of evolving heart failure, LV shape abnormalities precede the development of profound LV dysfunction, dilation, and overt activation of the sympathetic nervous system.
Adrenal Glands↗