NOS1AP genetic variation is associated with impaired healing of diabetic foot ulcers and diminished response to healing of circulating stem/progenitor cells.

It is unclear why many with diabetes develop foot ulcers (DFU) and why some do not heal. It could be associated with genetic variation. We have previously shown that NOS1AP variation is associated with lower extremity amputation in those with diabetes and that circulating stem progenitor cell concentration (SPC) is associated with impaired foot ulcer healing in those with diabetes. The goal of this study was to determine if NOS1AP variation is associated with impaired wound healing and with SPC mobilization in those with DFU. In longitudinal cohort study we demonstrate that NOS1AP variants rs16849113 and rs19649113 are associated with impaired wound healing and with SPC mobilization in those with DFU. We believe that further study of NOS1AP is merited and that it NOS1AP might be associated with a functional impairment.

Vasculogenic stem cell mobilization and wound recruitment in diabetic patients: increased cell number and intracellular regulatory protein content associated with hyperbaric oxygen therapy.

Diabetic patients undergoing hyperbaric oxygen therapies (HBO(2)T) for refractory lower extremity neuropathic ulcers exhibit more than a twofold elevation (p=0.004) in circulating stem cells after treatments and the post-HBO(2)T CD34(+) cell population contains two- to threefold higher levels of hypoxia inducible factors-1, -2, and -3, as well as thioredoxin-1 (p<0.003), than cells present in blood before HBO(2)T. Skin margins obtained from 2-day-old abdominal wounds exhibit higher expression of CD133, CD34, hypoxia inducible factor-1, and Trx-1 vs. margins from refractory lower extremity wounds and expression of these proteins in all wounds is increased due to HBO(2)T (p<0.003). HBO(2)T is known to mobilize bone marrow stem cells by stimulating nitric oxide synthase. We found that nitric oxide synthase activity is acutely increased in patients' platelets following HBO(2)T and remains elevated for at least 20 hours. We conclude that HBO(2) T stimulates vasculogenic stem cell mobilization from bone marrow of diabetics and more cells are recruited to skin wounds.

Prediction of Limb Salvage Following Percutaneous Vascular Intervention Using a Composite Tibial Artery Perfusion Score.

PURPOSE: To assess a novel tibial artery perfusion score (TPS) for predicting limb salvage in critical limb ischemia (CLI) patients undergoing percutaneous vascular intervention (PVI). PATIENTS AND METHODS: A consecutive cohort of 115 CLI patients undergoing PVI in 144 limbs from 2011 to 2016 was analyzed. TPS comprised a 27-point scale based on: (1) patent tibial vessels following PVI, (2) severity of calcification of the tibial arteries, (3) presence of an intact pedal arch following intervention, (4) whether or not revascularization was direct or indirect based on the target angiosome, (5) presence of angiosome blush at the completion of index intervention. Limbs were stratified into (1) High [21-27 points], (2) Medium [13-20 points], and (3) Low [0-12 points] TPS. Predictive value of TPS was evaluated using logistic regression and Cox proportional hazards models. RESULTS: The median follow-up was 15.7 months (range 0.4-69.9 months). Limb salvage in High, Medium, and Low TPS groups was 90.6%, 85.9%, and 55.6%, respectively, as freedom from the composite outcome: (1) limb complication resulting in death, (2) tibial bypass surgery, (3) above-the-knee amputation, or (4) below-the-knee amputation in patients without supratibial disease at the time of PVI. TPS was significantly associated with limb salvage defined as freedom from both the composite outcome and major amputation. CONCLUSIONS: Based on this preliminary investigation, TPS was associated with limb salvage in CLI limbs, particularly in high-risk limbs. Further validation in a prospective cohort may identify patients with high-risk limbs in need of closer surveillance and earlier reintervention. LEVEL OF EVIDENCE: Level IV, case series.

Measurements of CD34+/CD45-dim Stem Cells Predict Healing of Diabetic Neuropathic Wounds.

Management of neuropathic foot ulcers in patients with diabetes (DFUs) has changed little over the past decade, and there is currently no objective method to gauge probability of successful healing. We hypothesized that studies of stem/progenitor cells (SPCs) in the early weeks of standard wound management could predict who will heal within 16 weeks. Blood and debrided wound margins were collected for 8 weeks from 100 patients undergoing weekly evaluations and treatment. SPC number and intracellular content of hypoxia-inducible factors (HIFs) were evaluated by flow cytometry and immunohistochemistry. More SPCs entered the bloodstream in the first 2 weeks of care in patients who healed (n = 37) than in those who did not (n = 63). Logistic regression demonstrated that the number of blood-borne SPCs and the cellular content of HIFs at study entry and the first-week follow-up visit predicted healing. Strong correlations were found among week-to-week assessments of blood-borne SPC HIF factors. We conclude that assays of SPCs during the first weeks of care in patients with DFUs can provide insight into how well wounds will respond and may aid with decisions on the use of adjunctive measures.