Exercise performance-based outcomes of medically treated patients with coronary artery disease and profound ST segment depression.

OBJECTIVES: We sought to determine the relationship between exercise duration and cardiovascular outcomes in patients with profound (> or =2 mm) ST segment depression during exercise treadmill testing (ETT). BACKGROUND: Patients with stable symptoms but profound ST segment depression during ETT are often referred for a coronary intervention on the basis that presumed severe coronary artery disease (CAD) will lead to unfavorable cardiovascular outcomes, irrespective of symptomatic and functional status. We hypothesized that good exercise tolerance in such patients treated medically is associated with favorable long-term outcomes. METHODS: We prospectively followed 203 consecutive patients (181 men; mean age 73 years) with known stable CAD and > or =2 mm ST segment depression who are performing ETT according to the Bruce protocol for an average of 41 months. The primary end point was occurrence of myocardial infarction (MI) or death. RESULTS: Eight (20%) of 40 patients with an initial ETT exercise duration < or =6 min developed MI or died, as compared with five (6%) of 84 patients who exercised between 6 and 9 min and three (3.8%) of 79 patients who exercised > or =9 min (p = 0.01). Compared with patients who exercised < or =6 min, increased ETT duration was significantly associated with a reduced risk of MI/death (6 to 9 min: relative risk [RR] = 0.25, 95% confidence interval [CI] 0.08 to 0.76; >9 min: RR = 0.14, 95% CI 0.04 to 0.53). This protective effect persisted after adjustment for potentially confounding variables. We observed a 23% reduction in MI/death for each additional minute of exercise the patient was able to complete during the index ETT. CONCLUSIONS: Optimal medical management in stable patients with CAD with profound exercise-induced ST segment depression but good ETT duration is an appropriate alternative to coronary revascularization and is associated with low rates of MI and death.

Enteropathogenic Escherichia coli adherence to intestinal epithelial monolayers diminishes barrier function.

The mechanism by which enteropathogenic Escherichia coli (EPEC) causes diarrhea remains elusive. Several alterations within the host cell have been demonstrated to occur following EPEC attachment including increases in intracellular Ca2+ concentration and rearrangement and phosphorylation of several cytoskeletal proteins. The consequences of these intracellular perturbations on host cell function, however, have not been determined. The aim of this study was to examine the effect of EPEC adherence on intestinal epithelial barrier function. T84 cell monolayers were infected with either wild-type EPEC or a nonadherent isogenic derivative. Transepithelial electrical resistance, a measure of barrier function, decreased 33.5 +/- 6.4% after a 6-h incubation with the wild-type strain. Electron microscopy revealed ultrastructurally normal cells, and lactate dehydrogenase release assays failed to demonstrate cytotoxicity. Dual 22Na+ and [3H]mannitol flux studies localized the permeability defect to tight junctions. In addition, cumulative flux of the paracellular marker mannitol was four- to fivefold greater across monolayers infected with wild-type EPEC. Sequestration of intracellular calcium stores by dantrolene completely abrogated the resistance drop associated with EPEC attachment. These data demonstrate that adherence of EPEC to intestinal epithelial cell monolayers disrupts tight junction barrier function via a calcium-requiring event.

Gallstones: choosing the right therapy despite vague clinical clues.

Therapeutic decisions are quite clear-cut for asymptomatic gallstone disease and acute cholecystitis. However, the appropriate therapeutic course for older patients with chronic cholecystitis may be less obvious. Watchful waiting may be reasonable for patients with mild and infrequent symptoms. For healthy patients, cholecystectomy is recommended if symptoms are becoming more frequent and severe. Laparoscopy may reduce the complication rate and be safely performed even in those with underlying medical illness. Oral dissolution therapy can be attempted for qualifying symptomatic patients who are at poor surgical risk or who refuse surgery. Shock wave lithotripsy and contact dissolution therapy show some promise but are currently experimental.

Results of a second-opinion trial among patients recommended for coronary angiography.

OBJECTIVE: To assess the feasibility of carrying out a second-opinion trial for patients urged to undergo coronary angiography and to assess the long-range outcome of such patients denied that procedure, and the criteria evolved for reaching such a conclusion. DESIGN: A case series of patients referred for a second opinion as to the need for coronary angiography. Patients were followed up by questionnaire, telephone call, and center visits. SETTING: Cardiovascular referral center and teaching hospital in Boston, Mass. PATIENTS: One hundred seventy-one patients with coronary artery disease (144 men, average age 60 years; range, 36 to 88 years). Three patients became unavailable for follow-up during a mean of 46.5 months. OUTCOME MEASURES: Concordant-discordant outcome as to the second opinion, cardiac events, invasive interventions, quality of life questionnaire, and level of symptoms. RESULTS: One hundred thirty-four (80%) of the 168 patients were judged not to require angiography; it was recommended in six. In 28 (16%) recommendation was deferred pending further studies. At a mean follow-up of 46.5 months among the 168 patients, there were seven cardiac deaths (annualized cardiac mortality of 1.1%); 19 patients experienced a new myocardial infarction (2.7% annualized rate), while 27 patients (4.3%) were judged to have developed unstable angina. Twenty-six patients (15.4%) ultimately underwent either coronary bypass or angioplasty. CONCLUSIONS: In a large fraction of medically stable patients with coronary disease who are urged to undergo coronary angiography, the procedure can be safely deferred. While there may be a limitation in terms of generalizing this experience to all patients with coronary disease, we reasonably conclude that an estimated 50% of coronary angiography currently being undertaken in the United States is unnecessary, or at least could be postponed.

Inhibition of specific pathways of myeloid cell differentiation by an activated Hox-2.4 homeobox gene.

Abnormal expression of homeobox genes is one of the abnormalities associated with the development of murine and human leukemia. Myeloid leukemic cells that can be induced to differentiate to mature cells by interleukin 6 were stably transfected with an activated Hox-2.4 homeobox gene. Expression of the Hox-2.4 gene in the transfected clones inhibited specific pathways of the myeloid differentiation program induced by interleukin 6. The expression of some genes associated with differentiation was almost completely blocked, and the expression of other genes was either partially inhibited or not affected. The results support the hypothesis that abnormal expression of Hox-2.4 may contribute to the development of leukemia by interfering with the differentiation program.

A deletion and a rearrangement distinguish between the intracisternal A-particle of Hox-2.4 and that of interleukin-3 in the same leukemic cells.

Two intracisternal A-particle (IAP) insertions have been identified in WEHI-3B myeloid leukemic cells, one at the interleukin-3 (IL-3) gene and another at the homeobox gene Hox-2.4. In contrast to the 5-kb IL-3-IAP, the Hox-2.4-IAP is only 2.1 kb in size and contains a rearrangement. The homology throughout the remaining sequences suggests that both IAPs originated from a common progenitor molecule. Both proviral insertions have resulted in transcriptional activation of the adjacent genes, which appears to be a significant step in the leukemogenic process in these leukemic cells.

The oncogenic potential of an activated Hox-2.4 homeobox gene in mouse fibroblasts.

The homeobox gene Hox-2.4 is transcriptionally activated in cells of the mouse myeloid leukemia WEHI-3B. The constitutive Hox-2.4 expression in WEHI-3B cells is due to insertion of a transposable element belonging to the family of intracisternal A particles. In this study, we demonstrated the oncogenic potential of this activated homeobox gene. NIH 3T3 fibroblast clones bearing the activated Hox-2.4 gene produced fibrosarcomas in nude mice.

The betrayal of homeo box genes in normal development: the link to cancer.

The homeo box genes encode proteins that function in a complex regulatory network that specifies the precise temporal and spatial expression of genes in the developing embryo. Recent work has shown that these proteins can act directly as transcription factors. I argue here that, when altered by somatic mutation, the products of homeo box genes are likely to acquire activities that contribute to the oncogenic process.

The effect of caffeine on ventricular ectopic activity in patients with malignant ventricular arrhythmia.

We evaluated the effect of caffeine on ventricular ectopic activity in a group of 50 consecutive patients with malignant ventricular arrhythmia. The clinical arrhythmia in these patients (mean age, 61 years) was recurrent ventricular tachycardia in 21 (42%), ventricular fibrillation in three (6%), and symptomatic nonsustained ventricular tachycardia in 26 (52%). Forty-two (84%) had either ischemic heart disease or cardiomyopathy. Each patient underwent two short-term drug trials on successive days, receiving either decaffeinated coffee mixed with 200 mg of caffeine or the decaffeinated drink alone. Continuous electrocardiographic recordings were made during the 30-minute control period, the three-hour observation period, and the hourly bicycle exercise tests. Forty-five patients (90%) exhibited ventricular couplets and 29 patients (58%) had salvos of ventricular tachycardia during the testing. However, no differences between the caffeine and decaffeinated trials were observed in either individual or group data on total or repetitive ventricular arrhythmia. Serum catecholamine levels reflected the average increase in serum caffeine level but were not associated with enhanced arrhythmia. We found no evidence that a modest dose of caffeine is arrhythmogenic, even among patients with known life-threatening arrhythmia.

DNA rearrangement of a homeobox gene in myeloid leukaemic cells.

A homeobox gene rearrangement has been detected in WEHI-3B mouse myeloid leukaemic cells. The rearranged gene was identified as Hox-2.4 which is a member of the Hox-2 gene cluster on mouse chromosome 11. Both the normal and the rearranged genes were cloned and analysed, and the rearranged genomic Hox-2.4 gene was sequenced. The results indicate that the rearrangement is due to insertion of an intracisternal A particle 5' upstream to Hox-2.4 and that this resulted in constitutive expression of the homeobox gene. It is suggested that constitutive expression of the homeobox gene may interrupt the normal development program in these leukaemic cells.

Deletion of a homeobox gene in myeloid leukemias with a deletion in chromosome 2.

Mouse myeloid leukemias are characterized by a frequent deletion in one chromosome number 2. We now show that there is a deletion of one copy of the Hox-4.1 homeobox gene in the myeloid leukemias with this deletion in chromosome 2. It is suggested that deletion of this homeobox gene plays a role in determining the abnormal developmental program in myeloid leukemia.

Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human.

A variety of genes have been identified that specify the synthesis of the components of guanine nucleotide-binding proteins (G proteins). Eight different guanine nucleotide-binding alpha-subunit proteins, two different beta subunits, and one gamma subunit have been described. Hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids was used to assign many of these genes to human chromosomes. The retinal-specific transducin subunit genes GNAT1 and GNAT2 were on chromosomes 3 and 1; GNAI1, GNAI2, and GNAI3 were assigned to chromosomes 7, 3, and 1, respectively; GNAZ and GNAS were found on chromosomes 22 and 20. The beta subunits were also assigned--GNB1 to chromosome 1 and GNB2 to chromosome 7. Restriction fragment length polymorphisms were used to map the homologues of some of these genes in the mouse. GNAT1 and GNAI2 were found to map adjacent to each other on mouse chromosome 9 and GNAT2 was mapped on chromosome 17. The mouse GNB1 gene was assigned to chromosome 19. These mapping assignments will be useful in defining the extent of the G alpha gene family and may help in attempts to correlate specific genetic diseases with genes corresponding to G proteins.

Determinants of survival in patients with malignant ventricular arrhythmia associated with coronary artery disease.

The long-term survival data in patients with coronary artery disease and a history of malignant ventricular arrhythmia, defined as noninfarction ventricular fibrillation (VF) or hemodynamically compromising ventricular tachycardia (VT) followed for up to 9 years, were analyzed. In this group of 161 patients there was a total of 57 deaths, of which 35 (63%) were sudden. Life-table analysis demonstrated a 10% sudden death rate for all patients in the first year and a 7% annual rate in the subsequent 4 years. In patients managed noninvasively, the overall mortality rate was 27% over 9 years, or 3% per year. Suppression of ventricular tachycardia on both ambulatory monitoring and exercise testing was associated with improved survival. In patients evaluated by electrophysiologic testing the sudden death rate was 1.4% per year over an average of 5 years. This survival rate was not different compared with the noninvasive group (p = 0.09). Measures of left ventricular dysfunction and the frequency of ventricular arrhythmia before and after drug therapy were associated with a risk of sudden cardiac death by univariate analysis. Multivariate regression analysis identified 4 variables as independent predictors of sudden cardiac death: rales (p = 0.009), the number of runs of VT during exercise testing while receiving antiarrhythmic drug therapy (p = 0.0003), a history of congestive heart failure (p = 0.0009) and the number of premature beats on Holter monitoring (p = 0.01). These findings support the concept that suppression of repetitive arrhythmia on Holter monitor and exercise testing is a marker for improved survival among patients with malignant ventricular arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Mapping and gene order of U1 small nuclear RNA, endogenous viral env sequence, amylase, and alcohol dehydrogenase-3 on mouse chromosome 3.

Linkage was established between a number of genes that map on chromosome 3 by studying the distribution patterns of DNA polymorphisms and protein electrophoretic mobility polymorphisms in recombinant inbred (RI) strains of mice. This analysis resulted in the following suggested gene order between the newly assigned genes and previously mapped genes: gamma-fibrinogen (Fgg), Xmmv-22 of mink cell focus-inducing (MCF) virus, U1b small nuclear RNA gene cluster (Rnu-1b), amylase (Amy-1,2), cadmium resistance (cdm), alcohol dehydrogenase-3 (Adh-3), alcohol dehydrogenase-1 (Adh-1). In situ hybridization to chromosome spreads confirmed the assignment of the Ulb small nuclear RNA (snRNA) gene cluster and the gamma-fibrinogen gene to the center of chromosome 3.

Considerations of current methods for drug selection in treating malignant ventricular arrhythmias.

The current burgeoning interest in antiarrhythmic drugs derives in large measure from a growing concern with the enormous problem of sudden cardiac death. Until the latter half of the twentieth century, beyond a nodding acknowledgment of its massive prevalence, this syndrome received but scant attention from the medical profession. In the early 1960s a number of insights changed perceptions as well as practice. These related to 4 postulates: (1) sudden cardiac death, in the majority of victims, was due to ventricular tachyarrhythmias either initiated by or culminating rapidly in ventricular fibrillation; (2) the lethal arrhythmia was not the consequence of irreversible pathomorphologic impairment of the contractile apparatus, but rather the expression of an electrophysiologic derangement; (3) the triggering of ventricular fibrillation was the result of an electrical accident both reversible as well as preventable; (4) the potential victim was identifiable either by the presence of certain grades of ventricular ectopic activity or by exposure of repetitive ectopic activity or by exposure of repetitive ventricular arrhythmias by electrophysiologic techniques. The innovations that have led to these insights and their consequences have been numerous and continuous. Among these are direct current defibrillation, cardioversion, coronary care units, bystander-initiated cardiopulmonary resuscitation, ambulatory electrocardiographic monitoring and exercise stress testing for exposing ventricular arrhythmias, electrophysiologic provocative testing and mapping techniques, overdrive programmable pacemakers as well as implantable defibrillators and cardioverters, and surgical, electrical and laser techniques for ablating the nidus or interrupting the pathways of the arrhythmias.

New murine homeoboxes: structure, chromosomal assignment, and differential expression in adult erythropoiesis.

The nucleotide sequence, chromosomal assignment, and preliminary transcriptional analysis of four murine homeoboxes is presented. Three of these are linked to the Hox-2 gene complex on chromosome 11, whereas the fourth, Hox-4, was assigned to mouse chromosome 12. A comparative analysis of homeobox sequences reveals that two of our sequences represent the previously described Hox-2.3 loci, whereas a third, mh19, could represent the predicted Hox-2.6 locus. Homeoboxes Hox-2.2 and Hox-2.3 are the cognates of two previously reported human homeoboxes that belong to a similar gene cluster on a closely related human chromosome (Chr 17), suggesting that homeoboxes may have been preserved as clusters during evolution. Moreover Hox-4, mh19, and the previously described Hox-1.5 homeobox form a separate subgroup of mammalian homeoboxes (90-92% amino acid and nucleotide homology). All four homeoboxes are expressed in the mouse embryo. Of special interest is the expression of mh19, a 4.2-kb transcript of which appears to be connected to the induced differentiation of Friend erythroleukemia cells.

Results of a second-opinion program for coronary artery bypass graft surgery.

Second opinions for surgical procedures are now being sought by patients or are required by insurance carriers. We examined outcomes among 88 patients (76 men; average age, 59 years) referred for a second opinion as to the need for coronary artery bypass graft surgery. All patients had undergone coronary arteriography, which disclosed in 63 (72%) multivessel coronary artery disease, while in the remaining 25 patients single-vessel disease involved the left anterior descending coronary artery. Continuation of medical therapy was recommended for 74 (84%) of the 88 patients. Sixty of these 74 patients chose this option and continued to receive medical therapy without any fatalities during a follow-up period of 27.8 months. The remaining 14 patients elected to cross over to surgical therapy at an average of 11.3 months from the second opinion. We conclude that second opinions for selected, motivated patients slated for coronary artery bypass graft operation afford a significant and safe option. Moreover, a majority of patients will adhere to a second opinion recommending medical therapy, thus reducing the need for surgical intervention by as much as 50%. Since the study was based on a small sample size of self-selected patients, these data require caution in extrapolating to the general population with coronary artery disease.