Tumor necrosis factor-α in cisplatin nephrotoxicity: A homebred foe?

A robust inflammatory response involving tumor necrosis factor-α (TNFα) is induced during cisplatin nephrotoxicity. Using chimeric models, Reeves and colleagues now demonstrate that resident kidney cells, rather than infiltrating immune cells, are the major producers of TNF-α. Blockade of TNFα attenuates inflammation and associated kidney injury

Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins

Kinesins are a superfamily of microtubule-based ATP-powered motors, important for multiple, essential cellular functions. How microtubule binding stimulates their ATPase and controls force generation is not understood. To address this fundamental question, we visualized microtubule-bound kinesin-1 and kinesin-3 motor domains at multiple steps in their ATPase cycles - including their nucleotide-free states - at ~7Å resolution using cryo-electron microscopy. In both motors, microtubule binding promotes ordered conformations of conserved loops that stimulate ADP release, enhance microtubule affinity and prime the catalytic site for ATP binding. ATP binding causes only small shifts of these nucleotide-coordinating loops but induces large conformational changes elsewhere that allow force generation and neck linker docking towards the microtubule plus end. Family-specific differences across the kinesin-microtubule interface account for the distinctive properties of each motor. Our data thus provide evidence for a conserved ATP-driven mechanism for kinesins and reveal the critical mechanistic contribution of the microtubule interface

Adsorption of viruses on magnetic particles-II. Degradation of MS2 bacteriophage by adsorption to magnetite

The adsorption by magnetite of MS2 bacteriophage from 100 mg 1-1 NaCl solutions was studied using MS2 bacteriophage labelled with 32P in the RNA and 3H in the protein. After agitation for 20 min, the supernatant from suspensions of finely-divided magnetite and MS2 phage in 100 mg 1-1 NaCl, was assayed for remaining infective particles. Phage adsorption to magnetite was shown to occur over the range pH 4-7.5. At phH 6, 99.99% of the MS2 particles were removed from the supernatant and 32P and 3H were associated with the magnetite. When this magnetite was resuspended in 100 mg 1-1 NaCl at pH 10. 32P and 3H was released into the supernatant, although infectious MS2 particles could not be detected. Extracted, purified MS2 RNA labelled with 32P and MS2 protein labelled with 3H were used to study the adsorption and release of the virus components. Both the RNA and protein were bound at pH 6. When the pH was raised to 10, all 32P and 96% of the 3H was released into the supernatant. It is concluded that virus adsorbed to magnetite is disrupted at pH 10, and its components released into the medium. The free virus retains its infectivity at pH 10

Elemental diet for refractory atopic eczema.

A total of 37 children with refractory wide-spread atopic eczema were treated with an antigen avoidance regimen comprising hospitalisation, exclusive feeding with an elemental formula for a median duration of 30 days, and measures to reduce exposure to pet and dust mite antigens at home. After the initial period of food exclusion, food challenges were performed at intervals of seven days, and the patients followed up for at least 12 months. Ten of the children (27%) either failed to respond to the regimen or relapsed within 12 months. Improvement in the eczema was seen in 27/37 (73%) patients, by discharge from hospital their disease severity score had fallen to a median of 27% of the pretreatment figure, and only 3/27 required topical corticosteroids. There were no clinical or laboratory findings which could be used to predict the outcome. Drawbacks to the regimen were prolonged hospitalisation (median 70 days), a fall in body weight and serum albumin concentration, and a risk of anaphylactic shock (4/37 cases). A strict antigen avoidance regimen may be associated with improvement of atopic eczema where conventional treatments have failed

Diastolic ventricular interaction in chronic heart failure: Relation to heart rate variability and neurohumoral status

It is likely that abnormal baroreflex control mechanisms are at least partially responsible for autonomic dysfunction in chronic heart failure. We recently demonstrated that diastolic ventricular interaction is associated with impaired baroreflex control of vascular resistance in heart failure. We reasoned that by constraining left ventricular filling, such interaction would decrease baroreflex activity and, thereby, increase sympathetic and decrease parasympathetic outflow. We hypothesized, therefore, that diastolic ventricular interaction in chronic heart failure patients would be associated with autonomic dysfunction