Valeria Ruotolo

Proinflammatory modulation of the surface and cytokine phenotype of monocytes in patients with acute Charcot foot.

OBJECTIVE Despite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed. RESEARCH DESIGN AND METHODS The immune phenotype of peripheral monocytes was studied by fluorescence-activated cell sorter analysis comparing patients with acute Charcot (n = 10) in both the active and recovered phase, diabetic patients with neuropathy (with or without osteomyelitis), and normal control subjects. RESULTS When compared with diabetic control subjects and healthy subjects, monocytes from acute Charcot patients showed a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of surface costimulatory molecules, and increased resistance to serum withdrawal-induced apoptosis. In addition, the pattern of circulating cytokines confirmed activation of proinflammatory cytokines. No modulation of the monocyte phenotype was documented in diabetic control subjects and healthy subjects, thus indicating that the proinflammatory alterations of monocytes are specific and causative of acute Charcot. CONCLUSIONS Together, these data provide evidence for the role of proinflammatory changes in the immune phenotype of monocytes in the pathogenesis of acute Charcot. These alterations may explain the abnormally intense and prolonged inflammatory response that characterizes this disorder and may represent a potential therapeutic target for specific pharmacological interventions.

Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up

This study evaluated the efficacy and tolerability of an autologous tissue-engineered graft—a 2-step HYAFF autograft—in the treatment of diabetic foot ulcers compared with standard care. In all, 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for ≥1 month) were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). Efficacy and adverse events were assessed weekly for 12 weeks, at 20 weeks, and at 18 months. The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. At 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group (mean 40 vs 50 days; P = .018). Weekly percentage ulcer reduction was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treated group as compared with 43% of controls. Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers ( P = .035). Adverse events were similar in both groups. The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers.

non-Healing foot ulCers in diabetiC patients: general and loCal interfering Conditions and management options WitH advanCed Wound dressings

Medical knowledge about wound management has improved as recent studies have investigated the healing process and its biochemical background. Despite this, foot ulcers remain an important clinical problem, often resulting in costly, prolonged treatment. A non-healing ulcer is also a strong risk factor for major amputation. Many factors can interfere with wound healing, including the patients general health status (i.e., nutritional condition indicated by albumin levels) or drugs such as steroids that can interfere with normal healing. Diabetic complications (i.e., renal insufficiency) may delay healing and account for higher amputation rates observed in diabetic patients under dialysis treatment. Wound environment (e.g., presence of neuropathy, ischaemia, and infection) may significantly influence healing by interfering with the physiological healing cascade and adding local release of factors that may worsen the wound. The timely and well-orchestrated release of factors regulating the healing process, observed in acute wounds, is impaired in non-healing wounds that are blocked in a chronic inflammatory phase without progressing to healing. This chronic phase is characterised by elevated protease activity (EPA) of metalloproteinases (MMPs) and serine proteases (e.g., human neutrophil elastase) that interfere with collagen synthesis, as well as growth factor release and action. EPA (mainly MMP 9, MMP-8 and elastase) and inflammatory factors present in the wound bed (such as IL-1, IL-6, and TNFa) account for the catabolic state of non-healing ulcers. The availability of wound dressings that modulate EPA has added new therapeutic options for treating non-healing ulcers. The literature confirms advantages obtained by reducing protease activity in the wound bed, with better outcomes achieved by using these dressings compared with traditional ones. New technologies also allow a physician to know the status of the wound bed environment, particularly EPA, in a clinical setting. These may be helpful in guiding a clinicians options in treating very difficult-to-heal ulcers.

A new natural history of Charcot foot: clinical evolution and final outcome of stage 0 Charcot neuroarthropathy in a tertiary referral diabetic foot clinic.

Purpose The purpose of this study is to describe the usefulness of 18F-FDG PET/CT scanning in the diagnosis and follow-up of stage 0 Charcot foot (CNO) and CNO outcomes when therapeutic options are driven by this image modality. Patients and Methods We selected 25 out of 40 diabetic patients with an acute CNO, without any bone involvement at x-ray (stage 0 CNO). Diagnostic criteria were inflammatory clinical signs of the affected foot and skin temperature difference greater than 2°C compared with the contralateral foot (&Dgr;T). All patients underwent x-ray, MRI, and 18F-FDG PET/CT scanning (expressed as standardized uptake value, SUVmax) at baseline (T0). All patients underwent another 18F-FDG PET/CT within 1 month after &Dgr;T was less than 2°C [clinical recovery (T1)] and again every 3 months until SUVmax was less than 2 [final recovery (T2)]; at this time, MRI confirmed the end of the inflammatory condition. Results T0 &Dgr;T was 3.04 ± 1.65°C. All patients showed T0 SUVmax of the affected foot higher than the contralateral one (3.83 ± 1.087 vs. 1.24 ± 0.3; P < 0.001). At clinical recovery (T1), defined by &Dgr;T below 2°C, the inflammatory signs were no longer present (T0 vs. T1 &Dgr;T = 3.04 ± 1.65 vs. 0.9 ± 0.55°C; P < 0.0001). At T1, SUVmax was unchanged from T0 (3.80 ± 1.69 vs. 3.83 ± 1.09; P = ns). At final recovery (T2), &Dgr;T was 0.74 ± 0.29°C (similar to T1 &Dgr;T), while the SUVmax dropped from T1 to T2 (3.8 ± 1.69 vs. 1.72 ± 0.52; P < 0.0001). Standard therapy was total contact cast and removable cast walker until T2 (15.12 ± 5.45 mo). No patient developed foot bone fractures nor had relapses during follow-up (21.75 ± 16.7 mo). Discussion PET/CT scan allows the quantification of the inflammatory process; therefore, it may drive clinical decisions in the management of acute CNO better than clinical criteria. None of our patients developed foot bone fractures or had relapses during follow-up driven by PET/CT scan.

Limb Salvage in Patients With Diabetes Is Not a Temporary Solution but a Life-Changing Procedure

Our limb salvage protocol for patients with diabetes at risk for amputation due to critical limb ischemia, foot ulcer, or gangrene includes early and aggressive surgical debridement, immediate broad-spectrum antibiotic therapy, and peripheral transluminal angioplasty as the first-choice revascularization procedure (1). In 2010 (2), we described the long-term outcomes (mean follow-up 20 ± 13 months) of 456 patients treated with this protocol: ulcers were healed in 62.3% (group A), major amputations performed in 14.7% (group B), death occurred in 14.9% (group C), and ulcers remained unhealed for >12 months in 8.1% (group D). As the long-term efficacy of this approach is still controversial (3), we have now evaluated the limb- or life-related outcomes in the same cohort of patients after a further …

High Matrix Metalloproteinase Levels Are Associated With Dermal Graft Failure in Diabetic Foot Ulcers

The aim of our study is to analyze factors, including matrix metalloproteinase (MMP) levels, that could influence the integration of dermal grafts in diabetic foot ulcers. From September 2012 to September 2013, 35 diabetic patients with IIA lesion (Texas Wound Classification) and an extensive foot tissue loss were considered suitable for dermal graft. Before the enrollment we ensured the best local conditions: adequate blood supply, control of infection, and offloading. The MMP level of each lesion was evaluated blindly before the application of dermal substitutes. At 1-month follow-up, we analyzed the correlation between clinical patient characteristics, local wound features including MMP levels, dermal substitute applied, and the outcome expressed in terms of dermal graft integration. We observed dermal graft integration in 28/35 patients (80% of our population). In multivariate analysis high MMP level was the only negative predictor for dermal graft integration (P < .0007). In addition, we divided the patients into 2 groups according to MMP levels: group 1 with low protease activity (24 patients) and group 2 with elevated protease activity (11 patients). The integration of the dermal graft was 100% in group 1 (n = 24 patients) and 36.4% in group 2 (n = 4patients), P < .0001. According to our data, the evaluation of MMP levels may be useful to choose the right strategy to get the best results in terms of clinical success and cost saving. However, further studies are necessary to confirm these findings.

Comment on Hoffstad et al. Diabetes, Lower-Extremity Amputation, and Death. Diabetes Care 2015;38:1852–1857

We have read with interest the article by Hoffstad et al. (1), as lower-extremity amputation (LEA) is a topic in which we have had a long-standing interest (2,3). Thus, we would like to share some of our thoughts about its findings. This article focuses its attention on the large increase in the incidence of death among patients with diabetes who underwent a LEA, as has been previously reported by several authors, including ourselves (1,3). This article further highlights the incomplete relationship between mortality and known diabetic complications, such as cardiovascular disease or renal insufficiency, and suggests that the presence of other unspecified factor(s) may be …