Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro.

One mechanism considered responsible for the hypercalcemia that frequently accompanies malignancy is secretion by the tumor of a circulating factor that alters calcium metabolism. The structure of a tumor-secreted peptide was recently determined and found to be partially homologous to parathyroid hormone (PTH). The amino-terminal 1-34 region of the factor was synthesized and evaluated biologically. In vivo it produced hypercalcemia, acted on bone and kidney, and stimulated 1,25-dihydroxy-vitamin D3 formation. In vitro it interacted with PTH receptors and, in some systems, was more potent than PTH. These studies support a long-standing hypothesis regarding pathogenesis of malignancy-associated hypercalcemia.

The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

The biological response to progesterone is mediated by two distinct forms of the human progesterone receptor (hPR-A and hPR-B). In most cell contexts, hPR-B functions as a transcriptional activator of progesterone-responsive genes, whereas hPR-A functions as a transcriptional inhibitor of all steroid hormone receptors. We have created mutations within the carboxyl terminus of hPR which differentially effect the transcriptional activity of hPR-B in a cell- and promoter-specific manner. Analogous mutations, when introduced into hPR-A, have no effect on its ability to inhibit the transcriptional activity of other steroid hormone receptors. The observed differences in the structural requirements for hPR-B and hPR-A function suggest that transcriptional activation and repression by PR are mediated by two separate pathways within the cell. In support of this hypothesis, we have shown that hPR-A mediated repression of human estrogen receptor (hER) transcriptional activity is not dependent on hER expression level but depends largely on the absolute expression level of hPR-A. Thus, it appears that hPR-A inhibits hER transcriptional activity as a consequence of a noncompetitive interaction of hPR-A with either distinct cellular targets or different contact sites on the same target. We propose that hPR-A expression facilitates a ligand-dependent cross-talk among sex steroid receptor signaling pathways within the cell. It is likely, therefore, that alterations in the expression level of hPR-A or its cellular target can have profound effects on the physiological or pharmacological responses to sex steroid hormone receptor ligands.

High performance liquid chromatographic analysis of catecholamines in growing and non-growing Tetrahymena pyriformis.

Tetrahymena pyriformis, strains NT-1 and W, harvested in logarithmic (growing) and stationary (non-growing) phases, were found by high-performance liquid chromatography to contain considerable quantities of dopamine. In addition, small amounts of epinephrine and norepinephrine were detected. Logarithmic-phase strain NT-1 cells contained 249 +/- 44 pg dopamine/10(6) cells compared to 477 +/- 42 pg/10(6) cells for logarithmic-phase strain W cells for logarithmic-phase strain W cells. The dopamine content of stationary-phase cells was approximately half the value of the logarithmic-phase cells. There was a significant amount of dopamine in the growth medium from stationary-phase cultures and, to a lesser extent, logarithmic-phase cells.

Intraoperative cardioplegic contrast echocardiography for assessing myocardial perfusion during open heart surgery.

Aortic root hypothermic, hyperkalemic cardioplegic perfusion has been shown to preserve ventricular function during open heart surgery. However, significant coronary artery stenoses may prevent adequate perfusion of myocardial regions distal to the lesions, leading to intraoperative ischemia and damage. The purpose of this study was to evaluate for the first time in human patients the use of intraoperative contrast cardioplegic echocardiography for identifying potentially jeopardized myocardial regions as defined by cardiac catheterization. Forty-two patients, 23 men and 19 women, aged 28 to 83 years (mean 56.7 +/- 2), who had undergone cardiac catheterization and coronary arteriography, underwent open heart surgery; 30 had coronary artery disease. Echocardiograms of the left ventricle, performed on the open heart in the papillary muscle short-axis plane during routine aortic root cardioplegia were divided into three regions according to the coronary anatomy: septal (left anterior descending artery), anterolateral (left circumflex) and inferoposterior (right coronary artery). Intraoperatively, myocardial segments at greatest potential ischemic risk were identified by several findings alone or in combination: lack of spontaneous contrast and delayed whiting out or persistent fine fibrillation. The ability of intraoperative echographic interpretation to identify high risk segments based on preoperative catheterization findings was excellent. Thus, the sensitivity of cardioplegic contrast echocardiography for predicting significant (greater than 70% stenosis) coronary lesions was 96, 100 and 58% for left anterior descending, left circumflex and right coronary artery regions, respectively. Specificity was 94, 78 and 100% for anterior descending, circumflex and right coronary artery regions, respectively. Overall sensitivity and specificity for all regions was 82 and 92%, respectively. Importantly, the echocardiogram was most helpful in observing septal region perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative two-dimensional echocardiography: new application of an old technique.

Intraoperative two-dimensional echocardiography is a new diagnostic and monitoring technique that provides immediate information, unavailable from routine hemodynamic measurements, on both myocardial and valvular function. The presence and severity of valvular regurgitation can be assessed from the visualized flow pattern of microbubbles generated by an injection of saline solution: reflux flow into the retrograde chamber represents valvular insufficiency. The extent of valvular regurgitation can be determined immediately after conservative valve repair (annuloplasty or commissurotomy) or replacement to avoid the patient's leaving the operating suite with significant but undetected valvular insufficiency. Additionally, intraoperative echocardiography permits rapid evaluation of left ventricular systolic and diastolic volumes and myocardial contractility, thereby facilitating therapeutic interventions in the operating room. It also permits assessment of congenital heart defects and the competency of their repair. Pulsed, continuous and color-flow real time Doppler imaging methods allow further intraoperative definition of stenotic and regurgitant lesions.

Localization of aortic dissection intimal flap by intraoperative two-dimensional echocardiography.

Ascending (type I) aortic dissection carries a high morbidity and mortality. Proper identification of the proximal origin of the dissection and determination of concomitant aortic valve involvement significantly facilitate surgical repair, which may improve survival. In this case, intraoperative two-dimensional echocardiography with contrast injections was used to image the heart and great vessels before and after cardiopulmonary bypass. The proximal origin of the intimal flap of a type I dissection was identified, and primary aortic valve disease was excluded. Postprocedure intraoperative echocardiography demonstrated that the site of repair was imaged and that aortic regurgitation was absent. Intraoperative contrast two-dimensional echocardiography may be a valuable new tool to provide information otherwise unavailable by routine techniques.

Mitral valvuloplasty is superior to valve replacement for preservation of left ventricular function: an intraoperative two-dimensional echocardiographic study.

To investigate the mechanism and time of onset of ventricular dysfunction after mitral valve replacement, 18 patients with pure, severe mitral regurgitation (of whom 10 underwent mitral valve repair and 8 standard mitral valve replacement with papillary muscle excision) were studied by intraoperative two-dimensional echocardiography immediately before and immediately after the operative procedure. No patient sustained a perioperative myocardial infarction or had any residual mitral regurgitation. Although preoperative hemodynamics were similar, postoperatively the patients with valve repair had a lower pulmonary capillary wedge pressure than did the patients with valve replacement (8.6 +/- 1.9 versus 14.4 +/- 7.5 mm Hg, p less than 0.04). Although intraoperative echocardiographic ejection fraction fell significantly after mitral valve replacement (0.64 +/- 0.11 to 0.40 +/- 0.09, p less than 0.0001), it was maintained after valve repair (0.44 +/- 0.20 to 0.49 +/- 0.16, p = NS). Additionally, regional myocardial contractile abnormalities in the anterior and posterior septum were detected immediately after the procedure by intraoperative echocardiography in the patients with valve replacement, but not in those with repair. These postoperative regional contractile abnormalities after papillary muscle resection have not been described previously. Resection of the papillary muscles may disrupt the muscle bundle alignment and induce contractile abnormalities remote from the excised muscle. This study demonstrated that significant global and regional ventricular dysfunction develops immediately after removal of the papillary muscles, whereas myocardial contractility is preserved in patients undergoing mitral valve repair. Therefore, with intraoperative echocardiography to assure minimal residual regurgitation, surgeons should attempt to preserve ventricular function by performing mitral valve reconstruction in patients with mitral regurgitation.

Left ventricular to left atrial communication secondary to a paraaortic abscess: color flow Doppler documentation.

Aortic root abscess occurs frequently in aortic prosthetic valve infective endocarditis. The present echocardiographic report documents a ruptured abscess that led to a direct communication between the left ventricular outflow tract and the left atrium confirmed by real-time (color flow) Doppler imaging.

Transesophageal echocardiography: procedures and clinical application.

In existence for more than a decade, transesophageal echocardiography has gained renewed interest because of technologic advances including high resolution transducers, multiple imaging planes and Doppler color flow mapping. The heart is imaged from within the esophagus with a gastroscope-mounted transducer, obviating technical difficulties encountered in transthoracic echocardiography. Transesophageal echocardiography is utilized intraoperatively to monitor patients undergoing open heart surgery or high risk cardiac patients undergoing noncardiac surgery. In the ambulatory patient, the procedure facilitates imaging of many structures (including the left atrium and appendage, mitral and aortic native and prosthetic valves and thoracic aorta), with better resolution than that obtained by routine transthoracic echocardiography. Technical aspects of transesophageal echocardiography as well as its indications and limitations are reviewed.

Atrial kinetics and left ventricular diastolic filling in the healthy elderly.

A delay of left ventricular isovolumic relaxation and decrease in myocardial compliance may result in a decline of measured early filling rates in elderly subjects. Previous studies of diastolic function, however, have not excluded coronary artery disease or addressed the contribution of atrial contraction to diastole. The present study evaluated radionuclide-derived diastolic variables in 13 healthy elderly volunteers aged 75 +/- 6 years without symptoms or risk factors for coronary disease who had normal findings on the stress electrocardiogram, stress gated blood pool imaging and two-dimensional echocardiogram. Results were compared with those of a group of 10 healthy young volunteers aged 26 +/- 5 years. High count, 32 frame, double-buffered gated blood pool acquisitions were obtained at rest in the left anterior oblique view with an RR interval variation less than 5%. Left ventricular time-activity curves were analyzed and flow-volume loops for each group were constructed. In the healthy elderly: peak early diastolic filling rate is decreased, time of peak early filling and time to first third of diastolic filling are delayed, and peak late left ventricular filling rate and percent of atrial filling volume are augmented, suggesting an adaptive response of the atria to diminished left ventricular compliance.

Intraoperative contrast echocardiography to evaluate mitral valve operations.

Intraoperative two-dimensional contrast echocardiography was performed on 29 patients undergoing open heart surgery to determine the presence of mitral regurgitation before and immediately after the operative procedure: 14 patients had predominant mitral stenosis, 9 had severe mitral regurgitation and 6 had no mitral valve disease (control subjects). Two-dimensional echocardiography was performed by applying a 5 MHz transducer directly on the heart during injection of saline solution through an apical ventricular sump or transseptal needle, generating contrast microbubbles, with imaging in two planes. Baseline studies were performed after thoracotomy and pericardiotomy before cardiopulmonary bypass, and a second study was done after the operative procedure, with the patient off cardiopulmonary bypass with hemodynamic stabilization before chest closure. No control subject had contrast evidence of mitral regurgitation before or after cardiopulmonary bypass. Two of three patients with mitral valvuloplasty and two of five with commissurotomy required a second operative procedure before chest closure because of persistent mitral regurgitation detected by intraoperative two-dimensional contrast echocardiography. Thirteen of the 15 patients with valve replacement had no mitral regurgitation after cardiopulmonary bypass. Intraoperative two-dimensional echocardiographic findings correlated with data from postoperative clinical examinations and two-dimensional echocardiography-Doppler studies. It is concluded that two-dimensional echocardiography with contrast is an important intraoperative tool for assessing the presence and relative severity of mitral regurgitation after mitral commissurotomy, valvuloplasty or valve replacement. This technique may allow surgeons to be more aggressive in combining reparative operative procedures (that is, commissurotomy and valvuloplasty) in an attempt to retain native valves.

Pericardial mesothelioma masquerading as a benign pericardial effusion.

A 53 year old asymptomatic man presented with a primary pericardial mesothelioma masquerading as a benign pericardial effusion. Although M-mode echocardiography showed an echo-free space, two-dimensional echocardiography and thoracic computed tomography demonstrated that the suspected effusion was caused by a mass surrounding the heart. Newer noninvasive techniques can be valuable for the early detection of pericardial tumor.

Microbubbles have intracardiac velocities similar to those of red blood cells.

The slope of an individual contrast trajectory on M-mode echocardiography represents the projection of the intracardiac velocity vector of a microbubble in the direction of the sound beam. Doppler echocardiography measures this projection of red blood cell velocity. To ascertain whether microbubbles have similar intracardiac velocities to those of red blood cells, 11 subjects were studied during intravenous injections of 5% dextrose solution. The flow across the tricuspid and pulmonary valves was examined. Microbubble velocity was measured by M-mode contrast slope analysis and simultaneously by Doppler technique. Results from both methods were correlated with red blood cell velocity measured by Doppler recording at the same time in the cardiac cycle, shortly before appearance of contrast medium (3 to 8 beats before the corresponding contrast velocity measurements). In all subjects, 10 sets of three velocities each (M-mode slope and Doppler data before and during contrast injection) were obtained for each valve. Visual inspection of the Doppler tracings showed similar velocity profiles before and during contrast appearance; the signal intensity was greater with contrast. Quantitatively, microbubble velocity assessed by M-mode trajectory slopes correlated well with the Doppler-derived velocity of red blood cells (r = 0.98, p less than 0.001, slope of the regression line = 0.99, standard error of the estimate = 7 cm/s). Doppler velocities measured with and without contrast medium showed a similar correlation (r = 0.99, p less than 0.001, slope of regression = 1.01, standard error of the estimate = 6 cm/s). In individual subjects, the correlation coefficient between microbubble and red blood cell velocities ranged form 0.978 to 0.998.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic abnormalities and disease severity in Fabry's disease.

Fabry's disease is an X-linked recessive genetic deficiency of the enzyme alpha-galactosidase A, which leads to the pathologic deposition of neutral glycosphingolipids in lysosomes of the vascular endothelium of the heart, brain and kidney. The disease is progressive in hemizygous male patients, with increasing involvement of the major organs leading to death. Because cardiac involvement is a constant feature, echocardiograms were performed on 35 patients with Fabry's disease, 23 hemizygotes (aged 28.6 +/- 14 years) and 12 heterozygotes (aged 31.6 +/- 6 years), to determine whether cardiac involvement could be detected noninvasively. The results demonstrated that hemizygous male patients had a greater aortic root diameter, thicker interventricular septum and greater ventricular mass than did heterozygous female patients. Left ventricular mass per square meter of body surface area correlated well with clinical disease severity (r = 0.68, p less than 0.05), suggesting progressive glycosphingolipid deposition. Older heterozygotes (greater than 25 years old) had more severe evidence of cardiac disease than did younger male patients. Although mitral valve prolapse was identified in 12 (54%) of 23 male hemizygotes and in 7 (58%) of 12 female heterozygotes its presence did not correlate with clinical disease severity or other echocardiographic variables. Therefore, echocardiographic evidence of Fabry's disease appears to correlate with age-related disease severity and may be a useful noninvasive marker to follow disease progression and possible regression when appropriate therapy becomes available.

Doppler echocardiographic analysis of left ventricular filling in treated hypertensive patients.

Early detection and prevention of cardiac dysfunction is an important goal in the management of hypertensive patients. In this study, Doppler echocardiography was used to evaluate the pattern of left ventricular diastolic filling in 38 subjects: 18 treated hypertensive patients (blood pressure 141 +/- 17/83 +/- 10 mm Hg, mean +/- SD) without other coronary risk factors and 20 risk-free normotensive subjects of similar age (47 +/- 10 and 49 +/- 13 years, respectively). Peak velocity of late left ventricular filling due to the atrial contraction was greater in hypertensive compared with normotensive subjects (69 +/- 14 versus 52 +/- 13 cm/s; p less than 0.001). Peak velocity of late filling was significantly greater in hypertensive versus normotensive subjects in those aged 50 years or younger and those older than age 50 (65 +/- 12 versus 50 +/- 11; p less than 0.01 and 75 +/- 15 versus 56 +/- 15 cm/s; p less than 0.05, respectively). In hypertensive subjects, peak velocity of late filling did not correlate with routine indexes of hypertensive heart disease (including posterior wall thickness and left ventricular mass), systolic and diastolic blood pressure or duration of hypertension. These results indicate that increased velocity of late left ventricular filling may be independent of left ventricular hypertrophy and persist despite effective blood pressure control.

Quantification of cardiac conduction abnormalities using segmental vector Fourier analysis of radionuclide gated blood pool scans.

Timing abnormalities of myocardial contractility may occur as inter- or intraventricular asynchrony. Gated blood pool scintigraphy was performed on 21 patients with a normal ejection fraction and the following electrocardiograms: six normal, six with left bundle branch block, four with right bundle branch block and five with right ventricular pacemaker rhythm. A phase and amplitude of the first harmonic of the Fourier transform was obtained for each pixel, and left and right ventricles were trisected. A mean vector phase for each region was obtained by vector summation. Regional and global values were analyzed within each group and compared with normal values. The phase differences between the entire left and right ventricles (mean +/- standard deviation) were: 9 +/- 3 in the normal patients, 38 +/- 8 (p less than 0.01) in patients with left bundle branch block, -6 +/- 7 (p less than 0.05) in patients with right bundle branch block and 15 +/- 9 (difference not significant) in patients with pacemaker rhythm. The phase differences between left ventricular posterolateral and septal regions were -4 +/- 2 in the normal patients, 10 +/- 5 (p less than 0.01) in patients with left bundle branch block, -7 +/- 10 (p less than 0.05) in patients with right bundle branch block and 10 +/- 5 (p less than 0.01) in patients with pacemaker rhythm. Within the right ventricle, phase differences between the apical and septal segments were 14 +/- 9 in the normal patients, 14 +/- 10 (NS) in patients with left bundle branch block, -2 +/- 3 (p less than 0.01) in patients with right bundle branch block and -22 +/- 18 (p less than 0.01) in patients with pacemaker rhythm. Interventricular phase differences were greatest in patients with left bundle branch block and absent or reversed in right bundle branch block.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between exercise-induced changes in ejection fraction and systolic loading conditions at rest in aortic regurgitation.

To examine the role of systolic wall stress at rest in determining left ventricular performance during exercise in aortic regurgitation (AR), systolic wall stress (measured by M-mode echocardiography) was related to changes in left ventricular function during maximal exercise (evaluated by radionuclide ventriculography) in 30 patients with chronic aortic regurgitation. Of these 30 patients, 7 had a normal exercise response, defined as an absolute increase in ejection fraction of 5% or greater (Group I) and 23 had abnormal exercise response, defined as no change (less than 5% change) or a decline (less than or equal to 5%) in ejection fraction (Group II). Patients in Group I had a significantly lower radius/wall thickness ratio (2.5 +/- 0.2 versus 3.1 +/- 0.1, p less than 0.01) and lower peak systolic wall stress (123 +/- 11 versus 211 +/- 12 X 10(3) dynes/cm2, p less than 0.01) than patients in Group II. An increase in ejection fraction during exercise was seen in 6 of the 9 patients with normal systolic wall stress at rest (less than 150 X 10(3) dynes/cm2), but in only 1 of 21 patients with elevated systolic wall stress (p less than 0.001). Peak systolic wall stress at rest varied linearly, and inversely with changes in left ventricular ejection fraction during exercise (r = 0.60, p less than 0.001). Groups I and II did not differ in ejection fraction at rest, clinical symptoms or maximal work load achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Normalization of left ventricular mass and associated changes in neurohormones and atrial natriuretic peptide after 1 year of sustained nifedipine therapy for severe hypertension.

Sixteen patients with severe hypertension were treated for 1 year with extended release nifedipine, during which time serial changes in left ventricular mass index and associated alterations in left ventricular systolic function, left ventricular filling, plasma renin activity, atrial natriuretic peptide and catecholamines were evaluated. Mean seated blood pressure (+/- SE) was significantly reduced from 200 +/- 8/122 +/- 3 to 144 +/- 5/89 +/- 2 mm Hg (p less than 0.0001) at 1 year. After 6 months, left ventricular mass index was significantly reduced by 19% from 121 +/- 8 to 96 +/- 7 g/m2 and this reduction was sustained at 1 year. Septal and posterior wall thickness were reduced from 13.4 +/- 0.1 to 11.2 +/- 0.04 mm and from 12.8 +/- 0.1 to 10.0 +/- 0.03 mm (p less than 0.001), respectively. The prevalence of left ventricular hypertrophy decreased from 63% to 25%. Left ventricular fractional shortening increased from 34 +/- 2% to 41 +/- 3% (p less than 0.05) and the relation between fractional shortening and end-systolic stress did not change. Over the year of sustained blood pressure reduction, the peak velocity of early filling increased from 57 +/- 3 to 63 +/- 4 cm/s (p = 0.07), peak velocity of late filling did not change and the ratio of late to early peak left ventricular filling velocity significantly decreased (p less than 0.05). Plasma atrial natriuretic peptide levels, markedly elevated at entry, decreased from 70 +/- 15 to 41 +/- 8 pg/ml at 1 year (p less than 0.05). Plasma renin activity and catecholamine levels were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of abnormal left ventricular filling in early hypertension.

Thirty-seven untreated subjects with borderline or mild hypertension were studied to establish the prevalence and clinical characteristics associated with abnormal left ventricular filling in this disorder. Subjects were referred to this study because of casual office blood pressure measurements of greater than or equal to 140/90 mm Hg; all were less than 50 years old, had no other cardiovascular or systemic disease and had not received antihypertensive medication for at least 1 year. To precisely determine blood pressure, measurements were made over 30 min with the patient in the supine position and during awake hours with ambulatory monitoring. Left ventricular mass was determined echocardiographically, and Doppler echocardiography was used to assess left ventricular filling. No subject had increased left ventricular mass, but 8 (22%) of the 37 had abnormal left ventricular filling. All eight subjects with abnormal left ventricular filling had an ambulatory systolic blood pressure greater than 130 mm Hg and a supine systolic blood pressure greater than 122 mm Hg. Abnormal filling was not related to left ventricular mass or heart rate. In multivariate analysis, the degree of abnormal filling could best be predicted from a combination of age and supine systolic blood pressure (r = 0.69; p less than 0.001). This study suggests that in untreated early essential hypertension, abnormal left ventricular filling is present in greater than 20% of subjects, precedes detectable left ventricular hypertrophy and is related to age and prevailing level of blood pressure.

Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens.

We have developed a series of in vitro models with which to evaluate the biological activity of estrogen receptor (ER) agonists and antagonists. Using a protease digestion assay we show that the conformational changes induced within ER are distinct for agonists and antagonists. However, this assay is unable to discriminate between pure antagonists like ICI164,384 and partial agonists such as 4-OH tamoxifen or keoxifene. Using a chimeric ER-VP16 construct, we demonstrate that both pure antagonists and partial agonists deliver ER to its DNA target within cells. However, the ability of the DNA-bound receptor to activate transcription in the presence of a given antagonist is dependent on cell and promoter context. These data, suggesting functional differences among ER antagonists, were confirmed by additional experiments demonstrating that their ability to modulate the transcriptional activity of a series of ER mutants is dramatically different. Depending on the cell and promoter context and the particular ER form expressed, 4-OH tamoxifen and the related compound, keoxifene, functioned as partial agonists. Importantly, the transcriptional profiles of these two compounds were dissimilar, suggesting that they are functionally different from each other and from ICI164,384, which does not display agonist activity under any context examined. Our results reveal functional differences between these clinically important antiestrogens and suggest that the distinct biologies manifest by these compounds in vivo relate to their ability to differentially regulate ER function.