When the heart is stopped for good: hypotension-bradycardia paradox revisited

In vasovagal syncope, occurrence of bradycardia/asystole in the wake of hypotension has often been considered paradoxical. The major objective of this teaching module is to critically examine the pathophysiological mechanism and significance of the hypotension-bradycardia paradox unique to this condition. We narrate here how we discussed the pathophysiology of vasovagal syncope in a large classroom session attended by 275 doctors and medical students. A case study was used to describe the typical clinical presentation of vasovagal syncope. The pathophysiological mechanisms involved were then discussed systematically using a series of open-ended questions. We made it clear 1) that the occurrence of bradycardia or asystole in the face of acute severe hypotension is a mechanism to possibly minimize further blood loss, prevent myocardial damage, and increase ventricular filling; and 2) that fainting, which occurs as a consequence of this, is a homeostatic mechanism that serves to restore venous return and cerebral blood flow before blood pressure is normalized by neural reflex mechanisms. Eighty-four percent of participants reported that they were satisfied with the session. The information contained herein could be used to explain to any suitable audience the neural regulation of blood pressure in the face of acute severe hypotension and the pathophysiology of vasovagal syncope.     

Stopping ras in its tracks

Ras interacts with many downstream effectors that regulate complex cytoplasmic signaling networks. In this issue, Gupta et al. (2007) use mouse models of Ras-mediated tumorigenesis to show that the interaction of Ras with a single isoform of phosphatidylinositol 3-kinase (PI3K), called p110alpha (PIK3CA), is critical for tumor formation. This result will stimulate re-evaluation of pharmacological approaches to target Ras for cancer treatment.     

Killing the messenger: short RNAs that silence gene expression

Short interfering RNAs can be used to silence gene expression in a sequence-specific manner in a process that is known as RNA interference. The application of RNA interference in mammals has the potential to allow the systematic analysis of gene expression and holds the possibility of therapeutic gene silencing. Much of the promise of RNA interference will depend on the recent advances in short-RNA-based silencing technologies.     

SU(VAR)3-9 is a conserved key function in heterochromatic gene silencing

This review summarizes genetic, molecular and biochemical studies of the SU(VAR)3-9 protein and the evidence for its key role in heterochromatin formation and heterochromatic gene silencing. The Su(var)3-9 locus was first identified as a dominant modifier of position-effect variegation (PEV) in Drosophila melanogaster. Together with Su(var)2-5 and Su(var)3-7, Su(var)3-9 belongs to the group of haplo-suppressor loci which show a triplo-dependent enhancer effect. All three genes encode heterochromatin-associated proteins. Su(var)3-9 is epistatic to the PEV modifier effects of Su(var)2-5 and Su(var)3-7, and it also dominates the effect of the Y chromosome on PEV. These genetic data support a central role of the SU(VAR)3-9 protein in heterochromatic gene silencing, one that is correlated with its activity as a histone H3-K9 methyltransferase (HMTase). In fact, SU(VAR)3-9 is the main chromocenter-specific HMTase of Drosophila. SU(VAR)3-9 and HP1, the product of Su(var)2-5, are main constituents of heterochromatin protein complexes and the interaction between these two proteins is interdependent. Functional analysis in fission yeast, Drosophila and mammals demonstrate that SU(VAR)3-9-dependent gene silencing processes are conserved in these organisms. This is also demonstrated by the rescue of Drosophila Su(var)3-9 mutant phenotypes with human SUV39H1 transgenes.