Value of digoxin in heart failure and sinus rhythm: new features of an old drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.     

Posttranslational modifications of the 5'-AMP-activated protein kinase beta1 subunit

The AMP-activated protein kinase (AMPK) consists of catalytic alpha and noncatalytic beta and gamma subunits and is responsible for acting as a metabolic sensor for AMP levels. There are multiple genes for each subunit and the rat liver AMPK alpha1 and alpha2 catalytic subunits are associated with beta1 and gamma1 noncatalytic subunits. We find that the isolated gamma1 subunit is N-terminally acetylated with no other posttranslational modification. The isolated beta1 subunit is N-terminally myristoylated. Transfection of COS cells with AMPK subunit cDNAs containing a nonmyristoylatable beta1 reduces, but does not eliminate, membrane binding of AMPK heterotrimer. The isolated beta1 subunit is partially phosphorylated at three sites, Ser24/25, Ser182, and Ser108. The Ser24/25 and Ser108 sites are substoichiometrically phosphorylated and can be autophosphorylated in vitro. The Ser-Pro site in the sequence LSSS182PPGP is stoichiometrically phosphorylated, and no additional phosphate is incorporated into this site with autophosphorylation. Based on labeling studies in transfected cells, we conclude that alpha1 Thr172 is a major, although not exclusive, site of both basal and stimulated alpha1 phosphorylation by an upstream AMPK kinase.     

Usefulness of tomography in the evaluation of patients with temporomandibular disorders: a retrospective clinical study

OBJECTIVES: To evaluate the effect of temporomandibular joint tomography on the diagnosis and management of temporomandibular disorders and to determine whether there were any clinical predictors of usefulness of tomography in providing new information helpful in the treatment of these patients. STUDY DESIGN: The charts of 116 patients with temporomandibular joint tomograms were reviewed retrospectively for presenting signs and symptoms, initial clinical diagnosis, and alterations in diagnosis and management as a result of tomography. RESULTS: Common clinical diagnoses included osteoarthrosis (54%) and internal derangement (42%). Tomography changed the diagnosis in 24%, mainly adding or subtracting osteoarthrosis, and altered the management in 17%. Most of the latter were minor changes in treatment recommendations. There were few clinical variables that were related to whether tomography changed diagnosis or management. CONCLUSIONS: Tomography seems to have a minimal effect on the diagnosis or management of temporomandibular disorders based on the results of this retrospective study.     

Molecular cDNA cloning and tissue distribution of mRNA encoding a novel ATP-binding cassette (ABC) half-transporter

After feeding a commercial rodent chow for 8 weeks, tissues from male and female rats were collected and examined for selenium content, glutathione peroxidase (GPX) activities and selenoprotein W (Se-W) levels. There were no differences (P > 0.05) between plasma selenium content, plasma GPX activity, whole blood selenium content, or whole blood GPX activity between male and female rats. There was also no gender effect on selenium concentration in muscle, brain, spleen, and skin, but selenium concentration in liver was higher (P < 0.05) in female than in male rats. Western blots indicated that the tissue distribution of Se-W was similar in male and female rats. Se-W protein level was high in testes of male rats but very low in ovaries of female rats. Muscle and skin from female rats had significantly higher (P < 0.05) Se-W levels than from male rats. Consistent with Se-W content, the Se-W mRNA levels from female skins were significantly higher (P < 0.05) than from male rats. The expression of Se-W was different in various tissues and gender influenced this regulation in some tissues.     

Mental disorders in elderly suicide

The purpose of this study was to investigate the prevalence and comorbidity of current mental disorders defined by DSM-III-R among elderly suicide victims and to compare them with the mental disorders among younger victims. Using a psychological autopsy method, we collected comprehensive data on all suicides in Finland during 1 year. Retrospective Axis I-III consensus diagnoses were assigned to a random sample consisting of 43 victims aged 60 years or over and 186 victims aged under 60 from the nationwide suicide population. At least one Axis I diagnosis was made for 91% of the elderly victims. Major depression as the principal diagnosis was more common among the elderly victims. Almost all elderly female victims were major depressives. Psychiatric comorbidity was more common among elderly male than among elderly female victims. More of the elderly victims (88%) than the younger (36%) received Axis III diagnoses. Suicide among the elderly without a diagnosable mental disorder and somatopsychiatric comorbidity seems to be rare.     

Vertebral artery dissection

Vertebral artery dissections (VADs) following a variety of minor traumatic mechanisms have been previously reported. This article reports 2 cases of VAD with delayed recognition following motor vehicle collisions (MVCs). The first VAD patient developed major neurologic abnormalities 28 hours after an MVC. The second VAD patient presented with 3 weeks of neck and head pain beginning 8 weeks after an MVC and subsequent chiropractic manipulation. The anatomy and pathophysiology of VAD are reviewed. Early ED recognition prior to the onset of major neurologic deficits (e.g., paresis, dysarthria, ataxia, or altered mental status) is emphasized. An algorithm for the ED management of the entity is suggested.     

B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS)

OBJECTIVES: In this B-mode ultrasound study we assessed pravastatin treatment effects on carotid and femoral artery walls and investigated the correlations between the state and evolution of peripheral and coronary atherosclerosis. BACKGROUND: The Regression Growth Evaluation Statin Study (REGRESS) was an 11-center, 2-year, double-blind, placebo-controlled, prospective study of 885 men with coronary artery disease (CAD) (total cholesterol 4 to 8 mmol/liter). The study primarily investigated pravastatin treatment effects on the coronary lumen. This report focuses on the 255 patients who participated in the REGRESS ultrasound study. METHODS: Carotid and femoral artery walls were imaged at baseline and at 6, 12, 18 and 24 months. Pravastatin treatment effect was defined as the difference in progression of the combined intima-media thicknesses (IMT) between treatment groups. RESULTS: Pravastatin treatment effects were highly significant (combined IMT: p = 0.0085; combined far wall IMT: p < 0.0001; common femoral artery far wall IMT: p = 0.004). Correlations between the IMTs of the arterial wall segments ranged from -0.17 to 0.81. Baseline correlations between IMT and percent coronary lumen stenoses ranged from 0.23 to 0.36. Baseline IMT correlated with the mean coronary segment diameter (r = -0.32, p = 0.001) and minimal coronary obstruction diameter (r = -0.27, p = 0.005). There were no individual correlations between IMT and coronary lumen variables (p > 0.30). CONCLUSIONS: Pravastatin treatment effects on carotid and femoral artery walls were observed. B-mode ultrasound imaging studies of peripheral arterial walls could not describe the state and evolution of the coronary lumen in the individual patient, but proved to be a highly suitable tool for the assessment of antiatherosclerotic properties of agents.