Quantitative evaluation of dermatological antiseptics.

Topical antiseptics are frequently used in dermatological management, yet evidence for the efficacy of traditional generic formulations is often largely anecdotal. We tested the in vitro bactericidal activity of four commonly used topical antiseptics against Staphylococcus aureus, using a modified version of the European Standard EN 1276, a quantitative suspension test for evaluation of the bactericidal activity of chemical disinfectants and antiseptics. To meet the standard for antiseptic effectiveness of EN 1276, at least a 5 log10 reduction in bacterial count within 5 minutes of exposure is required. While 1% benzalkonium chloride and 6% hydrogen peroxide both achieved a 5 log10 reduction in S. aureus count, neither 2% aqueous eosin nor 1 : 10 000 potassium permanganate showed significant bactericidal activity compared with control at exposure periods of up to 1 h. Aqueous eosin and potassium permanganate may have desirable astringent properties, but these results suggest they lack effective antiseptic activity, at least against S. aureus.

Cystic fibrosis.

There are now more adult than paediatric cystic fibrosis (CF) patients and their life expectancy continues to improve. This means that CF patients will be more commonly encountered in a variety of hospital settings including fertility services, gastrointestinal (GI) clinics, diabetes clinics, surgical wards, and acute admissions. Cystic fibrosis units welcome early contact when patients are admitted to other units and it is important to have a structured approach to their assessment and management.

Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation.

Terminally differentiated neutrophils are short-lived but the key effector cells of the innate immune response, and have a prominent role in the pathogenesis and propagation of many inflammatory diseases. Delayed apoptosis, which is responsible for their extended longevity, is critically dependent on a balance of intracellular survival versus pro-apoptotic proteins. Here, we elucidate the mechanism by which the cyclin-dependent kinase (CDK) inhibitor drugs such as R-roscovitine and DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) mediate neutrophil apoptosis. We demonstrate (by a combination of microarray, confocal microscopy, apoptosis assays and western blotting) that the phosphorylation of RNA polymerase II by CDKs 7 and 9 is inhibited by R-roscovitine and that specific effects on neutrophil transcriptional capacity are responsible for neutrophil apoptosis. Finally, we show that specific CDK7 and 9 inhibition with DRB drives resolution of neutrophil-dominant inflammation. Thus, we highlight a novel mechanism that controls both primary human neutrophil transcription and apoptosis that could be targeted by selective CDK inhibitor drugs to resolve established inflammation.

Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents.

The cyclin-dependent kinase inhibitor (CDKi) drugs such as R-roscovitine have emerged as potential anti-inflammatory, pharmacological agents that can influence the resolution of inflammation. Usually, once an inciting inflammatory stimulus has been eliminated, resolution proceeds by prompt, safe removal of dominant inflammatory cells. This is accomplished by programmed cell death (apoptosis) of prominent effector, inflammatory cells typified by the neutrophil. Apoptosis of neutrophils ensures that toxic neutrophil granule contents are securely packaged in apoptotic bodies and expedites phagocytosis by professional phagocytes such as macrophages. A panel of CDKi drugs have been shown to promote neutrophil apoptosis in a concentration- and time-dependent manner and the archetypal CDKi drug, R-roscovitine, overrides the anti-apoptotic effects of powerful survival factors [including lipopolysaccharide (LPS) and granulocyte macrophage-colony stimulating factor (GM-CSF)]. Inflammatory cell longevity and survival signalling is integral to the inflammatory process and any putative anti-inflammatory agent must unravel a complex web of redundancy in order to be effective. CDKi drugs have also been demonstrated to have significant effects on other cell types including lymphocytes and fibroblasts indicating that they may have pleiotropic anti-inflammatory, pro-resolution activity. In keeping with this, CDKi drugs like R-roscovitine have been reported to be efficacious in resolving established animal models of neutrophil-dominant and lymphocyte-driven inflammation. However, the mechanism of action behind these powerful effects has not yet been fully elucidated. CDKs play an integral role in the regulation of the cell cycle but are also recognized as participants in processes such as apoptosis and transcriptional regulation. Neutrophils have functional CDKs, are transcriptionally active and demonstrate augmented apoptosis in response to CDKi drugs, while lymphocyte proliferation and secretory function are inhibited. This review will discuss current understanding of the processes of inflammation and resolution but will focus on CDKis and their potential mechanisms of action.

Relevance of granulocyte apoptosis to resolution of inflammation at the respiratory mucosa.

The respiratory mucosa is responsible for gas exchange and is therefore, of necessity, exposed to airborne pathogens, allergens, and foreign particles. It has evolved a multi-faceted, physical and immune defense system to ensure that in the majority of instances, potentially injurious invaders are repelled. Inflammation, predominantly mediated by effector cells of the granulocyte lineage including neutrophils and eosinophils, is a form of immune defense. Where inflammation proves unable to remove an inciting stimulus, chronic inflammatory disease may supervene because of the potential for tissue damage conferred by the presence of large numbers of frustrated, activated granulocytes. Successful recovery from inflammatory disease and resolution of inflammation rely on the clearance of these cells. Ideally, they should undergo apoptosis prior to phagocytosis by macrophage, dendritic, or epithelial cells. The outcome of inflammation can have serious sequelae for the integrity of the respiratory mucosa leading to disease. Therapeutic strategies to drive resolution of inflammation may be directed at the induction of granulocyte apoptosis and the enhancement of granulocyte clearance.