ObjectiveThere is a paucity of research on patients presenting with uninfected diabetic foot ulcers (DFU) that go on to develop infection. We aimed to investigate the incidence and risk factors for developing infection in a large regional cohort of patients presenting with uninfected DFUs.MethodsWe performed a secondary analysis of data collected from a validated prospective state-wide clinical diabetic foot database in Queensland (Australia). Patients presenting for their first visit with an uninfected DFU to a Diabetic Foot Service in one of thirteen Queensland regions between January 2012 and December 2013 were included. Socio-demographic, medical history, foot disease history, DFU characteristics and treatment variables were captured at the first visit. Patients were followed until their DFU healed, or if their DFU did not heal for 12-months, to determine if they developed a foot infection in that period.ResultsOverall, 853 patients were included; mean(standard deviation) age 62.9(12.8) years, 68.0% male, 90.9% type 2 diabetes, 13.6% indigenous Australians. Foot infection developed in 342 patients for an overall incidence of 40.1%; 32.4% incidence in DFUs healed <3 months, 55.9% in DFUs healed between 3–12 months (p<0.05). Independent risk factors (Odds Ratio (95% confidence interval)) for developing infection were: DFUs healed between 3–12 months (2.3 (1.6–3.3)), deep DFUs (2.2 (1.2–3.9)), peripheral neuropathy (1.8 (1.1–2.9)), previous DFU history (1.7 (1.2–2.4)), foot deformity (1.4 (1.0–2.0)), female gender (1.5 (1.1–2.1)) and years of age (0.98 (0.97–0.99)) (all p<0.05).ConclusionsA considerable proportion of patients presenting with an uninfected DFU will develop an infection prior to healing. To prevent infection clinicians treating patients with uninfected DFUs should be particularly vigilant with those presenting with deep DFUs, previous DFU history, peripheral neuropathy, foot deformity, younger age, female gender and DFUs that have not healed by 3 months after presentation.

Extracellular vesicles (EVs) are mammalian cell-derived nano-scale structures enclosed by a lipid bilayer that were previously considered to be cell debris with little biological value. However, EVs are now recognized to possess biological function, acting as a packaging, transport and delivery mechanisms by which functional molecules (i.e., miRNAs) can be transferred to target cells over some distance. To examine the miRNA from keratinocyte-derived EVs, we isolated three distinct populations of EVs from both HaCaT and primary human keratinocytes (PKCs) and characterized their biophysical, biochemical and functional features by using microscopy, immunoblotting, nanoparticle tracking, and next generation sequencing. We identified 1,048; 906; and 704 miRNAs, respectively, in apoptotic bodies (APs), microvesicles (MVs) and exosomes (EXs) released from HaCaT, and 608; 506; and 622 miRNAs in APs, MVs and EXs released from PKCs. In which, there were 623 and 437 identified miRNAs common to three HaCaT-derived EVs and PKC-derived EVs, respectively. In addition, we found hundreds of exosomal miRNAs that were previously un-reported. Differences in the abundance levels of the identified EV miRNAs could discriminate between the three EV populations. These data contribute substantially to knowledge within the EV-identified miRNA database, especially with regard to keratinocyte-derived EV miRNA content.

Extracellular vesicles (EVs) are membrane-enclosed vesicles that are released into the extracellular environment by various cell types, which can be classified as apoptotic bodies, microvesicles and exosomes. EVs have been shown to carry DNA, small RNAs, proteins and membrane lipids which are derived from the parental cells. Recently, several studies have demonstrated that EVs can regulate many biological processes, such as cancer progression, the immune response, cell proliferation, cell migration and blood vessel tube formation. This regulation is achieved through the release and transport of EVs and the transfer of their parental cell-derived molecular cargo to recipient cells. This thereby influences various physiological and sometimes pathological functions within the target cells. While intensive investigation of EVs has focused on pathological processes, the involvement of EVs in normal wound healing is less clear; however, recent preliminarily investigations have produced some initial insights. This review will provide an overview of EVs and discuss the current literature regarding the role of EVs in wound healing, especially, their influence on coagulation, cell proliferation, migration, angiogenesis, collagen production and extracellular matrix remodelling.

Aging is associated with a vasoconstrictive, pro-coagulant, and pro-inflammatory profile of arteries and a decline in the bioavailability of the endothelium-derived molecule nitric oxide. Dietary nitrate elicits vasodilatory, anti-coagulant and anti-inflammatory effects in younger individuals, but little is known about whether these benefits are evident in older adults. We investigated the effects of 140 mL of nitrate-rich (HI-NI; containing 12.9 mmol nitrate) versus nitrate-depleted beetroot juice (LO-NI; containing ≤0.04 mmol nitrate) on blood pressure, blood coagulation, vascular inflammation markers, plasma nitrate and nitrite before, and 3 h and 6 h after ingestion in healthy older adults (five males, seven females, mean age: 64 years, age range: 57–71 years) in a randomized, placebo-controlled, crossover study. Plasma nitrate and nitrite increased 3 and 6 h after HI-NI ingestion (p < 0.05). Systolic, diastolic and mean arterial blood pressure decreased 3 h relative to baseline after HI-NI ingestion only (p < 0.05). The number of blood monocyte-platelet aggregates decreased 3 h after HI-NI intake (p < 0.05), indicating reduced platelet activation. The number of blood CD11b-expressing granulocytes decreased 3 h following HI-NI beetroot juice intake (p < 0.05), suggesting a shift toward an anti-adhesive granulocyte phenotype. Numbers of blood CD14++CD16+ intermediate monocyte subtypes slightly increased 6 h after HI-NI beetroot juice ingestion (p < 0.05), but the clinical implications of this response are currently unclear. These findings provide new evidence for the acute effects of nitrate-rich beetroot juice on circulating immune cells and platelets. Further long-term research is warranted to determine if these effects reduce the risk of developing hypertension and vascular inflammation with aging.

Aim No studies have investigated if national guidelines to manage diabetic foot disease differ from international guidelines. This study aimed to compare guidelines of Western Pacific nations with the International Working Group on the Diabetic Foot (IWGDF) guidance documents. Methods The 77 recommendations in five chapters of the 2015 IWGDF guidance documents were used as the international gold standard reference. The IWGDF national representative(s) from 12 Western Pacific nations were invited to submit their nation's diabetic foot guideline(s). Four investigators rated information in the national guidelines as “similar,” “partially similar,” “not similar,” or “different” when compared with IWGDF recommendations. National representative(s) reviewed findings. Disagreements in ratings were discussed until consensus agreement achieved. Results Eight of 12 nations (67%) responded: Australia, China, New Zealand, Taiwan, and Thailand provided national guidelines; Singapore provided the Association of Southeast Asian Nations guidelines; and Hong Kong and the Philippines advised no formal national diabetic foot guidelines existed. The six national guidelines included were 39% similar/partially similar, 58% not similar, and 2% different compared with the IWGDF recommendations. Within individual IWGDF chapters, the six national guidelines were similar/partially similar with 53% of recommendations for the IWGDF prevention chapter, 42% for wound healing, 40% for infection, 40% for peripheral artery disease, and 20% for offloading. Conclusions National diabetic foot disease guidelines from a large and diverse region of the world showed limited similarity to recommendations made by international guidelines. Differences between recommendations may contribute to differences in national diabetic foot disease outcomes and burdens.

Endoplasmic reticulum (ER)–plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below 40 nm and the membranes are connected by protein tethers. A number of molecular tools and technical approaches have been recently developed to visualise, modify and characterise properties of ER–PM junctions. The junctions serve as the platforms for lipid exchange between the organelles and for cell signalling, notably Ca2+ and cAMP signalling. Vice versa, signalling events regulate the development and properties of the junctions. Two Ca2+‐dependent mechanisms of de novo formation of ER–PM junctions have been recently described and characterised. The junction‐forming proteins and lipids are currently the focus of vigorous investigation. Junctions can be relatively short‐lived and simple structures, forming and dissolving on the time scale of a few minutes. However, complex, sophisticated and multifunctional ER–PM junctions, capable of attracting numerous protein residents and other cellular organelles, have been described in some cell types. The road from simplicity to complexity, i.e. the transformation from simple ‘nascent’ ER–PM junctions to advanced stable multiorganellar complexes, is likely to become an attractive research avenue for current and future junctologists. Another area of considerable research interest is the downstream cellular processes that can be activated by specific local signalling events in the ER–PM junctions. Studies of the cell physiology and indeed pathophysiology of ER–PM junctions have already produced some surprising discoveries, likely to expand with advances in our understanding of these remarkable organellar contact sites.

These findings delineate the expression of CDCP1 in human epidermal keratinocytes during epidermogenesis and demonstrate that CDCP1 is involved in keratinocyte migration.

No abstract