The combination of increased concentrations of MMPs with decreased concentrations of TIMP-2 in chronic diabetic foot ulcers compared with healing wounds in normal patients suggests that the increased proteolytic environment contributes to the failure of diabetic wounds to heal. New treatment strategies for healing chronic diabetic foot ulcers could be directed towards reducing concentrations of MMPs and increasing levels of TIMPs.

Diabetic foot ulceration is a serious complication of diabetes mellitus worldwide and the most common cause of hospitalization in diabetic patients. The etiology of diabetic foot ulcerations is complex due to their multifactorial nature; in the pathophysiology of diabetic foot ulceration polyneuropathy is important. Proper adherence to standard treatment strategies and interdisciplinary cooperation can reduce the still high rates of major amputations.

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During early wound healing (WH) events Connexin 43 (Cx43) is down-regulated at wound margins. In chronic wound margins, including diabetic wounds, Cx43 expression is enhanced suggesting that down-regulation is important for WH. We previously reported that the Cx43 mimetic peptide Gap27 blocks Cx43 mediated intercellular communication and promotes skin cell migration of infant cells in vitro. In the present work we further investigated the molecular mechanism of Gap27 action and its therapeutic potential to improve WH in skin tissue and diabetic and non-diabetic cells. Ex vivo skin, organotypic models and human keratinocytes/fibroblasts of young and old donors and of diabetic and non-diabetic origin were used to assess the impact of Gap27 on cell migration, proliferation, Cx43 expression, localization, phosphorylation and hemichannel function. Exposure of ex vivo WH models to Gap27 decreased dye spread, accelerated WH and elevated cell proliferation. In non-diabetic cell cultures Gap27 decreased dye uptake through Cx hemichannels and after scratch wounding cells showed enhanced migration and proliferation. Cells of diabetic origin were less susceptible to Gap27 during early passages. In late passages these cells showed responses comparable to non-diabetic cells. The cause of the discrepancy between diabetic and non-diabetic cells correlated with decreased Cx hemichannel activity in diabetic cells but excluded differences in Cx43 expression, localization and Ser368-phosphorylation. These data emphasize the importance of Cx43 in WH and support the concept that Gap27 could be a beneficial therapeutic to accelerate normal WH. However, its use in diabetic WH may be restricted and our results highlight differences in the role of Cx43 in skin cells of different origin.

The authors report no conflicts of interest in this work.

Clinicians are in need of better diagnostic markers for rapid diagnosis of severe infections. Therefore, we studied the diagnostic significance of mean cell volume of neutrophils (MNV) and monocytes (MMV) compared with Interleukin-6 (IL-6), C-reactive protein (CRP) and white blood cell count for predicting systemic clinical infection (sepsis). MNV and MMV were obtained by volume conductivity scatter (VCS) technique of the Coulter LH 750 hematology analyzer during automated differential counts, and blood samples from patients with sepsis (n = 37), nonsystemic bacterial infections (n = 39) and controls (n = 48) were studied. We observed a significant increase in MNV and MMV in the sepsis group compared with limited infections and controls. However, at a designated cut-off point of 250 pg/ml, IL-6 seemed to be the best predictor for sepsis with a sensitivity of 93% and a specificity of 76%. Compared with CRP (cut-off point 60 mg/dl), MNV at a cut-off of 150 had a comparable sensitivity and specificity and was the most predictive VCS parameter. Taken together, MNV and MMV seemed to be potential parameters to discriminate between sepsis and nonsystemic infections.

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