Digoxin distribution between plasma and myocardium in hypoxic and non-hypoxic dogs

Summary The relationship between plasma and myocardial digoxin concentrations was investigated in hypoxic and nonhypoxic dogs. The results indicate that hypoxic dogs have lower plasma levels, higher myocardial levels, and an altered myocardial distribution when compared to non-hypoxic dogs.     

Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

FK506 binding proteins 12 and 12.6 (FKBP12 and FKBP12.6) are intracellular receptors for the immunosuppressant drug FK506 (ref. 1). The skeletal muscle ryanodine receptor (RyR1) is isolated as a hetero-oligomer with FKBP12 (ref. 2), whereas the cardiac ryanodine receptor (RyR2) more selectively associates with FKBP12.6 (refs 3, 4, 5). FKBP12 modulates Ca2+ release from the sarcoplasmic reticulum in skeletal muscle and developmental cardiac defects have been reported in FKBP12-deficient mice, but the role of FKBP12.6 in cardiac excitation-contraction coupling remains unclear. Here we show that disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy in male mice, but not in females. Female hearts are normal, despite the fact that male and female knockout mice display similar dysregulation of Ca2+ release, seen as increases in the amplitude and duration of Ca2+ sparks and calcium-induced calcium release gain. Female FKBP12.6-null mice treated with tamoxifen, an oestrogen receptor antagonist, develop cardiac hypertrophy similar to that of male mice. We conclude that FKBP12.6 modulates cardiac excitation-contraction coupling and that oestrogen plays a protective role in the hypertrophic response of the heart to Ca2+ dysregulation.     

The interaction of warfarin with antacid constituents in the gut

Summary A study was made of the effect of 4 constituents of antacid preparations on the absorption of the coumarin derivate warfarin sodium using an in vitro experimental model. The constituents tested were activated dimethicone (a silicone) magnesium trisilicate, bismuth carbonate and the adsorbant, kaolin. Slight decreased intestinal absorption was shown by magnesium trisilicate (19%) and bismuth carbonate (7%), the other 2 components showing no effects.     

Monoenergetic beams of relativistic electrons from intense laser-plasma interactions

High-power lasers that fit into a university-scale laboratory can now reach focused intensities of more than 10(19) W cm(-2) at high repetition rates. Such lasers are capable of producing beams of energetic electrons, protons and gamma-rays. Relativistic electrons are generated through the breaking of large-amplitude relativistic plasma waves created in the wake of the laser pulse as it propagates through a plasma, or through a direct interaction between the laser field and the electrons in the plasma. However, the electron beams produced from previous laser-plasma experiments have a large energy spread, limiting their use for potential applications. Here we report high-resolution energy measurements of the electron beams produced from intense laser-plasma interactions, showing that--under particular plasma conditions--it is possible to generate beams of relativistic electrons with low divergence and a small energy spread (less than three per cent). The monoenergetic features were observed in the electron energy spectrum for plasma densities just above a threshold required for breaking of the plasma wave. These features were observed consistently in the electron spectrum, although the energy of the beam was observed to vary from shot to shot. If the issue of energy reproducibility can be addressed, it should be possible to generate ultrashort monoenergetic electron bunches of tunable energy, holding great promise for the future development of 'table-top' particle accelerators.     

Identification of the cellular receptor for anthrax toxin.

The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.