Pathophysiology and prognostic significance of Holter-detected ST segment depression after myocardial infarction. The Tissue Plasminogen Activator: Toronto (TPAT) Study Group.

OBJECTIVES: We performed Holter monitoring on days 4 and 7 after acute myocardial infarction in 109 patients to assess whether ST segment shift would identify those with more severe coronary artery disease, left ventricular dysfunction and unfavorable prognosis. BACKGROUND: Silent myocardial ischemia is a frequent and prognostically significant event after acute myocardial infarction. However, the specific pathophysiologic mechanisms and the impact of thrombolytic therapy are uncertain. METHODS: In addition to Holter monitoring, patients underwent exercise testing, radionuclide angiography on days 1 and 9 and quantitative coronary angiography on day 9. RESULTS: Thirty-five patients (32%) had ST segment depression and had similar recombinant tissue-type plasminogen activator (rt-PA) treatment assignment and a reduced cross-sectional area of the infarct-related artery (0.59 +/- 0.57 vs. 1.04 +/- 1.26 mm2, p < 0.05). Global left ventricular function improved from day 1 to day 9 in patients without (4% +/- 11%, p < 0.001) but not in those with (0% +/- 7%) ST segment depression. In-hospital event rates were similar; however, follow-up 18 +/- 11 months after hospital discharge revealed a greater frequency of death and recurrent myocardial infarction in patients with compared with those without ST segment depression (27% vs. 6%, p = 0.03). CONCLUSIONS: After acute myocardial infarction, approximately one third of patients have ST segment depression on Holter monitoring, independent of the use of thrombolytic therapy. The unfavorable prognosis observed in these patients may be related to greater lumen obstruction in the infarct-related artery and lack of improvement in left ventricular function.

The spectrum of right ventricular involvement in inferior wall myocardial infarction: a clinical, hemodynamic and noninvasive study.

The clinical experience with 37 patients with acute transmural inferior wall myocardial infarction who were assessed for evidence of right ventricular involvement is reported. On the basis of currently accepted hemodynamic criteria, 29 patients (78%) had evidence suggestive of right ventricular infarction. However, only 5 (20%) of 25 patients demonstrated right ventricular uptake of technetium pyrophosphate on scintigraphy. Two-dimensional echocardiography or isotope nuclear angiography, or both, were performed in 32 patients; 20 studies (62%) showed evidence of right ventricular wall motion disturbance or dilation, or both. Twenty-one patients demonstrated a late inspiratory increase in the jugular venous pressure (Kussmaul's sign). The presence of this sign in the clinical setting of inferior wall myocardial infarction was predictive for right ventricular involvement in 81% of the patients in this study. It is suggested that right ventricular involvement in this clinical setting is common and includes not only infarction but also dysfunction without detectable infarction, which is likely on an ischemic basis.

Tissue plasminogen activator: Toronto (TPAT) placebo-controlled randomized trial in acute myocardial infarction.

The efficacy and safety of recombinant tissue plasminogen activator (rt-PA) administered on a dosing per weight basis was evaluated in a randomized, placebo-controlled, double-blind trial in 115 patients with acute myocardial infarction. The principal outcomes were global and regional left ventricular function in the distribution of the qualifying myocardial infarction, determined 9 days after the onset of symptoms. Global and regional ejection fraction values were significantly better for patients treated with rt-PA than for placebo-treated patients (the differences were 5.8 +/- 2.7% units [p = 0.017] and 7.1 +/- 3.1% units [p = 0.012], respectively). This benefit was also evident from visual assessment of left ventricular segmental wall motion. After adjustment for differences in important prognostic variables at baseline, the estimates of treatment effect were 4.0 +/- 2.4% units (p = 0.048) for global and 4.3 +/- 2.6% units (p = 0.047) for regional ejection fraction. Early patency of the infarct-related vessel was demonstrable in 7 (29%) of 24 placebo-treated patients and 18 (78%) of 23 rt-PA-treated patients, whereas 15 (56%) of 27 patients in the placebo group and 23 (72%) of 32 in the rt-PA group had a patent infarct-related vessel at hospital day 9. There was no significant difference in irreversible or reversible defect size as assessed by thallium scintigraphy on day 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary patency, infarct size and left ventricular function after thrombolytic therapy for acute myocardial infarction: results from the tissue plasminogen activator: Toronto (TPAT) placebo-controlled trial. TPAT Study Group.

Infarct size, left ventricular function and infarct-related coronary artery patency were examined in 108 patients who took part in a previously reported placebo-controlled trial of recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction. Coronary angiography was performed 17 +/- 0.8 h after initiation of treatment in 47 patients (group A) or at 10 days in 61 patients (group B). Both groups underwent radionuclide ventriculography 3.8 +/- 0.8 h and again on day 9 after treatment and quantitative thallium scintigraphy on day 8. In group A, the infarct-related artery was patent in 53%; these patients had a smaller global (15.1 +/- 2.5% vs. 25.7 +/- 4.7%, p = 0.029) and regional (14.7 +/- 2.5% vs. 24.1 +/- 4.7%, p = 0.044) fixed thallium defect than did those with an occluded artery. Infarct regional ejection fraction improved by 10.1 +/- 2.1% between early and late studies when the infarct-related artery was patent and by 4.8 +/- 1.4% if it was occluded (p = 0.048); changes in global and noninfarct regional ejection fraction were similar irrespective of perfusion status. Infarct regional ejection fraction and fixed thallium defect were inversely related only when the infarct-related artery was occluded (r = -0.83, p less than 0.0001). In group B, 10 day patency of the infarct-related artery was 67%; there was no difference in patency by treatment assignment or in left ventricular function or infarct size between patients with and without infarct-related artery patency. There was no evidence of an effect of rt-PA therapy beyond that expressed through coronary patency alone in either group A or group B.

Impact of tissue plasminogen activator and heparin versus heparin alone on quantitative coronary angiographic findings in myocardial infarction. The Toronto Tissue Plasminogen Activator Trial Study Group.

The influence of tissue plasminogen activator (t-PA) and heparin versus heparin alone on anatomic characteristics of patent infarct-related coronary arteries and the development of these angiographic descriptors in coronary arteries that remain patent during the hospital course was examined in 108 patients who participated in a placebo-controlled trial of recombinant tissue-type plasminogen activator in acute myocardial infarction. Coronary angiography was performed 18 +/- 6 hours after treatment in 47 patients (group A) and at 10 days in 61 patients (group B). Quantitative coronary angiography of the infarct-related lesion was performed, and luminal irregularity was quantitated with an ulceration index. Of the 47 patients in group A, 7 (29%) treated with placebo had Thrombolysis in Myocardial Infarction grade 2 or 3 perfusion, whereas 18 (78%) treated with t-PA had grade 2 or 3 (p < 0.001); there was no difference between patients who had grade 2 or 3 perfusion in group B (placebo 59% vs t-PA 75%). In group A, at 10 days, the luminal area of the infarct artery had increased from 0.59 +/- 0.11 to 0.9 +/- 0.24 mm2 and from 0.75 +/- 0.16 to 1.31 +/- 0.39 mm2 for placebo- and t-PA-treated patients, respectively (p < 0.04). There was no change in the ulcerative index over time in either placebo- or t-PA-treated patients. It is concluded that early after infarction, t-PA produces marked and rapid improvement in overall patency as compared with heparin, although this difference was attenuated at 10 days because of spontaneous recanalization in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between infarct artery patency at late angiography after acute myocardial infarction and signal-averaged electrocardiography.

The angiograms of 89 patients were reviewed from the LATE Ancillary Study (randomized trial of recombinant tissue plasminogen activator vs placebo in patients with symptom onset after 6 hours of myocardial infarction) to determine patency of the infarct-related artery (IRA). In the occluded IRA group (n = 35), the incidence of signal-averaged electrocardiographic abnormality (fQRS > 120 ms) was significantly higher (p = 0.04), the filtered QRS duration was significantly longer (p = 0.007), and the V40 was significantly shorter (p = 0.02), compared with the patent IRA group (n = 54).

Metabolism of isoprenaline in dog and man.

1. The metabolism of isoprenaline has been studied in man and dog following intravenous and oral or intra-duodenal administration.2. Intravenous isoprenaline was excreted largely unchanged in urine in both species. Only one-third of the radioactivity in urine was in the form of the O-methyl metabolite.3. After oral doses in man or intraduodenal doses in dogs, plasma radioactivity was almost entirely as conjugated isoprenaline and this metabolite accounted for more than 80% of radioactivity in urine.4. Catechol-O-methyl transferase may be less important than Uptake(2) in limiting the pharmacological action of isoprenaline.5. Pharmacological response (heart-rate increase) was related to plasma concentration of isoprenaline only after rapid intravenous injections. In dogs, following prolonged infusion or intraduodenal doses, heart rate returned to base-line values when plasma concentrations of isoprenaline were high.

Cardiac murmur associated with an abnormal chest x-ray film.

Investigation of a cardiac murmur and thrill in an asymptomatic 35-year-old man revealed a foreign body lying within the left ventricular cavity. Upon questioning, the man revealed that he had been shot in the chest years earlier. This is the first reported adult case of a retained intracardiac bullet causing a ventricular septal defect.

The accuracy and interobserver agreement in detecting the 'gallop sounds' by cardiac auscultation.

STUDY OBJECTIVES: To determine the observer accuracy and interobserver agreement in identifying S4 and S3 by cardiac auscultation and whether they improve with increasing observer experience. DESIGN: Prospective, blinded study. SETTING: Cardiology and general internal medicine wards in a university-affiliated teaching hospital. PATIENTS: Forty patients with a cardiac diagnosis and 6 patients without were studied. MEASUREMENTS AND RESULTS: Two cardiologists, one general internist, three senior and two junior postgraduate internal medicine trainees, blinded to the patients' characteristics, examined the patients and documented their findings on a questionnaire. Computerized phonocardiogram was obtained in all patients as a gold standard and was interpreted by a blinded, independent cardiologist. The mean positive predictive values for S4 and S3 were 51% (range, 24 to 100%) and 71% (range, 50 to 88%), respectively. The mean negative predictive values for S4 and S3 were 82% (range, 67 to 94%) and 64% (range, 56 to 85%), respectively. The overall interobserver agreements for detecting S4 was K = 0.05 (95% confidence interval [CI], 0.01 to 0.09) and S3 was K = 0.18 (95% CI, 0.13 to 0.24). There was no apparent trend in the accuracy or interobserver agreement with regard to the level of observer experience. CONCLUSION: The agreement between observers and the phonocardiographic gold standard in the correct identification of S4 and S3 was poor and the lack of agreement did not appear to be a function of the experience of the observers. The overall interobserver agreement for the detection of either S4 or S3 was little better than chance alone.

Speech dysfunction of obstructive sleep apnea. A discriminant analysis of its descriptors.

We have previously demonstrated a relationship between abnormal speech and obstructive sleep apnea in a small subject sample. The present study was designed to replicate the previous one with a much larger population, analyze the perceptual characteristics of the speech quality, and determine the degree to which each of three descriptors of speech abnormality contributed to the perception of speech abnormality. Ten graduate students in speech pathology listened in two 1.5 hour sessions to 252 random speech samples presented on a master tape. There were 81 subjects comprised of 27 sleep apnea patients, 27 matched chronic obstructive pulmonary disease control patients, and 27 matched normal control subjects. Rating the speech along an equally-appearing interval scale from 1 to 7, the judges heard abnormal resonance, articulation or phonation in 74 percent of the sleep apnea subjects, 53 percent of the COPD subjects, and 7 percent of the normal subjects (significant difference by chi 2 test at the .01 level of confidence). Discriminant function equations based on these speech descriptors correctly identified 96.3 percent of the normal subjects and 63.0 percent of the sleep apnea subjects. Analysis of abnormal speech resonance, articulation and phonation may identify obstructive sleep apnea or may provide insight into its pathology.

Prevention of acute pulmonary edema after bone marrow transplantation.

In a retrospective review of 21 bone marrow transplantation procedures (BMT), we identified ten episodes of acute pulmonary edema coinciding with significant weight gain in the second week after BMT. When we prospectively observed nine consecutive BMT recipients, six patients developed acute pulmonary edema associated with significant (p less than 0.05) weight gain and an increase in echocardiographically determined left ventricular end diastolic diameter. These findings led to a prospective prophylactic intervention study of 30 consecutive BMT patients. Prophylactic intervention consisting of reduced fluid volume of parenteral alimentation, and diuretic therapy was instituted at any clinical sign of fluid overload. No episode of pulmonary edema occurred. The dramatic difference--acute pulmonary edema occurred in 16/30 untreated vs 0/30 treated cases--suggests that this post-BMT complication is critically related to fluid balance and can be prevented by careful clinical examination, close monitoring of weight change, avoidance of fluid overload and the appropriate use of diuretic therapy.

Age effects on central nervous system activity reflected in the olfactory event-related potential. Evidence for decline in middle age.

A series of studies in this laboratory using the olfactory event-related potential (OERP) have examined the underlying central nervous system activity associated with age-related changes in olfactory functioning. Early (sensory) components of the OERP showed reduced amplitude and longer latency in elderly subjects, with larger effects in males. Amplitudes are already decreased in middle age. The late cognitive component, P3, showed a longer latency as well as a decreased amplitude in the elderly, with effect sizes for age significantly larger for the late component than for the early components. We report here the significantly longer latency, particularly for the P3, in middle-aged persons, suggesting age-related slowing of olfactory information processing as early as the 50s. Results suggest that the elderly brain, and indeed, the middle-aged brain shows smaller responses to odors, is less able to allocate attentional resources and slows in its olfactory cognitive processing. The OERP is a potent reflection of these changes.

Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha-fetoprotein, hCG, and unconjugated estriol: a prospective 2-year study.

OBJECTIVE: To evaluate prospectively maternal serum screening with alpha-fetoprotein (AFP), hCG, and unconjugated estriol (uE3) as a screen for fetal Down syndrome. METHODS: Women less than 35 years of age were offered screening between 15-20 weeks' gestation. Screening results calculated by an algorithm to be equal to or greater than 1:274 (the risk of a 35-year-old for fetal Down syndrome at the second trimester) were considered positive. If gestational age was confirmed by ultrasonography, genetic counseling and amniocentesis were offered. RESULTS: In the first 2 years of our program, 9530 women were screened, of which 686 (7.2%) were found to be screen-positive. Ultrasonographic examination explained the abnormal values in 379 (4.0%). The remaining 307 (3.2%) received genetic counseling and 214 (2.2%) elected amniocentesis or CVS. Four cases of fetal Down syndrome and one de novo chromosomal marker were detected. In three additional cases of fetal Down syndrome, triple-analyte screening failed to identify the pregnancies to be at increased risk. None of the seven cases of fetal Down syndrome would have been detected through screening with maternal serum alpha-fetoprotein (MSAFP) and age alone. CONCLUSIONS: Measurement of MSAFP, hCG, and uE3 in women less than 35 years old is an effective screening test for fetal Down syndrome, with a sensitivity of 57% in our study and an amniocentesis rate (false-positive rate) of 3.2%.

Left ventricular mass regression early after aortic valve replacement.

BACKGROUND: Regression of left ventricular hypertrophy is an important and well-recognized salutary effect of aortic valve replacement. The earliest evidence of left ventricular mass regression after aortic valve replacement and the influence of prosthesis type are not well known, and were the focus of this study. METHODS: Transthoracic echocardiography was used to measure left ventricular mass index preoperatively and before discharge in 57 consecutive patients undergoing isolated aortic valve replacement (with or without coronary artery bypass grafting). RESULTS: Three patients were excluded from the study because of inability to obtain accurate M-mode echocardiographic images for left ventricular mass measurement preoperatively (1) or postoperatively (2). Of the remaining 54 patients, mechanical bileaflet valves were used in 19, stented tissue bioprostheses were implanted in 15, and a stentless porcine bioprosthesis was chosen for 20. Postoperative echocardiograms were obtained 4.9 +/- 2.3 days after aortic valve replacement (range, 2 to 9 days). A two-way repeated-measures analysis of variance demonstrated a significant reduction of left ventricular mass index before discharge (preoperative 141.4 +/- 45.2 g/m2, postoperative 127.5 +/- 32.8 g/m2; p = 0.0005) but no differences between prostheses. CONCLUSIONS: Left ventricular mass regression begins early after aortic valve replacement, probably because of reduction of transvalvular gradients and left ventricular wall stress. At least in the very early postoperative period, the type of prosthesis does not influence the extent of mass regression.

Analysis of deaths while waiting for cardiac surgery among 29,293 consecutive patients in Ontario, Canada. The Steering Committee of the Cardiac Care Network of Ontario.

OBJECTIVES: To assess death rates among patients waiting for cardiac valve surgery or isolated coronary artery bypass surgery (CABG), and to determine independent risk factors for death while waiting for isolated CABG. DESIGN: Prospective cohort analysis based on an inclusive registry. SETTING: Nine cardiac surgical units in Ontario, Canada. PATIENTS: 29,293 consecutive patients scheduled for cardiac surgery between October 1991 and June 1995. MAIN OUTCOME MEASURES: Death rates while waiting for surgery were determined among patients scheduled for isolated CABG, isolated valve surgery, or combined procedures. Predictors of death among patients with isolated CABG were determined from multivariate analysis. RESULTS: There were 141 deaths (0.48%) among 29,293 patients. Adjusting for age, sex, and waiting time, patients waiting for valve surgery had a significantly increased risk of death compared with patients waiting for CABG alone (adjusted odds ratio 1.88, 95% confidence interval (CI) 1.23 to 2.88, p = 0.004). Results were similar for patients waiting for combined valve and CABG procedures compared with those who were waiting for isolated CABG. Independent risk factors for death while waiting for isolated CABG included: impaired left ventricular function (odds ratio 2.47, 95% CI 1.59 to 3.84, p < 0.001); advancing age (for each decade, odds ratio 1.41, 95% CI 1.10 to 1.80, p = 0.007); male sex (odds ratio 1.95, 95% CI 1.00 to 3.81, p = 0.05); and waiting longer than the maximum time recommended in Canadian guidelines for a patient's clinical profile (odds ratio 1.59, 95% CI 1.01 to 2.51, p = 0.044). After scaling waiting time to surgery or death continuously in days, the same predictors emerged. CONCLUSIONS: Patients waiting for valve surgery have a higher risk of death than patients waiting for isolated CABG. Guidelines to promote safer and fairer queuing for non-CABG cardiac surgery are needed. Shorter waiting lists, better compliance with existing guidelines, and guideline revisions to upgrade patients with left ventricular dysfunction could generate additional reductions in the already low risk of death for patients waiting for isolated CABG.

Neuropsychological testing and assessment scales for dementia of the Alzheimer's type.

Neuropsychological assessment plays an important role in the process of diagnosing DAT. Whereas the brief screens are sensitive to the cognitive deficits associated with DAT, full battery measures should be used to rule out early dementia or to differentiate among the various dementing illnesses. Following diagnosis, there are numerous assessment measures that facilitate management and placement decisions. These measures include instruments that help stage the illness to determine severity, instruments that evaluate the patient's capacity to perform activities of daily living, and measures that evaluate for the behavior symptoms common in later-stage dementia.

Chemotherapeutic stress mediated by certain antitumor antibiotics induces an atypical CD69+ surface phenotype in peripheral T-lymphocytes.

Surface antigen CD69 is a Type II integral membrane protein that is generally considered a cell activation marker expressed very early in the normal lymphocyte activation cascade. The conformation of this surface antigen suggests a putative role in transmembrane signal transduction, yet the precise function of this surface antigen has not been clearly elucidated. We had previously reported robust atypical CD69 expression in peripheral T-lymphocytes as concentration-dependent, phenotypic responses to actinomycin D-induced chemotherapeutic stress in the absence of secondary stimulation. Additional antitumor antibiotics were evaluated for inductive potential, and the incidence and respective magnitudes of this chemotherapeutic stress-induced shift in lymphocytic CD69 expression were assessed. Results indicated that atypical CD69 expression is a common response to chemotherapy drug-induced stress. Differences in the respective percentages of CD69 + T-lymphocytes, and the resulting numbers of CD69 surface antigens ultimately expressed by these cells, were documented following in vitro drug exposure. The effective drug concentrations required to mediate detectable shifts in the CD69+ phenotype differed among the selected drugs, as well, suggesting a concentration-dependent induction mechanism putatively related to drug modality. Static CD69 expression responses in CD3+ peripheral T-lymphocytes were also documented, which further suggests that the different intracellular modalities do not mediate proportional T-lymphocyte responses through elevated CD69 expression.

Regression by differentiation in the Sinclair swine model of cutaneous melanoma.

The spontaneous regression of melanoma in Sinclair miniature swine involves the replacement of tumours by pigmented cells, hitherto interpreted as pigment-laden macrophages (PLMs). We hypothesized that these residual cells are terminally differentiated melanoma cells, not monocyte-derived macrophages. Swine melanoma explants with no regression were transplanted into severe combined immunodeficient (SCID) mice. Harvested transplant sites were examined by routine light and electron microscopy techniques. Paraffin sections were also stained with Hoeschst dye and examined by fluorescence microscopy. All but one site had completely regressed and were replaced by PLM-like cells. Hoeschst staining indicated they were of swine, not mouse, origin. The ultrastructural features of the single, partially regressed lesion demonstrated many premelanosomes in these cells. We conclude that tumour differentiation is an important mechanism of regression in the Sinclair swine melanoma model.

Long-term results of tibiotalar arthrodesis.

One hundred and one tibiotalar arthrodeses were performed using a single surgical technique that has not been previously reported. The average follow-up was ten years (range, two to twenty-five years). The rate of pseudarthrosis was 5 per cent, four to five times less than in other recent large reports. Pseudarthrosis occurred only in patients with a sensory deficit. Secure fusion was radiographically documented in 95 per cent and the functional clinical result was good to excellent in 90 per cent. The ideal fusion position was found to be neutral or slight equinus angulation, and varus-valgus angulation equal to that of the contralateral side. More than 7 degrees of varus angulation of the heel was associated with symptomatic lateral metatarsalgia in all feet in which it occurred. Radiographic measurement documented an average 85 per cent (11-degree) increase in postoperative tarsal motion. Neither symptoms nor function correlated with the degree of tarsal hypermobility.

Plasma measures of beta-endorphin/beta-lipotropin-like immunoreactivity in chronic pain syndrome and psychiatric subjects.

This study compared basal concentrations of plasma beta-endorphin/beta-lipotropin-like immunoreactivity and dexamethasone suppression of cortisol in seven chronic pain patients, seven psychiatric disorder patients, and seven normal volunteers. Pain patients and psychiatric patients showed significantly higher basal concentrations of beta-endorphin/beta-lipotropin-like immunoreactivity compared to normal volunteers. Pain patients also had significantly higher beta-endorphin/beta-lipotropin-like immunoreactivity than psychiatric patients, even though there was no significant difference in severity of depressive symptomatology as assessed by Beck and Hamilton scores. Resistance to dexamethasone occurred in 57% of pain patients. These results may indicate that biological markers for depression occur in populations of chronic pain patients, or may reflect levels of central nervous system arousal in response to stress, pain, or nonaffective phenomena.