Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25- (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor-ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.     

The clinical relevance of adrenomedullin: a promising profile?

Adrenomedullin (AM) is a peptide that possesses potentially beneficial properties. Since the initial discovery of the peptide by Kitamura et al. in 1993, the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. Its early promise as a potential mediator/modulator of disease was not, however, entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid peptide. Plasma levels of AM have now been shown to be increased in a number of pathological states, including congestive heart failure, sepsis, essential hypertension, acute myocardial infarction, and renal impairment. These earliest associations have been further supplemented with evidence of a role for AM in other pathologies including, most intriguingly, cancer. In this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.     

Intravenous anesthetics

Intravenous anesthetics continue to be a mainstay in the modern anesthesiologist's armamentarium. In this review the authors will discuss new advancements in the use of propofol, as well as a greater understanding as to its mechanism of action. Further, we will discuss the use of target controlled infusion systems, touch upon the possible benefits of the ultra-short acting opioids, and consider the role of alpha-2 agonists as an adjunct to anesthetic management.     

Adolescent perceptions of smoking imagery in film

Smoking amongst adolescents in New Zealand continues to be a problem, with more than a one-third increase in smoking prevalence between 1992 and 1997. Favourable portrayals of smoking in the media have been cited as potential motivators of the initiation of smoking among adolescents. To date, however, its role in influencing smoking perceptions and behaviours has not received systematic analysis. A qualitative study was conducted to explore how adolescents interpret and decode smoking imagery in movies. Data was collected through focus groups. Same-gender groups of 12- and 13-year-old students were interviewed at their schools. Participants discussed their recollections of and responses to portrayals of smoking in recently viewed films, as well as their perceptions of smoking in general. Students perceived that smoking in film is both highly prevalent and recognisable, and they regarded on-screen-smoking imagery as an accurate reflection of reality. Adolescents in this study were predominantly nonchalant towards the inclusion of smoking images in film, and they perceived an unrealistically high prevalence of smoking amongst peers and adults. Their noncholant response is linked with the perception that smoking is normal and prevalent and with the broad understanding of the constructed nature of media imagery. Smoking imagery in film may play a critical role in reinforcing cultural interpretations of tobacco use, such as its role as a means of stress relief, development of self-image and as a marker of adult independence.     

Sorbinil pharmacokinetics in male and female elderly volunteers.

Sorbinil pharmacokinetics were studied, following a single oral dose, in eight male and eight female healthy, elderly volunteers. Elimination half-life tended to be longer in males than in females. There was no sex difference in AUC or renal clearance. The long elimination half-life of sorbinil in the elderly suggests that accumulation is likely to occur with chronic dosing.     

Broken pump or leaky filter? Renal dysfunction in heart failure a contemporary review

Renal dysfunction is a frequent and progressive complication of chronic heart failure and is a powerful predictor of cardiovascular mortality. It is intimately associated with cardiovascular disease even in its earliest stages. Although cardiovascular and renal disease share many risk factors, the prognostic implications do not simply reflect widespread atherosclerotic vascular disease as this appears to be as important in those with heart failure secondary to idiopathic dilated cardiomyopathy as it is in those with coronary artery disease. There may be a role in the progression of heart failure, as the deleterious effects of even “mild” renal impairment seem to be borne out in predicting outcome, in a broad range of heart failure patients including those with heart failure and preserved systolic function. Renal dysfunction is both an indication for, as well as frequently limiting intervention with intensive disease modifying therapy. Although renal impairment is common in heart failure and these patients are at higher risk for adverse events including death, they are under represented in clinical trials.