Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP

AIMS/HYPOTHESIS: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As monocytes may contribute to the excessive inflammatory responses in such wounds, this study focussed on the effects of maggot secretions on the pro-inflammatory activities of these cells. METHODS: Freshly isolated monocytes were incubated with a range of secretions for 1 h and then stimulated with lipopolysaccharides (range 0-100 ng/ml) or lipoteichoic acid (range 0-5 microg/ml) for 18 h. The expression of cell surface molecules, cytokine and chemokine levels in culture supernatants, cell viability, chemotaxis, and phagocytosis and killing of Staphylococcus aureus were measured. RESULTS: Maggot secretions dose-dependently inhibited production of the pro-inflammatory cytokines TNF-alpha, IL-12p40 and macrophage migration inhibitory factor by lipopolysaccharides- and lipoteichoic acid-stimulated monocytes, while enhancing production of the anti-inflammatory cytokine IL-10. Expression of cell surface receptors involved in pathogen recognition remained unaffected by secretions. In addition, maggot secretions altered the chemokine profile of monocytes by downregulating macrophage inflammatory protein-1beta and upregulating monocyte chemoattractant protein-1 and IL-8. Nevertheless, chemotactic responses of monocytes were inhibited by secretions. Furthermore, maggot secretions did not affect phagocytosis and intracellular killing of S. aureus by human monocytes. Finally, secretions induced a transient rise in the intracellular cyclic AMP concentration in monocytes and Rp-cyclic AMPS inhibited the effects of secretions. CONCLUSIONS/INTERPRETATION: Maggot secretions inhibit the pro-inflammatory responses of human monocytes through a cyclic AMP-dependent mechanism. Regulation of the inflammatory processes by maggots contributes to their beneficial effects on chronic wound

A comparison of customised and prefabricated insoles to reduce risk factors for neuropathic diabetic foot ulceration: a participant-blinded randomised controlled trial.

UNLABELLED: BACKGROUND: Neuropathic diabetic foot ulceration may be prevented if the mechanical stress transmitted to the plantar tissues is reduced. Insole therapy is one practical method commonly used to reduce plantar loads and ulceration risk. The type of insole best suited to achieve this is unknown. This trial compared custom-made functional insoles with prefabricated insoles to reduce risk factors for ulceration of neuropathic diabetic feet. METHOD: A participant-blinded randomised controlled trial recruited 119 neuropathic participants with diabetes who were randomly allocated to custom-made functional or prefabricated insoles. Data were collected at issue and six month follow-up using the F-scan in-shoe pressure measurement system. Primary outcomes were: peak pressure, forefoot pressure time integral, total contact area, forefoot rate of load, duration of load as a percentage of stance. Secondary outcomes were patient perceived foot health (Bristol Foot Score), quality of life (Audit of Diabetes Dependent Quality of Life). We also assessed cost of supply and fitting. Analysis was by intention-to-treat. RESULTS: There were no differences between insoles in peak pressure, or three of the other four kinetic measures. The custom-made functional insole was slightly more effective than the prefabricated insole in reducing forefoot pressure time integral at issue (27% vs. 22%), remained more effective at six month follow-up (30% vs. 24%, p=0.001), but was more expensive (UK £656 vs. £554, p<0.001). Full compliance (minimum wear 7 hours a day 7 days per week) was reported by 40% of participants and 76% of participants reported a minimum wear of 5 hours a day 5 days per week. There was no difference in patient perception between insoles. CONCLUSION: The custom-made insoles are more expensive than prefabricated insoles evaluated in this trial and no better in reducing peak pressure. We recommend that where clinically appropriate, the more cost effective prefabricated insole should be considered for use by patients with diabetes and neuropathy. TRIAL REGISTRATION: Clinical trials.gov (NCT00999635). Note: this trial was registered on completion

Effects of Hydrogen Peroxide on Wound Healing in Mice in Relation to Oxidative Damage

10.1371/journal.pone.0049215PLoS ONE711

Influenza virus infection of newborn rats: Virulence of recombinant strains prepared from a cold-adapted, attenuated parent

Infant rats were infected with one of a series of influenza A viruses. The growth of viruses in the turbinates or lungs, and the ability of virus infection to potentiate a subsequent bacterial infection by Haemophilus influenzae (HIb), were measured. The three virus strains known to be virulent for man grew to relatively high titres-of 10 5.0 –10 6.8 EBID 50 /ml in the turbinates of infant rats at 48 hours post-infection, and virus infection enhanced subsequent systemic infection following intranasal inoculation of rats with HIb. In contrast, influenza virus A/Ann Arbor/6/60—P17 and the three recombinant viruses prepared from this strain, all of which are attenuated for man, replicated to significantly lower titres of 10 2.6 –10 4.1 EBID 50 /ml in infant rats turbinates, and failed to promote systemic infection by HIb to the same degree. The results, together with those of previous studies, suggest that the behaviour of influenza viruses in infant rats may be an indication for virus virulence for man, and thus provide a test which could facilitate the development of live, attenuated virus vaccines.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41687/1/705_2005_Article_BF01318055.pd

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.status: publishe