Progesterone receptor variants found in breast cells repress transcription by wild-type receptors.

Progesterone, through its nuclear receptors (PR), regulates the development and growth of breast cancers. PR also serve as markers of hormone dependence and prognosis in patients with this disease, and functional PR are required to mediate the antiproliferative effects of progestin therapies. We find that normal and malignant breast cells and tissues can express anomalous forms of PR transcripts. We have isolated four variant PR mRNAs that contain precise deletions of exons encoding sections of the DNA- and hormone-binding domains. The transcripts lack exon 2 (PRdelta2), exon 4 (PRdelta4), exon 6 (PRdelta6), or exons 5 and 6 (PRdelta5,6). On immunoblots, PRdelta4, delta6. and delta5, 6 cloned into the background of the PR A-isoform comigrate with similar proteins present in breast tumor extracts; delta6 and delta5, 6 are dominant-negative transcriptional inhibitors of wild-type A- and B-receptors. We propose that expression of variant PR can compromise the accuracy of receptor measurements as markers of hormone-dependent cancers, and can modify the responses of tumors to progestin therapies.

Pernicious anemia manifesting as angina pectoris.

Here we describe a case of angina pectoris in a patient for whom an extensive cardiovascular workup was done, with negative results. Eventually, the cause of his symptoms was found to be pernicious anemia. Although angina is an uncommon manifestation of pernicious anemia, a review of the literature suggests that the correlation between anemia and angina has been well described. Our case highlights an important differential diagnosis to consider for patients with exercise-induced chest pain and serves to emphasize the attention that should be focused on simple screening laboratory studies. The emphasis in this case is the sequence in which the studies are done. A simple complete blood count with proper interpretation and intervention at the outset of evaluation could possibly have prevented a number of unnecessary, invasive, and costly studies.

Imported malaria in the 1990s. A report of 59 cases from Houston, Tex.

OBJECTIVE: To determine the frequency, the clinical features, and the response to therapy of imported malaria that was diagnosed in the 1990s in a major North American city. METHOD: A retrospective case series from Houston, Tex, of 59 cases of imported malaria presenting between January 1990 and April 1993. RESULTS: Malaria was diagnosed in 59 patients, consisting of 12 cases among patients who had acquired the infection while they were living in endemic areas prior to immigration to the United States, 32 cases among US residents who were originally from endemic areas, and 15 cases among patients originally from North America or Europe. Only 12 patients had received malarial prophylaxis: eight with chloroquine, one with chloroquine and chloroguanide (proguanil), two with chloroquine and primaquine, and one with mefloquine taken intermittently. Eight presented with Plasmodium falciparum infection after receiving chloroquine, and one, after receiving chloroquine and chloroguanide. Two presented with malaria caused by Plasmodium vivax despite receiving chloroquine and primaquine as prophylaxis. In 25 cases, malaria was not considered as an initial diagnosis. Five patients presented with severe disease (three with severe hemolysis, two each with cerebral malaria and renal failure, and one with adult respiratory distress syndrome). Four of the five had initially received a misdiagnosis. Two patients died despite treatment with intravenous quinidine and exchange transfusions. Two patients with P vivax infection had multiple relapses despite courses of chloroquine and primaquine. Six patients were pregnant (including one with a fatal case), one congenital infection was identified. Six patients had not traveled outside of the United States in over 1 year. CONCLUSION: Imported malaria occurs frequently and usually results from the failure to use appropriate prophylaxis. Delayed diagnosis and misdiagnosis are common. Severe disease and fatal cases continue to be seen despite aggressive treatment. Drug resistance has continued to spread and now occurs with P vivax as well as P falciparum.

Asymptomatic telephone ECG transmissions as an outpatient surveillance system of ventricular arrhythmias: relationship to quantitative ambulatory ECG recordings.

Although ambulatory ECG recordings provide quantitative information in the follow-up of patients with ventricular arrhythmias, they are performed infrequently, potentially missing serious arrhythmias in the unmonitored periods. Telephone ECG systems offer "real-time" ECG information, theoretically functioning as an arrhythmia surveillance system. Thus we incorporated frequent telephone ECG transmissions in two antiarrhythmic drug protocols. The first investigation was designed to show the relationship of telephone and ambulatory ECGs in patients with frequent ventricular tachycardia (VT). The second protocol selected patients with "nonlife-threatening" frequent premature ventricular complexes (PVCs) in whom a second placebo period was instituted to simulate the clinical situation of asymptomatic arrhythmia increase. In both drug trials there was a strong linear relationship between the log-transformed PVC counts of telephone ECG and concomitant PVC, couplet, and VT frequencies on ambulatory ECG. In the VT population, greater than or equal to 1 PVC on telephone ECG reflected the presence of VT on ambulatory ECG (sensitivity 87%; specificity 77%). In the second study, telephone ECG transmissions with PVCs on three consecutive transmissions reflected the change from less than or equal to 10 PVCs/hour to greater than or equal to 40 PVCs/hour on ambulatory ECG within 48 hours. These data support the concept that daily surveillance by means of telephone ECG provides arrhythmia information of qualitative clinical relevance.

Hemodynamic effects of moricizine at rest and during supine bicycle exercise: results in patients with ventricular tachycardia and left ventricular dysfunction.

To evaluate the hemodynamic effects of moricizine, 20 patients with frequent nonsustained ventricular tachycardia (VT) with a mean left ventricular ejection fraction (EF) of 39 +/- 14% were enrolled in a prospective single-blind, placebo-controlled study. Hemodynamic measurements were performed at rest and during supine bicycle exercise on placebo and moricizine therapy (10 mg/kg/day). Although 16 of 19 patients experienced no rest or exercise deterioration in hemodynamic parameters during drug dosing, three patients had acute deterioration of pulmonary capillary wedge pressure and cardiac index (CI) on moricizine. During follow-up of 6 +/- 3 months, two subgroups were identified: 10 of 19 patients had effective long-term reduction in VT, whereas 9 of 19 patients had poor control of ventricular arrhythmia or congestive heart failure and were discontinued from the trial. Baseline EF and hemodynamic parameters at rest were similar in both patient subgroups. However, protocol dropouts had a hemodynamic response to exercise on moricizine that was significantly depressed as compared to patients with a favorable antiarrhythmic outcome (p less than 0.02). The following hemodynamic profile characterizes patients unlikely to have an antiarrhythmic response to moricizine: an increase in CI of less than 1.0 L/min/m2 and no increase in left ventricular stroke work index during supine exercise.

Complex ventricular arrhythmias associated with the mitral valve prolapse syndrome. Effectiveness of moricizine (Ethmozine) in patients resistant to conventional antiarrhythmics.

On the basis of epidemiologic studies, more than 10 million Americans have echocardiographic evidence of mitral valve prolapse. Although ventricular arrhythmias occur frequently (over 50 percent of patients with mitral valve prolapse), they rarely result in sustained ventricular tachycardia or sudden cardiac death. However, a common problem in clinical practice is a patient with mitral valve prolapse and symptomatic complex ventricular arrhythmias refractory or intolerant to both beta blockers and conventional type I antiarrhythmics. These drugs are known to have frequent side effects, toxicity, and proarrhythmic effects. In 17 patients with mitral valve prolapse who presented with symptomatic complex ventricular arrhythmias and who were unresponsive to an average of the three conventional agents, moricizine (Ethmozine) was effective in suppressing 90 percent of ventricular premature depolarizations, 99 percent of nonsustained runs of ventricular tachycardia, as well as all sustained runs of ventricular tachycardia, resulting in abolition of palpitations, dizziness, and syncopal episodes. Its efficacy as well as its low frequency of minor side effects makes it ideal for future consideration in the population with mitral valve prolapse, who are frequently young and may therefore require therapy for many years.

The changing base line of complex ventricular arrhythmias. A new consideration in assessing long-term antiarrhythmic drug therapy.

Initial base-line electrocardiograms are used to assess the efficacy of treatment for ventricular arrhythmias. This approach assumes that in the absence of treatment the frequency of arrhythmia would remain constant. To test the validity of this assumption, we studied 26 clinically stable patients with symptomatic but not life-threatening ventricular arrhythmias, during two periods of placebo treatment separated by a mean of 17 months. As compared with the initial placebo period, there were significant reductions in ventricular premature depolarizations (50 per cent), pairs (65 per cent), and ventricular tachycardia (83 per cent) during the second period of placebo administration (P less than or equal to 0.05 for all comparisons). Over one third of the patients gave the appearance of receiving successful therapy during the second placebo period, even when the reported spontaneous variability of ventricular arrhythmia was taken into consideration. If unrecognized, these long-term spontaneous changes in the frequency of arrhythmia could result in continuation of unnecessary and potentially toxic therapy and lead to incorrect conclusions regarding the efficacy of antiarrhythmic drugs in clinical trials. We therefore recommend that the frequency of arrhythmia be reassessed annually in the absence of treatment in patients similar to those in our study. These recommendations should not be applied to patients with life-threatening ventricular arrhythmias.

Analysis of the spontaneous variability of ventricular arrhythmias: consecutive ambulatory electrocardiographic recordings of ventricular tachycardia.

Results are reported of analysis of the variability of complex ventricular arrhythmias in a cohort of 110 patients selected for the presence of ventricular tachycardia (VT). All patients were enrolled in investigational antiarrhythmic drug trials and had an average of 4 consecutive days of placebo ambulatory electrocardiographic recording to serve as the database for this study. Using a statistical approach incorporating analysis of variance, the minimum percent reductions of ventricular premature complexes, couplets and VT were calculated to establish "drug effect" rather than variability at a significance level of 0.05. The relative variability of ventricular arrhythmias in prognostically important groups was also analyzed: (1) coronary artery disease (CAD) (n = 57) vs no CAD (n = 53); (2) patients with a left ventricular ejection fraction of 40% or less (n = 52) vs those with an ejection fraction greater than 40% (n = 58); and (3) patients with frequent runs of VT (10 or more runs/day, n = 63) vs infrequent VT (n = 47). Multiple regression analysis revealed that patients with CAD have significantly greater premature ventricular complex variability than patients without CAD (p less than 0.01). Also, patients with frequent VT runs have greater VT variability than that previously reported in smaller studies, thus requiring greater VT reductions to establish drug effect. Whether the variability of ventricular arrhythmia is itself an independent risk factor for sudden cardiac death is unknown.