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A prospective multicenter trial O R I G I N A L A R T I C L EOBJECTIVE -Diabetic foot ulceration is a preventable long-term complication of diabetes. A multicenter prospective follow-up study was conducted to determine which risk factors in foot screening have a high association with the development of foot ulceration.RESEARCH DESIGN AND METHODS -A total of 248 patients from 3 large diabetic foot centers were enrolled in a prospective study. Neuropathy symptom score, neuropathy disability score (NDS), vibration perception threshold (VPT), Semmes-Weinstein monofilaments (SWFs), joint mobility, peak plantar foot pressures, and vascular status were evaluated in all patients at the beginning of the study. Patients were followed-up every 6 months for a mean period of 30 months (range 6-40), and all new foot ulcers were recorded. The sensitivity, specificity, and positive predictive value of each risk factor were evaluated. RESULTS -Foot ulcers developed in 95 feet (19%) or 73 patients (29%) during the study.Patients who developed foot ulcers were more frequently men, had diabetes for a longer duration, had nonpalpable pedal pulses, had reduced joint mobility, had a high NDS, had a high VPT, and had an inability to feel a 5.07 SWF. NDS alone had the best sensitivity, whereas the combination of the NDS and the inability to feel a 5.07 SWF reached a sensitivity of 99%. On the other hand, the best specificity for a single factor was offered by foot pressures, and the best combination was that of NDS and foot pressures. Univariate logistical regression analysis yielded a statistically significant odds ratio (OR) for sex, race, duration of diabetes, palpable pulses, history of foot ulceration, high NDSs, high VPTs, high SWFs, and high foot pressures. In addition, 94 (99%) of the 95 ulcerated feet had a high NDS and/or SWF, which resulted in the highest OR of . Furthermore, in multivariate logistical regression analysis, the only significant factors were high NDSs, VPTs, SWFs, and foot pressures.CONCLUSIONS -Clinical examination and a 5.07 SWF test are the two most sensitive tests in identifying patients at risk for foot ulceration, especially when the tests are used in conjunction with each other. VPT measurements are also helpful and can be used as an alternative. Finally, foot pressure measurements offer a substantially higher specificity and can be used as a postscreening test in conjunction with providing appropriate footwear.

OBJECTIVE -To assess the ability of the 4-week healing rate to predict complete healing over a 12-week period in a large prospective multicenter trial of diabetic patients with foot ulceration.RESEARCH DESIGN AND METHODS -We examined the change in ulcer area over a 4-week period as a predictor of wound healing within 12 weeks in patients who were seen weekly in a prospective, randomized controlled trial.RESULTS -Wound area measurements at baseline and after 4 weeks were performed in 203 patients. The midpoint between the percentage area reduction from baseline at 4 weeks in patients healed versus those not healed at 12 weeks was found to be 53%. Subjects with a reduction in ulcer area greater than the 4-week median had a 12-week healing rate of 58%, whereas those with reduction in ulcer area less than the 4-week median had a healing rate of only 9% (P Ͻ 0.01). The absolute change in ulcer area at 4 weeks was significantly greater in healers versus nonhealers (1.5 vs. 0.8 cm 2 , P Ͻ 0.02). The percent change in wound area at 4 weeks in those who healed was 82% (95% CI 70 -94), whereas in those who failed to heal, the percent change in wound area was 25% (15-35; P Ͻ 0.001).CONCLUSIONS -The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This simple tool may serve as a pivotal clinical decision point in the care of diabetic foot ulcers for early identification of patients who may not respond to standard care and may need additional treatment.

We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.

OBJECTIVE -We have previously demonstrated that high plantar pressures can predict foot ulceration in diabetic patients. The aim of the present study was to evaluate both the relationship between forefoot and rearfoot plantar pressure in diabetic patients with different degrees of peripheral neuropathy and their role in ulcer development. RESEARCH DESIGN AND METHODS-Diabetic patients of a 30-month prospective study were classified according to the neuropathy disability score: scores of 0, 1-5, 6 -16, and 17-28 are defined as absent (n ϭ 20), mild (n ϭ 66), moderate (n ϭ 95), and severe (n ϭ 57) neuropathy, respectively. The F-Scan mat system was used to measure dynamic plantar pressures. The peak pressures under the forefoot and the rearfoot were selectively measured for each foot, and the forefoot-to-rearfoot ratio (F/R ratio) was calculated.RESULTS -Foot ulcers developed in 73 (19%) feet. The peak pressures were increased in the forefoot of the severe and moderate neuropathic groups compared with the mild neuropathic and nonneuropathic groups (6.2 Ϯ 4.5 and 3.8 Ϯ 2.7 vs. 3.0 Ϯ 2.1 and 3.3 Ϯ 2.1 kg/cm 2 [mean Ϯ SD], respectively; P Ͻ 0.0001). The rearfoot pressures were also higher in the severe and moderate neuropathic groups compared with the mild neuropathic and nonneuropathic groups (3.2 Ϯ 2.0 and 3.2 Ϯ 1.9 vs. 2.5 Ϯ 1.3 and 2.3 Ϯ 1.0, respectively; P Ͻ 0.0001). The F/R ratio was increased only in the severe group compared with the moderate and mild neuropathic and nonneuropathic groups (2.3 Ϯ 2.4 vs. 1.5 Ϯ 1.2, 1.3 Ϯ 0.9, and 1.6 Ϯ 1.0, respectively; P Ͻ 0.0001). In a logistic regression analysis, both forefoot pressure (odds ratio 1.19 [95% CI 1.11-1.28], P Ͻ 0.0001) and the F/R ratio (1.37 [1.16 -1.61], P Ͻ 0.0001) were related to risk of foot ulceration, whereas rearfoot pressure was not.CONCLUSIONS -Both the rearfoot and forefoot pressures are increased in the diabetic neuropathic foot, whereas the F/R ratio is increased only in severe diabetic neuropathy, indicating an imbalance in pressure distribution with increasing degrees of neuropathy. This may lend further evidence toward the concept that equinus develops in the latest stages of peripheral neuropathy and may play an important role in the etiology of diabetic foot ulceration.