Comparison of acute electrophysiological effects of amiodarone and its metabolite desethylamiodarone in Langendorff perfused guinea pig hearts

Summary During long-term treatment with amiodarone, slowing of conduction through the atrioventricular node, a prolongation of the QT-interval, and a prolongation of the atrial and ventricular myocardial refractoriness always developed. During short-term treatment, these effects were not found, except for depression of the AV-nodal conduction. This led to the suggestion that the electrophysiological effects of amiodarone during long-term treatment might be partly the result of the accumulation of its metabolite desethylamiodarone. Therefore, we examined the electrophysiological effects of amiodarone and desethylamiodarone on conduction and refractoriness in isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. Within 1 h of perfusion, desethyl-amiodarone caused a more pronounced prolongation of the AV-nodal, His-bundle, and intraventricular conduction intervals than did amiodarone. Desethylamiodarone, but not amiodarone led to a prolongation of the QT-interval. The refractoriness of sinoatrial-, AV-nodal conduction, and of the atrial myocardium were significantly more prolonged by amiodarone than by desethylamiodarone. Both compounds showed a comparable strong rate-dependent effect on AV-nodal refractoriness. The ventricular refractoriness was similarily prolonged by either compound. These results show that for the class-III effects (i.e., prolongation of repolarization period) observed under chronic treatment of amiodarone the metabolite desethylamiodarone may be responsible. Desethylamiodarone also exerts more pronounced effects on the fast-channel-dependent parts of the conduction system than does amiodarone, a fact indicated by a higher prolongation of His-bundle and intraventricular conduction.Supported by the Austrian Research Foundation, grant P 7141 and by the Austrian Development Fund, grant 5/545 and grant Z13/7098/513     

Frequency and thoroughness of STD/HIV risk assessment by physicians in a high-risk metropolitan area.

The US Preventive Services Task Force recommends that all primary care physicians assess the sexually transmitted disease/human immunodeficiency virus (STD/HIV) risk of all adolescent and adult patients. To determine whether factors amenable to change through continuing medical education are associated with frequent and thorough STD/HIV risk assessment, a telephone survey of primary care physicians in the Washington, DC metropolitan area was conducted (n = 961). Thirty-seven percent of physicians reported regularly asking new adult patients about their sexual practices; 60% asked new adolescent patients. STD/HIV risk questioning was associated with physicians' confidence in their ability to help prevent HIV, comfort with discussing patients' sexual practices, and perception of a large STD/HIV problem in their practice. These findings suggest that continuing medical education should target improvement in physicians' sexual practice questioning skills.     

Effects of castration on adipose tissue growth and regrowth in the male rat

Adipose tissue has been found to regrow in the male rat following surgical removal (lipectomy) of inguinal subcutaneous depots, but the degree of regrowth has varied widely across experiments. It is possible that at least part of the disparity of previous findings occurred because of differences among the experiments in the testicular integrity of experimental animals. To address this possibility, the present study examined effects of castration on adipose tissue regrowth in rats treated either as weanlings or as young adults. Male Sprague-Dawley rats, at either 4 or 15 weeks of age, were subjected to one of four surgical procedures: bilateral lipectomy of the inguinal subcutaneous depots; castration; lipectomy and castration; or sham surgery. Adipose tissue mass and cellularity were examined 6 months later. Castration reduced body weight gain, but castrated rats achieved a higher ratio of adipose weight to body weight than noncastrated rats. In rats lipectomized but not castrated at 15 weeks of age, partial regeneration and a small increase in growth of noninguinal subcutaneous adipose tissue combined to produce substantial restoration of adipose mass. The same surgery in 4-week-old rats did not result in significant restoration because growth of noninguinal subcutaneous adipose tissue was reduced. In rats that were both castrated and lipectomized, regrowth of adipose tissue was substantial regardless of age at time of surgery. Thus, castration is seen to impede body weight gain while sparing ordinary growth of adipose tissue and facilitating regrowth of adipose tissue following lipectomy. Since adipose tissue regrowth varied with age only in noncastrated rats, it appears to be facilitated as well by testicular maturation.     

Increased expression of the G gamma and A gamma globin genes associated with a mutation in the A gamma enhancer

We have previously described a unique type of delta beta-thalassemia in a Chinese family characterized by increased expression of the G gamma and A gamma fetal globin genes in the absence of a large deletion in the beta-globlin gene cluster. Our earlier study of the beta-globin gene on this delta beta-thalassemia chromosome showed a promoter mutation in the TATA box. In this report, we describe the results of our study of the fetal globin domain of this delta beta-thalassemia chromosome. We have cloned a 13-kb DNA fragment that includes the G gamma and the A gamma genes and the 3' A gamma enhancer element of this delta beta-thalassemia chromosome. DNA sequence analysis of the G gamma and A gamma-globin genes including their promoters did not show any mutations, but analysis of the putative enhancer element downstream from the A gamma-globin gene showed a C to T substitution 2,401 nucleotides downstream from the A gamma cap site. We performed DNA linkage analysis to determine if this mutation is unique to this chromosome or represents a common polymorphism. Our linkage analysis showed that this mutation is not a common polymorphism and that it is also not an intrinsic part of the haplotype of the chromosome on which it was found. We also studied the interaction of nuclear proteins from erythroid and nonerythroid cells with the DNA sequences surrounding this mutation. We have shown by in vitro DNase I footprinting that this mutation falls within a region that is occupied by a novel DNA-binding protein that binds to this site in nuclear extracts from erythroid, but not nonerythroid cells. The binding of this nuclear protein to DNA appears to be dependent on GATA-1 binding to an adjacent GATA-1 site. We have also developed a new functional assay to compare the activity of the normal and mutant A gamma enhancer elements in erythroid cells. Analysis of the activity of the mutant enhancer shows that the mutation completely eliminates all enhancer activity in this assay. These findings suggest that this mutation of the A gamma enhancer on a chromosome that carries a partially inactivated beta-globin gene may be responsible for the increased expression of both gamma-globin genes seen in this condition.     

Adipose tissue of morbidly obese patients: clinical implications of distribution, morphology, and metabolism

As a consequence of their increased total adipose tissue mass, morbidly obese patients have many more fat cells than individuals of normal weight and the cells are enlarged compared to normal. Contrary to earlier beliefs, fat cell numbers can increase throughout adult life. Once formed, fat cells do not undergo involution. Thus, it seems that an individual who has reached the morbidly obese state maintains an increased amount of body fat that limits his/her ability to achieve and maintain commonly accepted levels of "ideal" body weight. Recently the distribution of adipose tissue has been shown to be an important predictor of obesity-associated morbidity and mortality in large population studies. A "male" or central distribution of fat is a significant risk factor for the development of diabetes, hyperlipidemia, hypertension, and coronary heart disease. Sex- and site-specific variations in the distribution of adipose tissue cell size and metabolic activity have been demonstrated that may be of etiologic importance for the development of serious comorbid conditions in obesity.