Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase

Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.     

Impedance methods (apparent mass, driving point mechanical impedance and absorbed power) for assessment of the biomechanical response of the seated person to whole-body vibration

Exposure to whole-body vibration is a risk factor for the development of low back pain. In order to develop a fuller understanding of the response of the seated person to vibration, experiments have been conducted in the laboratory investigating the biomechanics of the seated person. Some of these methods are based on the driving force and acceleration at the seat and are reported in the literature as apparent mass, driving point mechanical impedance or absorbed power. This paper introduces the background behind such impedance methods, the theory and application of the methods. It presents example data showing typical responses of the seated human to whole-body vibration in the vertical, fore-and-aft and lateral directions. It also highlights problems that researchers might encounter in performing, analysing and interpreting human impedance data.     

The preclotting of porous arterial prostheses.

A four-step preclotting method is presented for use with porous filamentous Dacron prostheses in the fully-heparinized patient. The method employs controlled fibrin formation within graft interstices, heparin neutralization of all thrombin remaining in the graft wall, and delay of systemic heparin neutralization until 15--20 minutes after clamp release. The resulting flow surface is impervious, smooth and hypothrombogenic. Experimental data are presented which support the rationale of this four-step preclotting method. Four years of clinical experience with the method are summarized, involving 300 prosthesis limbs used in aortic bifurcation, aortofemoral, femorofemoral, axillary-femoral and femoropopliteal positions in 192 patients. A clinical perspective of preclotting techniques is presented in which the proper use of this new method is suggested.     

Autofluorescence removal, multiplexing, and automated analysis methods for in-vivo fluorescence imaging

The ability to image and quantitate fluorescently labeled markers in vivo has generally been limited by autofluorescence of the tissue. Skin, in particular, has a strong autofluorescence signal, particularly when excited in the blue or green wavelengths. Fluorescence labels with emission wavelengths in the near-infrared are more amenable to deep-tissue imaging, because both scattering and autofluorescence are reduced as wavelengths are increased, but even in these spectral regions, autofluorescence can still limit sensitivity. Multispectral imaging (MSI), however, can remove the signal degradation caused by autofluorescence while adding enhanced multiplexing capabilities. While the availability of spectral "libraries" makes multispectral analysis routine for well-characterized samples, new software tools have been developed that greatly simplify the application of MSI to novel specimens.     

Do underarm cosmetics cause breast cancer?

Although animal and laboratory studies suggest a possible link between certain chemicals used in underarm cosmetics and breast cancer development, there is no reliable evidence that underarm cosmetics use increases breast cancer risk in humans. This article reviews the evidence for and against the possible link between breast cancer and underarm cosmetics and highlights the need for further research to clarify this issue.     

Single-enantiomer drugs: elegant science, disappointing effects

Most new drugs are marketed as single enantiomers but many older agents are still available in racemic form. As these drugs reach the end of their patent life manufacturers become interested in marketing single enantiomer equivalents. This is called 'chiral switching' and it has been claimed that it will bring clinical benefits in terms of improved efficacy, more predictable pharmacokinetics or reduced toxicity. We reviewed the clinical evidence and prices for three recently marketed single enantiomer versions of widely used racemic drugs: escitalopram, esomeprazole and levosalbutamol. Claims of increased efficacy were based on comparisons of non-equivalent doses and any advantages seemed small and clinically unimportant. Prices of esomeprazole and levosalbutamol were higher than their racemic alternatives and we predict that these prices will remain high despite the market presence of generic versions of the racemates. Patent protection and a perception of superiority based on promotion rather than evidence will maintain price premiums for single enantiomer drugs that are not justified on the basis of clinical performance.