Wound healing is a complex physiological process comprised of discrete but inter-related and overlapping stages, requiring exact timing and regulation to successfully progress, yet occurs spontaneously in response to injury. It is characterised by four phases, coagulation, inflammation, proliferation and remodelling. Each phase is predominated by particular cell types, cytokines and chemokines. The innate immune system represents the first line of defence against invading microorganisms. It is entirely encoded with the genome, and comprised of a cellular response with specificity provided by pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). TLRs are activated by exogenous microbial pathogen associated molecular patterns (PAMPs), initiating an immune response through the production of pro-inflammatory cytokines and further specialist immune cell recruitment. TLRs are also activated by endogenous molecular patterns termed damage associated molecular patterns (DAMPs). These ligands, usually shielded from the immune system, act as alarm signals alerting the immune system to damage and facilitate the normal wound healing process. TLRs are expressed by cells essential to wound healing such as keratinocytes and fibroblasts, however the specific role of TLRs in this process remains controversial. This article reviews the current knowledge on the potential role of TLRs in dermal wound healing where inflammation arising from pathogenic activation of these receptors appears to play a role in chronic ulceration associated with diabetes, scar hypertrophy and skin fibrosis.

The effect of hyperglycaemia on pro-inflammatory pattern recognition receptors in human cells, including fibroblasts has been demonstrated previously; however, this study is the first to combine diabetic conditions with ischaemia. This study offers a mechanism of pathological overexpression and activation of innate immune pattern recognition receptors such as Toll-like receptor 4, leading to hyperinflammatory responses, through exposure to hyperglycaemia. This excess inflammation leads to the rapidly progressive destructive acute, and subsequently chronic, inflammation leading to non-healing wounds that occur in diabetic patients often with coexisting ischaemia. It provides the first evidence of a synergistic relationship between hyperglycaemia and ischaemia and suggests a possible explanation for the observation that clinical outcomes are significantly worse in diabetic patients in other ischaemic pathologies. Objective: Diabetes mellitus has reached epidemic proportions. Foot ulceration is a multifactorial complication of diabetes associated with marked morbidity and mortality. Innate immune Toll-like receptor 4 (TLR4) mediated inflammation has been implicated in the systemic pathogenesis of diabetes and may contribute to impairment of wound healing. This study investigates the effect of high glucose and hypoxic conditions on TLR4 activation and signalling in vitro and in vivo. Methods: Fibroblasts cultured at physiological glucose concentration (5.5 mM) were exposed to glucose concentrations from 0 mM to 25 mM, with duplicates placed in a hypoxic chamber. TLR4 inhibition was assessed in the 25 mM glucose groups. Diabetes was induced in wild type (WT) and TLR4 knockout (KO) C57BL/6 mice by intraperitoneal injection of low dose streptozocin (STZ). Hindlimb ischaemia was induced by femoral artery ligation four weeks post streptozocin, and a full thickness 4 mm skin wound inflicted below the knee. Wound healing was assessed via digital planimetry on days 3, 7, and 14 post surgery. Results: Hypoxic and high glucose (25 mM) conditions led to an increase in TLR4 protein expression, apoptosis, and interleukin (IL)-6 release. Inhibition with a TLR4 neutralising antibody and specific TLR4 antagonist ameliorated the effects of high glucose and ischaemia (p < .05). In vivo, wound healing was significantly impaired in the diabetic ischaemic group at day 14 (p < .05). Diabetic ischaemic wounds in TLR4 KO mice exhibited significantly improved healing rates compared with those in WT mice at all time points. Conclusion: Hypoxia stimulates upregulation of TLR4 protein expression and this effect is exaggerated by hyperglycaemia. In TLR4 KO mice, there is a significant improvement in the healing of diabetic ischaemic wounds compared with WT. It is suggested that a synergistic effect between hypoxia and hyperglycaemia impairing wound healing exists, through TLR4 mediated inflammation.

Diabetic foot ulcers (DFUs) are complex, chronic, and progressive wounds, and have a significant impact on morbidity, mortality, and quality of life. A particular aspect of DFU that has not been reviewed extensively thus far is its management in conjunction with peripheral limb edema. Peripheral limb edema is a feature of diabetes that has been identified as a significant risk factor for amputation in patients with DFU. Three major etiological factors in development of lymphedema with concurrent DFU are diabetic microangiopathy, failure of autonomic regulation, and recurrent infection. This review outlines the pathophysiology of lymphedema formation in patients with DFU and highlights the cellular and immune components of impaired wound healing in lymphedematous DFU. We then discuss the principles of management of DFU in conjunction with lymphedema.

Appendicitis is one of the most common surgical emergencies, and is usually diagnosed clinically on point tenderness in the right iliac fossa. The diagnosis can be difficult if there is abnormal anatomy. This case looks into the presentation of appendicitis within an incisional hernia secondary to radical nephrectomy. Appendicitis may present within hernias, and there should be a low threshold for computed tomography assessment of hernias when there is clinical doubt about the symptoms associated with the hernia.

cells (transplantation of ApoeÀ/À aortas into CCL5À/À ApoeÀ/À mice). Conclusion:These results indicate that CCL5 expressed in cells of the vascular wall plays an important role in the recruitment of monocytes / macrophages to transplanted vessels and may thereby contribute to the development of atherosclerotic lesions after aortic transplantation.