Diabetic foot ulcers (DFU) are a common problem in longstanding diabetes. However, mortality outcomes in Australian patients with DFU are still unclear. All patients with DFU presenting for the first time to the Multi-Disciplinary Foot Clinic (MDFC) at Royal Darwin Hospital, Northern Territory Australia, between January 2003 and June 2015 were included in this study. These patients were followed until 2017, or death. Individual patient data was extracted from hospital and primary care information systems. Kaplan-Meier survival curves were developed. The association between various risk factors and mortality was analysed using Cox regression. In total 666 subjects were screened, and 513 were included in the final analysis. Of these subjects, 247 were Indigenous and 266 were non-Indigenous. The median follow-up period was 5.8 years (IQR, 3.1–9.8). The mean age at inclusion was 59.9 ± 12.3 years and 62.8% were males. The majority (93.6%) had type 2 diabetes and the median diabetes duration was 7 years (IQR, 3–12). There were 199 deaths, with a 5-year-mortality rate of 24.6%, and a 10-year-mortality rate of 45.4%. The mean age at death was 64.6 ± 11.8 years. In a multivariate analysis, the following variables were associated with mortality (adjusted HR, 95% CI): age 1.04 (1.02–1.05, P < 0.001); chronic kidney disease 1.22 (1.11–1.33, P < 0.001), and plasma albumin 0.96 (0.94–0.99, P < 0.05). The most common causes of death were chronic kidney disease (24.6%), cardiovascular events (19.6%), sepsis (15.6%), respiratory failure (10.0%), malignancy (9.5%) and multi-organ failure (5.0%). Patients with DFU have high mortality. Age, chronic kidney disease, and low albumin levels increase the risk of mortality. Strategies should focus on ulcer prevention and aggressive risk factor reduction.

Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role in this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution with CD4⁺ T cells from BALB/c mice. Twelve days after CD4⁺ T cell reconstitution, purified macrophages (depleted of T cells) were isolated from CD4⁺ T cell-reconstituted FPP recipient mice and adoptively transferred to their nonreconstituted counterparts. After adoptive macrophage transfer, FPP recipient mice transferred with macrophages from CD4⁺ T cell-reconstituted mice demonstrated xenograft destruction along with massive macrophage infiltration at day 4 and complete graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients that received macrophages from nonreconstituted mice showed intact FPP xenografts with few infiltrating macrophages at both days 4 and 8 after macrophage transfer. The graft-infiltrating macrophages showed increased expression of their activation markers. Depletion of endogenous macrophages or any remaining CD4⁺ T cells did not delay graft rejection in the macrophage-transferred FPP recipients, whereas depletion of transferred macrophages with clodronate liposomes prevented graft rejection. Our results show that macrophages primed by FPP and activated by CD4⁺ T cells were attracted from the peripheral circulation and were capable of specific targeting and destruction of FPP xenografts. This suggests that in xenograft rejection, there are macrophage-specific recognition and targeting signals that are independent of those received by T cells.

Primary nonfunction of transplanted islets results in part from their sensitivity to reactive oxygen species (ROS) generated during the isolation and transplantation process. Our aim was to examine whether coexpression of antioxidant enzymes to detoxify multiple ROS increased the resistance of mouse islets to oxidative stress and improved the initial function of islet grafts. Islets from transgenic mice expressing combinations of human copper/zinc superoxide dismutase (SOD), extracellular SOD, and cellular glutathione peroxidase (Gpx-1) were subjected to oxidative stress in vitro. Relative viability after hypoxanthine/xanthine oxidase treatment was as follows: extracellular SOD + Gpx-1 + Cu/Zn SOD > extracellular SOD + Gpx-1 > extracellular SOD > wild type. Expression of all three enzymes was the only combination protective against hypoxia/reoxygenation. Islets from transgenic or control wild-type mice were then transplanted into streptozotocin-induced diabetic recipients in a syngeneic marginal islet mass model, and blood glucose levels were monitored for 7 days. In contrast to single- and double-transgenic grafts, triple-transgenic grafts significantly improved control of blood glucose compared with wild type. Our results indicate that coexpression of antioxidant enzymes has a complementary beneficial effect and may be a useful approach to reduce primary nonfunction of islet grafts.

Background and aims: En bloc resection is preferred for colonic laterally spreading tumors, but is limited to 20 mm with endoscopic mucosal resection (EMR) using normal saline submucosal injection. Our aims were to compare the efficacy and safety of circumferential submucosal incision prior to EMR (CSI-EMR) versus conventional EMR for en bloc resection of artificial lesions 40 × 40 mm in size using submucosal injection of succinylated gelatin in a porcine colon model. Subjects and methods: Two areas of normal rectosigmoid mucosa measuring 40 × 40 mm were marked with soft coagulation for en bloc resection in each of 10 pigs. By alternate allocation, one was removed with conventional snare-based EMR following submucosal injection of succinylated gelatin. The other was circumferentially incised using an insulated-tip knife, followed by submucosal succinylated gelatin injection followed by EMR of the isolated area. All procedures were performed by a single endoscopist with significant experience of EMR but none of endoscopic submucosal dissection (ESD). Euthanasia and colectomy were performed on day 10. Specimens and ex vivo colon resection sites were examined by a specialist gastrointestinal histopathologist blinded to the technique used. Results: En bloc excision rates were 70 % for CSI-EMR vs. 0 % for conventional EMR (p = 0.016). The median number of resections was 1 (interquartile range, IQR: 1 – 2) for CSI-EMR vs. 4 (3 – 6) for EMR (p < 0.001). Mean specimen dimensions were 50 × 43 mm for CSI-EMR vs. 37 × 32 mm for EMR (p = 0.001). Overall procedure duration (mean ± SD) was 30.3 ± 19.8 minutes for CSI-EMR vs. 12.4 ± 6.8 minutes (p = 0.003) for EMR. The mean duration of the final 5 CSI-EMRs was 17 minutes, with a statistically significant learning effect r = –0.7, p = 0.025. No perforations or bleeding occurred. All animals were euthanased on day 10. Histologically, CSI-EMR resulted in larger specimens and deeper submucosal resections. Conclusions: CSI-EMR with submucosal injection of succinylated gelatin is safe and superior to conventional EMR, consistently resulting in en bloc resections larger than 50 × 40 mm. With experience, total procedure duration is comparable.