Matrix metalloproteinases (MMPs) degrade extracellular matrix components. Increased MMP-9 content in diabetic skin contributes to skin vulnerability and refractory foot ulcers. To identify ways to decrease MMP-9 levels in skin, inhibition of MMP-9 expression in dermal fibroblasts using small interfering RNA was investigated in vitro.
A full-thickness wound was created on the midback of streptozotocin-induced diabetic rats; skin biopsies were performed 3 days later. Skin MMP-9 expression was observed by immunohistochemical analysis. Dermal fibroblasts from 1-day-old normal Sprague Dawley rats cultured with high glucose and homocysteine concentrations were transfected with small interfering RNA complexes. Cells were collected 30, 48, and 72 hours after transfection, and reverse transcription–polymerase chain reaction, Western blot analysis, and gelatin zymography for MMP-9 were performed.
Expression of MMP-9 was increased in diabetic rat skin, especially around wounds. After 30-, 48-, and 72-hour transfection with each MMP-9–specific small interfering RNA, reverse transcription–polymerase chain reaction showed markedly decreased MMP-9 messenger RNA expression, protein abundance, and activity. Of four MMP-9 small interfering RNAs, one sequence had a stable high inhibition rate (>70% at 30 and 48 hours after transfection).
Expression of MMP-9 was increased in diabetic rat skin, especially around wounds, and was markedly inhibited after MMP-9 small interfering RNA transfection in vitro (P < .05). These findings may provide new treatments for diabetic skin wounds. (J Am Podiatr Med Assoc 102(4): 299–308, 2012)
Recognizing the Prevalence of Changing Adult Foot Size
An Opportunity to Prevent Diabetic Foot Ulcers?
Ill-fitting shoes may precipitate up to half of all diabetes-related amputations and are often cited as a leading cause of diabetic foot ulcers (DFU), with those patients being 5 to 10 times more likely to present wearing improperly fitting shoes. Among patients with prior DFU, those who self-select their shoe wear are at a three-fold risk for reulceration at 3 years versus those patients wearing prescribed shoes. Properly designed and fitted shoes should then address much of this problem, but evidence supporting the benefit of therapeutic shoe programs is inconclusive. The current study, performed in a male veteran population, is the first such effort to examine the prevalence and extent of change in foot length affecting individuals following skeletal maturity. Nearly half of all participants in our study experienced a ≥1 shoe size change in foot length during adulthood. We suggest that these often unrecognized changes may explain the broad use of improperly sized shoe wear, and its associated sequelae such as DFU and amputation. Regular clinical assessment of shoe fit in at-risk populations is therefore also strongly recommended as part of a comprehensive amputation prevention program.
We investigated the validity of probe-to-bone testing in the diagnosis of osteomyelitis in a selected subgroup of patients clinically suspected of having diabetic foot osteomyelitis.
Between January 1, 2007, and December 31, 2008, inpatients and outpatients with a diabetic foot ulcer were prospectively evaluated, and those having a clinical diagnosis of foot infection and at least one of the osteomyelitis clinical suspicion criteria were consecutively included in this study.
Sixty-five patients met the inclusion criteria and were prospectively enrolled in the study. Forty-nine patients (75.4%) were hospitalized, and the remaining 16 (24.6%) were followed as outpatients. Osteomyelitis was diagnosed in 39 patients (60.0%). Probe-to-bone test results were positive in 30 patients (46.1%). The positive predictive value for the probe-to-bone test was fairly high (87%), but the negative predictive value was only 62%. The sensitivity and specificity of the test were 66% and 84%, respectively. White blood cell counts and mean C-reactive protein levels did not statistically significantly differ between groups. However, erythrocyte sedimentation rates greater than 70 mm/h reached statistical significance between groups. Wound area and depth were not found to be statistically significantly different between groups.
Positive probe-to-bone test results and erythrocyte sedimentation rates greater than 70 mm/h provide some support for the diagnosis of diabetic foot osteomyelitis, but it is not strong; magnetic resonance imaging or bone biopsy will probably be required in cases of doubt. (J Am Podiatr Med Assoc 102(5): 369–373, 2012)
This prospective longitudinal study assessed whether baseline mean skin temperature measurements are useful in predicting the most common foot-related complications of diabetes mellitus. We evaluated the mean of baseline skin temperatures taken bilaterally from six plantar sites in 1,588 patients with diabetes. There was no difference in skin temperature based on neuropathy, foot laterality, or foot risk category or between people with and without foot deformity and elevated plantar foot pressure. Whereas people with Charcot’s arthropathy had slightly but significantly higher mean temperatures (84.8° ± 3.5° F versus 82.5° ± 4.7° F), this was not true for those who developed ulcers or infections or who underwent amputations. The presence of vascular disease was not associated with lower skin temperatures. Mexican Americans (83.0° ± 4.6° F) and blacks (83.6° ± 4.5° F) had higher mean skin temperatures at baseline than did non-Hispanic whites (81.8° ± 4.6° F). Baseline measurement of nonfocal mean skin temperatures is not an effective means of screening people for future events. Regular assessment of skin temperatures, using the contralateral site as a physiologic control, may be a better use of this technology. (J Am Podiatr Med Assoc 93(6): 443-447, 2003)
Osteomyelitis is a common complication in the diabetic foot that can conclude with amputation. The purpose of this study was to evaluate the role of diffusion-weighted magnetic resonance imaging (DWI) in the diagnosis of osteomyelitis in diabetic foot ulcer (DFU).
Thirty patients with type 2 diabetes mellitus and a DFU were enrolled. Both DWIs and conventional MRIs were obtained. Apparent diffusion coefficient (ADC) measurements were made by transferring the images to a workstation. The measurements were made both from bone with osteomyelitis, or nearest to the injured area if osteomyelitis is not available, and from the adjacent soft tissue.
The patients comprised nine women (30%) and 21 men (70%) with a mean age of 58.7 years (range, 41–78 years). The levels of ADC were significantly low (P = .022) and the erythrocyte sedimentation rates were significantly high (P = .014) in patients with osteomyelitis (n = 9) compared with patients without osteomyelitis (n = 21). The mean ± SD bone ADC value (0.75 ± 0.16 × 10–3 mm2/sec) was significantly lower than the adjacent soft-tissue ADC value (0.90 ± 0.15 × 10–3 mm2/sec) in patients with osteomyelitis (P = .04).
It is suggested that DWI contributes to conventional MRI with short imaging time and no requirement for contrast agent. Therefore, DWI may be an alternative diagnostic method for the evaluation of DFU and the detection of osteomyelitis.
INTRODUCTION AND OBJECTIVES: The benefits of using amniotic tissue in skin regeneration are well documented. Today, cryopreservation technology allows for better availability and maintenance of mesenchymal stem cells. This is of particular interest in treating the diabetic foot ulcer as this population has fewer mesenchymal stem cells. The objective of this case series investigation was to compare the efficacy of cryopreserved human amniotic stem cells in treating foot wounds of different etiologies. We will present data and case photos for a diabetic foot ulcer, venous leg ulcer, arterial ankle ulcer, and a pyoderma gangrenosum ulcer
METHODS: Cryopreserved human amniotic stem cell grafts were applied to patients with chronic ulcers of different etiologies that had been subjected to at least 4 weeks of standard wound care and did not show adequate clinical progress. Wound area was recorded and photographed on weekly basis. Area reduction was charted over time and the results of each individual case were compared to one another.
RESULTS: All ulcers displayed results that well exceeded the established parameters of weekly healing rates for effective wound treatment modalities.
â€¢ Pyoderma gangrenosum displayed the poorest response to treatment. However, it is worth noting that the patient was not compliant in the prescribed adjunctive treatment regimen but managed to achieve 64% wound reduction.
â€¢ All ulcers showed the largest appreciable amount of healing in both total area reduction and week-to- week closure percentage after the first application.
CONCLUSIONS: Cryopreserved human amniotic stem cell grafts can aid in the decreasing the time to closure of various types of lower extremity ulcerations. The therapy is a clinically viable option for physicians to consider when formulating a treatment plan for a patient with an ulcer.
Ankle position sense may be reduced before the appearance of the clinical manifestation of diabetic peripheral neuropathy. This is known to impair gait and cause falls and foot ulcers. Early detection of impaired ankle proprioception is important because it allows physicians to prescribe an exercise program to patients to prevent foot complications.
Forty-six patients diagnosed as having type 2 diabetes mellitus and 22 control patients were included in the study. Presence of neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Level of foot care awareness was determined using the Nottingham Assessment of Functional Footcare (NAFF). Joint position sense was measured using a dynamometer.
Mean absolute angular error (MAAE) values were significantly higher in the neuropathy group compared with the control group (P < .05). Right plantarflexion MAAE values were significantly lower in the group without neuropathy compared with the group with neuropathy (P < .05). No correlation was found between MAAE values (indicating joint position sense) and age, educational level, disease duration, glycemic control, NAFF score, and MNSI history and examination scores in the groups with and without neuropathy (P > .05). Educational level and disease duration were found to be correlated with NAFF scores.
Increased MNSI history scores and increased deficits in ankle proprioception demonstrate that diabetic foot complications associated with reduced joint position sense may be seen at an increased rate in symptomatic patients.
Topical Application of a Gentamicin-Collagen Sponge Combined with Systemic Antibiotic Therapy for the Treatment of Diabetic Foot Infections of Moderate Severity
A Randomized, Controlled, Multicenter Clinical Trial
The aim of this pilot study was to determine the safety and potential benefit of adding a topical gentamicin-collagen sponge to standard of care (systemic antibiotic therapy plus standard diabetic wound management) for treating diabetic foot infections of moderate severity.
We randomized 56 patients with moderately infected diabetic foot ulcers in a 2:1 ratio to receive standard of care plus the gentamicin-collagen sponge (treatment group, n = 38) or standard of care only (control group, n = 18) for up to 28 days of treatment. Investigators performed clinical, microbiological, and safety assessments at regularly scheduled intervals and collected pharmacokinetic samples from patients treated with the gentamicin-collagen sponge. Test of cure was clinically assessed 14 days after all antibiotic therapy was stopped.
On treatment day 7, we noted clinical cure in no treatment patients and three control patients (P = .017). However, for evaluable patients at the test-of-cure visit, the treatment group had a significantly higher proportion of patients with clinical cure than did the control group (22 of 22 [100.0%] versus 7 of 10 [70.0%]; P =.024). Patients in the treatment group also had a higher rate of eradication of baseline pathogens at all visits (P ≤ .038) and a reduced time to pathogen eradication (P < .001). Safety data were similar for both groups.
Topical application of the gentamicin-collagen sponge seems safe and may improve clinical and microbiological outcomes of diabetic foot infections of moderate severity when combined with standard of care. These pilot data suggest that a larger trial of this treatment is warranted. (J Am Podiatr Med Assoc 102(3): 223-232, 2012)
Fifteen percent of individuals with diabetes will likely develop foot ulcers in their lifetime, and approximately 15% to 20% of these ulcers are estimated to result in lower extremity amputation. Techniques to prevent lower extremity amputation range from the simple but often neglected foot inspection to complicated vascular and reconstructive foot surgery. Appropriate management can prevent and heal diabetic foot ulcers, thereby greatly decreasing the amputation rate and medical care costs. Prevention is the key to treatment. The author discusses general guidelines for foot screening and identifies three specific goals for prevention of amputation: 1) identification of at risk individuals needing prevention and the specific factors placing them at risk; 2) protection of the foot against the adverse effects of external forces (pressure, friction, and shear); and 3) reduction of the incidence of diabetic foot ulcers through educational programs.
We investigated plantar loading asymmetry during gait in American Indians with and without diabetes and with diabetes and peripheral neuropathy.
A convenience sample of 96 American Indians with and without diabetes was divided into three groups: 20 with diabetes and peripheral neuropathy, 16 with diabetes without peripheral neuropathy, and 60 with no history of diabetes (control group). Plantar loading was measured during barefoot walking across a pressure platform. Five trials were collected per foot during level walking at a self-selected speed using the two-step method. Asymmetry in peak pressure-time integral and peak plantar pressure were calculated from ten plantar regions and compared among groups.
Significant pressure-time integral asymmetry occurred across the forefoot regions in American Indians with diabetes and peripheral neuropathy compared with the other two groups. Significant peak plantar pressure asymmetry occurred in the third metatarsal region in both groups with diabetes (with and without peripheral neuropathy) compared with the control group.
Overall, American Indians with diabetes seemed to show greater asymmetry in plantar loading variables across the forefoot region compared with those in the control group. Specifically, individuals with diabetes and peripheral neuropathy had the greatest amount of forefoot pressure-time integral asymmetry. Significant peak plantar pressure asymmetry occurred in the third metatarsal region of the forefoot in those with diabetes with and without peripheral neuropathy. Loading asymmetry may play a role in the development of foot ulcers in the forefoot region of American Indians with peripheral neuropathy and diabetes. (J Am Podiatr Med Assoc 103(2): 106–112, 2013)