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The barrier to rotation in the N-acetyl methyl ester of the thyroxine was found to be 8.6 kcal mol-1. Previous experiments determining the barrier to rotation in triiodothyropropionic acid in HCl-ethanol were shown to be in error.
We noted the earliest morphological changes in the motor endplates 8 weeks after the induction of streptozotocin diabetes in rats. Morphometric measurements showed reduced axonal areas of the lateral plantar and the sciatic nerves in the diabetic rats 28 but not 2 and 8 weeks after the experiment. These findings suggested distal axonopathy.
BACKGROUND: Although epidemiological studies have failed to demonstrate an increased incidence of breast cancer in women who had undergone prior prosthetic augmentation mammoplasty (PAM), it has been reported that when breast cancer arises in this group it presents mostly in a palpable form and at a more advanced stage. This is thought to be secondary to suboptimal mammographic evaluation caused by the masking effect of the implant. This study was undertaken to determine, in our experience, whether breast cancer arising in women who had undergone PAM could be detected in a prepalpable form by mammography and whether it presented at a more advanced stage as compared with nonaugmented women with breast cancer. METHODS: The charts of 22 patients, treated by at least one of the authors, in whom 23 breast cancers developed after PAM (group A) were retrospectively reviewed. The comparison groups consisted of 611 nonaugmented patients who underwent 636 procedures for the treatment of primary breast cancer at our institution (group B) and the surveillance, epidemiology, and end results (SEER) data (group C). Parameters studied were mode of detection, tumor size, axillary lymph node involvement, and histopathology. RESULTS: No significant differences between the groups were found in mean tumor size (group A vs. group B), the incidence of preinvasive cancer (group A vs. group B) or axillary lymph node involvement (group A vs. group B and group A vs. group C). Breast-preserving surgery was performed significantly less in augmented patients (group A vs. group B). CONCLUSION: We conclude that prepalpable and preinvasive breast cancer can be detected in the PAM patient by mammography and that the stage of presentation in this group is not significantly different than in nonaugmented patients. Total mastectomy is preferred over breast-preserving procedures for the treatment of breast cancer in the PAM patient.
From 1949 to 1977, 39 patients with localized malignant retrorectal tumors were treated at Memorial Sloan-Kettering Cancer Center. Chordomas were the most frequent histologic type (38 per cent of patients) followed by neurogenic tumors (15 per cent) chondrosarcomas, hemangiopericytomas, and embryonal adenocarcinomas (8 per cent each). Treatment consisted of surgical excision in 28 patients (18 of whom received adjuvant radiotherapy and/or chemotherapy). Ten patients were treated nonsurgically, receiving radiation and/or chemotherapy alone. Large tumors were most successfully managed by a combined surgical approach consisting of exploratory celiotomy, rectal mobilization, and bilateral hypogastric artery (with middle sacral artery and vein) ligation, followed by transsacral tumor excision with incontinuity sacrectomy. For all treated patients, survival at 5, 10, 15 and 20 years was 69 per cent, 50 per cent, 37 per cent and 20 per cent, respectively. Long-term disease-free survival (17 to 25 years post treatment) was noted in six patients. [Key words: Tumor(s), retrorectal, malignant; Tumor(s), treatment].
Epithelial cells were isolated from fetal bovine trachea by exposing and stripping the mucosal epithelium from the adjacent connective tissue. The tissue was minced and enzymically dissociated in Ca-Mg-free medium containing dispase and dithiothreitol. The stripping procedure and selective trypsinization produced epithelial cell cultures free of fibroblasts. Seeded on plastic, the plating efficiency was 21.5% with a doubling time of 24 h. Dome formation, evidence of occluding junctions and active ion transport characteristic of epithelial cells, was common. Growth of the cells on glass, collagen, and Engelbreth-Holm-Swarm (EHS) substrate demonstrated a striking difference in morphology. Cells grown on EHS presented a more distinctly three-dimensional growth pattern and many more microvilli when compared to cells grown on glass or collagen. The cells retained their epithelioid characteristics through more than 30 passages as shown by the presence of distinct apical and basolateral membranes, tight junctions, and positive keratin staining.
The failure of many cell culture isolates of Mycoplasma hyorhinis to grow on microbiological media has stressed the need for alternate assays to detect these organisms. The use of freshly prepared yeast extract in mycoplasmal media together with incubation in 5% CO2/air successfully detected M. hyorhinis in 12 of 12 infected cultures. These were not detected by the use of conventional mycoplasmal media using aerobic or anaerobic incubation. This assay may also be helpful in detection of other mycoplasmal species commonly isolated from cell cultures.
We have investigated the molecular phenotypic differences between Syrian hamster embryo (SHE) cells cultured at pH 6.7 or 7.3. Multiple pH-sensitive phenotypic differences were noted including changes in cellular morphology, a unique charge differential in a major cellular protein, nine uniquely expressed proteins, two unique phosphoserine/threonine phosphoproteins, one unique phosphotyrosine phosphoprotein, and the pH dependent mRNA level of a gap junctional gene (connexin 43). These differences, combined with previously described pH-specific differences (differential transformation rates and gap junctional communication), illustrate that culturing SHE cells in media that differ by 0.6 pH units (0.3 units on either side of pH 7.0) can have a profound influence on the cellular phenotype.
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Twelve patients with severe chronic congestive heart failure (CHF) underwent simultaneous evaluation of the pharmacokinetic, pharmacodynamic, and neurohumoral actions of a single 25 mg oral dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (CPT). Following drug administration, which raised plasma renin activity (PRA) and thereby indicated significant ACE inhibition, both free (unchanged) and total CPT (including active metabolites) were detectable in the blood with 40 minutes and peak blood levels of the agent were recorded 1 hour after CPT. Total CPT concentration was higher and persisted longer than free CPT, which became virtually nondetectable 8 hours after ingestion. Concomitantly, left ventricular function was markedly augmented by the oral ACE inhibition in all patients, with the magnitude of this improvement being closely related to the baseline PRA. Thus, the overall hemodynamic response to CPT, which rapidly appears in the bloodstream following drug intake in patients with advanced CHF, is a function of the extent of baseline renin-angiotensin-aldosterone activity.
Although the renin-angiotensin-aldosterone system has been implicated in the pathophysiology of chronic heart failure, the factors influencing the extent of renin activity have not been clarified. In the present study, we evaluated 34 patients with severe chronic congestive heart failure in terms of baseline plasma renin activity (PRA). No uniform relationships between PRA and urinary sodium excretion have been established. Although baseline PRA did not correlate with the baseline hemodynamic values, the extent of hemodynamic improvement following acute oral captopril (CPT) therapy (25 mg) was highly correlated with baseline PRA. The onset of action was rapid, so that the initial acute response could be readily assessed and at the same time could be used as a means to estimate baseline renin-angiotension-aldosterone activity. For long-term therapy, however, the response to CPT must be assessed in the context of several potentially simultaneous factors that might either enhance or compromise its effectiveness.
Both postural abnormalities and autonomic dysfunction have been identified in patients with chronic congestive heart failure (CHF). However, the effect of long-term vasodilator therapy on these phenomena has not been assessed. In this study the hemodynamic and plasma norepinephrine (PNE) responses to upright posture, as well as the cold pressor test and Valsalva's maneuver in 12 patients with severe chronic CHF during both acute and long-term captopril (CPT) therapy, were evaluated. This revealed an absence of the normal hemodynamic adjustments to upright posture and a blunted response of PNE. The heart rate and blood pressure responses to the cold pressor test and Valsalva's maneuver were similarly blunted. The reflex adjustments of systemic resistance during tilt improved with CPT therapy, but the absence of reflex tachycardia in the upright posture persisted. Additionally, there was improvement of the PNE response, and the responses of heart rate and blood pressure to the cold pressor test were virtually normalized during long-term CPT therapy. The abnormal response to the Valsalva maneuver persisted. In conclusion, hemodynamic and reflex-mediated responses to upright posture and the standard assessment of autonomic control mechanisms revealed abnormal patterns in heart failure. While the hemodynamic adjustment to postural changes and sympathetic responsiveness were improved with CPT, complete correction of these abnormalities did not occur. Whether the improvement was a nonspecific vasodilator effect or the result of specific CPT therapy remains to be determined.
The hemodynamic mechanism by which patients with chronic congestive heart failure (CHF) maintain their blood pressure (BP) in the upright posture is distinct from that of normal and hypertensive individuals. There are little data regarding the effects of chronic vasodilator therapy on the mechanisms controlling this response, especially in the presence of diuretic therapy. Therefore, 10 consecutive patients with severe chronic CHF underwent hemodynamic tilt study following acute and chronic captopril therapy. One patient developed orthostatic hypotension following first-dose captopril, but 6 of 10 had a mean BP decrease of 70 +/- 6 to 56 +/- 3 mm Hg on tilt following chronic captopril. This associated with significant reduction of plasma aldosterone, and was abolished on re-tilt following acute saline infusion. Therefore, during chronic captopril therapy of CHF, a reduction of diuretic dosage may be necessary to prevent orthostatic hypotension.
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There are few data to support the potential efficacy of combined vasodilator therapy for severe congestive heart failure. For documentation of the feasibility of such an approach, a short-term hemodynamic study utilizing captopril, an oral converting enzyme inhibitor, followed by the addition of nitroprusside infusion, was made of 11 patients with severe chronic congestive heart failure. Captopril alone resulted in reduction of mean arterial pressure (84 +/- 7 to 70 +/- 3 mm Hg), associated with increase of cardiac index and stroke index. There was also a significant reduction of systemic resistance and pulmonary wedge pressure. The initial hemodynamic response to captopril was correlated with initial plasma renin activity (all values at least p less than 0.05). The addition of nitroprusside to captopril resulted in further hemodynamic improvement. Reduction of mean arterial pressure, systemic vascular resistance, and pulmonary wedge pressure were all significant, as were increases of cardiac index and stroke index. The degree of hemodynamic improvement with this sequence of vasodilator therapy was linearly related to the reduction of mean arterial pressure. Therefore vasodilators with dissimilar mechanisms of action may have an additive effect. These data support the potential feasibility of combined, long-term oral vasodilator therapy in selected subgroups of patients with congestive heart failure.
The renin-angiotensin system has been shown to participate in the pathophysiology of chronic heart failure in many patients. However, the immediate assessment of this contribution in individual patients may sometimes be difficult. As a pharmacologic estimate of angiotensin II receptor activity, we infused the angiotensin II analogue, saralasin, in 20 patients with severe chronic congestive heart failure (CHF). The infusion resulted in blood pressure responses ranging from an agonist pressor response (increased systemic resistance) in patients with low intrinsic renin-angiotensin system activity, to an antagonist depressor response (decreased systemic resistance) in patients with marked activation of the renin-angiotensin system. The ability of the saralasin response to pharmacologically estimate angiotensin II receptor activity in CHF was further revealed by two physiologic maneuvers that decrease endogenous circulating angiotensin II and angiotensin II receptor occupancy. Both converting enzyme inhibition with captopril and sodium repletion, factors known to decrease endogenous angiotensin II activity, provoked agonist responses to saralasin infusion. Furthermore, saralasin was able to reverse the orthostatic hypotension precipitated by converting enzyme inhibition of angiotensin-dependent vascular tone. In summary, saralasin provided a means to estimate angiotensin receptor activity and may therefore serve as a probe of angiotensin-mediated vasoconstriction in the pathophysiology of chronic CHF.
To determine if the addition of preload reduction with nitrates would potentiate the acute vasodilator actions of nifedipine, we titered intravenous nitroglycerin in seven patients with severe congestive heart failure after they received a single oral dose of nifedipine. The peak hemodynamic effect of nifedipine occurred at 30 minutes, with large reductions of systemic vascular resistance (1831 +/- 128 to 1132 +/- 154 dynes X sec X cm-5; p less than 0.001) and mean arterial pressure (87 +/- 7 to 71 +/- 7 mm Hg; p less than 0.01). This was associated with an increase of stroke volume index from 22 +/- 3 to 27 +/- 3 ml/m2 (p less than 0.01) but no significant changes in heart rate, right atrial pressure, or pulmonary wedge pressure. These hemodynamic changes were attenuated over a 2-hour observation period. At 2 hours, the addition of intravenous nitroglycerin resulted in large reductions in right atrial pressure (9 +/- 2 to 6 +/- 1; p less than 0.01) and pulmonary wedge pressure (23 +/- 2 to 17 +/- 2; p less than 0.001). This was associated with further increases in cardiac index (from 1.99 +/- .15 to 2.25 +/- .14 L/min/m2; p less than 0.001) and stroke volume index (26 +/- 3 to 29 +/- 3 ml/m2; p less than 0.01). Thus, the addition of nitroglycerin to nifedipine will optimize preload reduction and enhance the vasodilator action of nifedipine. Further controlled studies are necessary to determine the long-term hemodynamic effects and the clinical role of nifedipine and its combination with nitrates in patients with severe congestive heart failure.
Milrinone is a potent non-catecholamine, non-glycoside inotropic agent that can improve hemodynamic performance and functional capacity in patients with severe congestive heart failure. However, the potential effect of chronic inotropic stimulation on ventricular arrhythmias in patients with heart failure requires evaluation. We compared 24-hour ambulatory ECGs before and 2 to 4 weeks after initiation of chronic milrinone therapy in 20 patients with severe congestive heart failure (mean cardiac index 1.79 +/- 0.43 L/min/m2). A greater than tenfold increase in simple ventricular premature complex (VPC) density, a greater than tenfold increase in complex VPC form density, or an increase from 0 to greater than 5 episodes per 24 hours of any complex VPC form occurred in 35% (7 of 20) of patients. A greater than tenfold reduction in simple VPC density was noted in 5% (1 of 20), while 60% (12 of 20) of the study group had no significant change in ventricular arrhythmia profile on milrinone. The hemodynamic and functional response to milrinone, as well as entry hemodynamic profiles, were unrelated to the change in frequency or complexity of ventricular arrhythmias during therapy. Thus, milrinone therapy in congestive heart failure may be associated with the development of VPC complexity and with a significantly increased density of complex VPC forms.
Numerous Doppler echocardiographic methods to measure stroke volume have been proposed in experimental or clinical studies, but their relative accuracy in patients compared with an invasive reference standard remains uncertain. Accordingly, we compared Doppler with thermodilution stroke volume measurement in 18 hospitalized patients, 16 with an acute manifestation of coronary artery disease and two with chronic cardiomyopathies. Doppler time-velocity integrals were measured by darkest line (modal velocity) and the leading edge (maximal velocity) techniques at the aortic annular plane, the mitral orifice, and the mitral annular plane. Two-dimensional echocardiography was used to measure cross-sectional areas (M-mode-corrected at the mitral orifice). The combination of aortic annular cross-sectional area and the leading edge technique of measuring the time-velocity integral of blood flow at this site provided the most accurate measure of stroke volume (r = 0.87, p less than 0.0001, standard error of estimate = 11 cm3; mean difference from thermodilution = 2.8 ml +/- 8.9 ml, p = NS). It also resulted in the most accurate measurement of cardiac output (r = 0.88, p less than 0.0003; mean difference from thermodilution = 0.11 L/min +/- 0.69 L/min, p = NS). Other methods yielded values that correlated less closely and deviated systematically from thermodilution measurements. We therefore conclude that of the six common methods evaluated, the aortic annular leading edge method measures stroke volume with the best accuracy and is most suitable for clinical application.