Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers.

BACKGROUND: Cell therapy with autologous peripheral blood mononuclear cells (PB-MNCs) may help restore limb perfusion in patients with diabetes mellitus and critical limb-threatening ischemia (CLTI) deemed not eligible for revascularization procedures and consequently at risk for major amputation (no-option). Fundamental is to establish its clinical value and to identify candidates with a greater benefit over time. Assessing the frequency of PB circulating angiogenic cells and extracellular vesicles (EVs) may help in guiding candidate selection. METHODS: We conducted a prospective, non-controlled, observational study on no-option CLTI diabetic patients that underwent intramuscular PB-MNCs therapy, which consisted of more cell treatments repeated a maximum of three times. The primary endpoint was amputation rate at 1 year following the first treatment with PB-MNCs. We evaluated ulcer healing, walking capability, and mortality during the follow-up period. We assessed angiogenic cells and EVs at baseline and after each cell treatment, according to primary outcome and tissue perfusion at the last treatment [measured as transcutaneous oxygen pressure (TcPO2)]. RESULTS: 50 patients were consecutively enrolled and the primary endpoint was 16%. TcPO2 increased after PB-MNCs therapy (17.2 ± 11.6 vs 39.1 ± 21.8 mmHg, p < .0001), and ulcers healed with back-to-walk were observed in 60% of the study population (88% of survivors) during follow-up (median 1.5 years). Patients with a high level of TcPO2 (≥ 40 mmHg) after the last treatment showed a high frequency of small EVs at enrollment. CONCLUSIONS: In no-option CLTI diabetic patients, PB-MNCs therapy led to an improvement in tissue perfusion, a high rate of healing, and back-to-walk. Coupling circulating cellular markers of angiogenesis could help in the identification of patients with a better clinical benefit over time.

Dimethyl-2-oxoglutarate improves redox balance and mitochondrial function in muscle pericytes of individuals with diabetes mellitus.

AIMS/HYPOTHESIS: Treatment of vascular complications of diabetes remains inadequate. We reported that muscle pericytes (MPs) from limb muscles of vascular patients with diabetes mellitus display elevated levels of oxidative stress causing a dysfunctional phenotype. Here, we investigated whether treatment with dimethyl-2-oxoglutarate (DM-2OG), a tricarboxylic acid cycle metabolite with antioxidant properties, can restore a healthy metabolic and functional phenotype. METHODS: MPs were isolated from limb muscles of diabetes patients with vascular disease (D-MPs) and from non-diabetic control participants (ND-MPs). Metabolic status was assessed in untreated and DM-2OG-treated (1 mmol/l) cells using an extracellular flux analyser and anion-exchange chromatography-mass spectrometry (IC-MS/MS). Redox status was measured using commercial kits and IC-MS/MS, with antioxidant and metabolic enzyme expression assessed by quantitative RT-PCR and western blotting. Myogenic differentiation and proliferation and pericyte-endothelial interaction were assessed as functional readouts. RESULTS: D-MPs showed mitochondrial dysfunction, suppressed glycolytic activity and reduced reactive oxygen species-buffering capacity, but no suppression of antioxidant systems when compared with ND-MP controls. DM-2OG supplementation improved redox balance and mitochondrial function, without affecting glycolysis or antioxidant systems. Nonetheless, this was not enough for treated D-MPs to regain the level of proliferation and myogenic differentiation of ND-MPs. Interestingly, DM-2OG exerted a positive effect on pericyte-endothelial cell interaction in the co-culture angiogenesis assay, independent of the diabetic status. CONCLUSIONS/INTERPRETATION: These novel findings support the concept of using DM-2OG supplementation to improve pericyte redox balance and mitochondrial function, while concurrently allowing for enhanced pericyte-endothelial crosstalk. Such effects may help to prevent or slow down vasculopathy in skeletal muscles of people with diabetes. Graphical abstract.

Square, Random Fasciocutaneous Plantar Flaps for Treating Noninfected Diabetic Plantar Ulcers: A Patient Series.

In patients with diabetes, the off-loading cast has not been widely used to treat plantar ulcers because of its poor acceptance by patients and the high risk of side effects. We evaluated the safety and efficacy of an alternative surgical treatment: a square, fasciocutaneous random plantar flap to cover plantar ulcers. From December 2012 to February 2013, we enrolled 23 consecutive diabetic patients with deep neuropathic or neuroischemic plantar ulcers. Of these 23 patients, 9 underwent percutaneous transluminal angioplasty, 10 had the metatarsal removed, 3 underwent dorsiflexory, distal metatarsal osteotomies, 2 underwent first metatarsophalangeal joint resection and ray stabilization with Kirschner wires, and 1 each underwent midfoot exostectomy, sesamoidectomy, and partial calcanectomy. A square random fasciocutaneous plantar flap was created for all 23 patients. Two patients were excluded from the analysis for weightbearing on the involved foot within 24 hours of surgery. The healing rate was 100% for the remaining 21 patients, with healing by first intention in 15 (mean ± standard deviation time to healing 30 ± 13 days), by second intention in 5 (86 ± 40 days), and by surgical revision in 1. The overall mean healing time was 44 ± 31 days. During a mean follow-up of 724 ± 275 days, no ulcer recurred; however, 1 transfer ulcer appeared on an adjacent metatarsal head. The use of a square random fasciocutaneous plantar flap is a safe and effective surgical option for treating neuropathic plantar ulcers, offering a high healing rate, a short healing time, and a low rate of recurrence.

How complicated skin and soft tissue infections are treated in Italy: economic evaluation of inpatient intravenous antibiotic treatment in seven hospitals.

OBJECTIVES: Complicated skin and soft tissue infections (cSSTIs) are a common cause of morbidity at hospital level. This study aimed to evaluate the costs and outcomes of inpatient intravenous antibiotic therapy for the treatment of cSSTI in seven Italian hospitals. METHODS: A total of 307 patients were enrolled in a retrospective, multicentre, incidence-based, observational study. The target population consisted of hospitalised patients eligible to receive intravenous antibiotic therapy for cSSTI. Direct hospital costs were measured through a microcosting approach. RESULTS: Failure of initial antibiotic therapy occurred in 23% of patients. Average antibiotic treatment lasted 12.2 days; the average full cost of admission totalled euro5,530. If the initial antibiotic regimen fails to eradicate the infectious organism, the length of stay extends for 7 days and costs increase by euro2,850 per patient. Nevertheless, when taking into account the lower intensity of care during the last days of treatment, savings reduce costs to euro671 per patient. These could be increased by euro74 for each hospital day avoided because of faster antibiotic action. CONCLUSIONS: Efforts should be made to minimise the risk of selecting wrong antibiotics and to identify the quickest antibiotic in eradicating the infection.