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DIABETIC VASCULAR DISEASE AND WOUND COMPLICATIONS
ETRS Focus Meeting, March 2005, Southampton, UK

THE aim of this meeting was to discuss peripheral vascular disease in the diabetic with a focus on wounds. The meeting was organised by the Vascular Medicine Research Group (VMRG) under the auspices of the ETRS. It was held in the Avenue Campus, Highfield, University of Southampton, 22–23 March 2005.

Over 23 papers were presented and two workshops held over seven sessions. Invited lectures covered prevention, pathogenesis of foot complications and complications associated with clinical management of the diabetic foot. The plenary paper ‘the Diabetic foot – a global problem; the way ahead’ was presented by Andrew Boulton. This paper was based on the latest evidence and was, like all lectures by Andrew Boulton that I have attended, simply excellent.

Both workshops were packed and involved much debate. As the talks, these were also considered very useful based on feedback received after the meeting.

The meeting received excellent sponsorship from industry and educational grants from KCI and Smith & Nephew. The attendance was around 70 which is the size of other ETRS Focus meeting that I have attended. In summing up, Mike Edmonds, Consultant Physician, Kings College Hospital, London said the two days had been absorbing and rewarding. Mike also speculated that the ‘unusual’ focus of the meeting and its success suggested that a trail had been blazed for future events that concentrate on vascular disease in the diabetic. A selection of abstracts from this meeting have been published in the Int. J. Lower Extremity Wounds 2005; 4 (2), which is in Medline.

Raj Mani
Board member, European Tissue Repair Society.

ABSTRACTS

Pressure offloading and ‘advanced’ wound healing, isn’t it finally time for an arranged marriage?
David G Armstrong*1 and Andrew JM Boulton*2
*Department of Medicine, Manchester Royal Infirmary, Manchester, UK. 1. Prof. of Surgery, Rosaline Franklin University of Medicine & Science, North Chicago, USA
2. University of Miami School of Medicine, Miami, USA

Over the past ten years, there have been a number of industry- sponsored randomised trials (published and unpublished) that have evaluated a variety of wound healing agents. These ranged from cytokines to bioengineered tissues to collagen and acellular-matrix-based materials. Almost all of these agents have shown some degree of promise, either anecdotally or by way of trial, in healing both simple and complex diabetic foot wounds. None of these studies employed irremovable offloading. In fact, most either allowed individual centres to select the type of pressure relief or offered shoes or sandals to study participants. Commensurately, their overall healing rates do not compare favourably with simple irremovable pressure offloading modalities.

Is the answer really this simple? Are we, perhaps, comparing (in a clinical trial sense) apples with oranges? Were these robust, multi-centre RCT’s superior in organisation and implementation than the smaller, often one or two centre studies of offloading devices? The answer to this series of questions is most likely that, no, the answer is probably not that simple and, yes, these previous projects were well organised and implemented. Many would, therefore, end the argument at that point. They would argue that it is a moot point to try to compare trials performed at one or two so-called ‘centres of excellence’ with a multitude of industry-sponsored trials conducted at centres, worldwide. We however, would not propose a comparison. We would, rather, propose a compromise.

The Marriage
In consideration of the above, we propose an arranged therapeutic marriage in the design of new wound healing modalities for diabetic foot wounds and their subsequent clinical trials. We propose wound healing agents that do not require frequent dressing changes with robust pressure offloading modalities that are, by design, less easily removable. In a clinical trial sense, this would (by virtue of higher healing rates in both experimental and control groups) require greater numbers to show superiority. However, this same higher healing rate might also lead to more consistent results in more centres around the world and (commensurately) fewer lower extremity amputations. This brief lecture will provide a practical, yet evidencebased overview of pressure offloading modalities and suggest simple modifications that, when combined with more ‘advanced’ wound healing agents, may prove synergistic and, ultimately beneficial.

A diabetes foot protection team reduces duration of admission for diabetic foot disease
G Bowen1, H Barton1, R Trodden1, R Taheem1, H
Holt1, S Baxter2, C Shearman2, B Leatherdale1 and D Browne1. 1. Dept of Diabetes, Southampton University
Hospitals. 2. Dept of Vascular Surgery, Southampton University Hospitals.

Aims:
Patients with diabetic foot disease are a significant burden to health services resulting in significant bed occupancy. A multi-disciplinary diabetes foot protection (DFP) team was developed to co-ordinate management of inpatient diabetic foot disease. Causes of delayed discharge were identified and targeted. The impact of the DFP on bed occupancy by patients with diabetic foot disease was assessed.

Method:
Patients with an acute diabetic foot problem who were admitted to an acute hospital in the previous twelve months were identified from hospital computer records. In the six months prior to introduction of the DFP 44 patients were identified and in the six months following DFP 36 patients were admitted. Duration of individual admissions in bed days was calculated and length of hospital stays pre and post DFP were calculated. Results Bed occupancy (days per patient admission) was 54 (0–155) days (mean range) prior to introduction of DFP. Following introduction of DFP duration of admission was significantly reduced compared to pre DFP at 18 (0–79) days (z value –3.268; p<0.001).

Conclusion:
The introduction of a multidisciplinary diabetes foot protection team has been shown to reduce inpatient bed occupancy for patients with acute diabetes foot disease.

Foot and Ankle Fractures in Diabetic Patients and the Risk of Developing Charcot Foot
Gavin Bowyer1, Madeleine Sampson2. Southampton University Hospitals Trust; Departments of Trauma & Orthopaedics (1) and Radiology (2).
The aim of this paper is to raise awareness of the importance of low-energy or stress fractures occurring in the foot and ankle in diabetic patients. We present a range of foot and ankle fracutres that have occurred in this group. We review the reported risk factors for impaired and prolonged healing in these injuries. We highlight in particular the danger that these fractures may be a herald sign for the development of Charcot neuropathic osteoarthropathy. We make recommendations for the management of these cases: immobilisation must be continued until the fracture is clearly healed. The patient and those caring for them need to be aware of the signs of impending or early Charcot disease.

Fungal Skin and Nail Infection in Diabetics
Ivan Bristow, Lecturer, School of Health Professions & Rehabilitation Sciences, Faculty of Medicine, Health and Life Sciences, University of Southampton, SO17 1BJ

Fungal foot infection is a common disease affecting the adult population. Studies have clearly illustrated an increased prevalence in older subjects, patients with diabetes and peripheral vascular disease. If left untreated skin infection frequently develops into onychomycosis and subsequent nail dystrophy – a clinical sign that the skin infection has been long established. For some the condition has been demonstrated to adversely affect the patient’s quality of life but for many, fungal foot infection is innocuous. Of concern, is the ability of the condition to compromise skin integrity permitting secondary bacterial invasion. Recent work has identified the association between bacterial cellulitis and fungal foot infection. Despite advances in therapy, the prevalence rates across Europe remain unacceptably high which either suggests failure in recognition of the disease or insufficient treatment of the condition. Approaches to management in the UK are primarily based on the systemic agents terbinafine and itraconazole. Literature consistently suggests with both agents cure rates of around 60%–70% for onychomycosis can be expected. However, research has focused on the outcomes in diabetic populations and in the long term, relapse rates following clinical cure have been very disappointing. Recent studies have sought to improve cure rates and relapses by the concurrent use of topical and systemic agents (combination therapy) So far this has demonstrated increased cure rates and in early studies has been shown to be potentially more cost effective. As nail infection invariably begins as skin infection on the foot, prophylactic use of topical agents and focussed skin and nail care may hold the key to preventing onychomycosis in the first instance.

Metabolic Syndrome: Prevention and medical management
Christoper Byrne, Prof. of Diabetes and Endocrinology, University of Southampton Hospitals Trust NHS, Southampton SO16 6YD

The clustering of insulin resistance, dysglycaemia, dyslipidaemia and hypertension was originally defined as syndrome X by Reaven in 19881. The addition of central obesity to the cluster2 has led to definitions of the metabolic syndrome being developed between 1999 and 2001 by the World Health Organization (WHO)3, the European Group for the Study of Insulin Resistance (EGIR)4 and the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (abbreviated to Adult Treatment Panel [ATP III)5. Identification of individuals with metabolic syndrome is important because metabolic syndrome increases risk of type 2 diabetes and/or vascular disease by approximately 2–3 fold. In those individuals with type 2 diabetes the presence of each of the individual components of the syndrome further increases the risk of vascular disease.

The prevalence of the metabolic syndrome is affected by a myriad of both non-modifiable and modifiable interlinked factors. Overweight and obesity usually increase insulin resistance and are linked to worsening of many of the features of the metabolic syndrome. As the prevalence of overweight and obesity continues to increase the number of people with diabetes will increase from 171 million in 2000, to 366 million in 20306 and a large proportion of these individuals will have metabolic syndrome. To reduce the risks from the syndrome it is crucial to identify affected individuals, and where possible to treat the underlying factors contributing to the pathogenesis of the syndrome. Where it is not possible to alter factors contributing to the syndrome, management of each of the individual component features of the syndrome should be considered. Recently we have shown that the effect of the metabolic syndrome per se was to increase the risk of cardiovascular disease (CVD) events by approximately 2 fold in subjects with diabetes. (HR 2.18 [95%CI 1.20 – 3.96; p = 0.011]). After adjustment, an increase in the number of features of the metabolic syndrome was associated with an increase in the risk of a primary CVD event (p for trend = 0.03). There was just over a fivefold increase in the level of risk for those possessing five features of the metabolic syndrome (including diabetes) when compared to individuals with diabetes alone (HR 5.20 [95% CI 1.17 – 23.20; p = 0.031). The evidence is beginning to suggest that treatments such as lipid lowering therapy attenuate the impact of metabolic syndrome to cause CVD. The purpose of this presentation is to discuss: the pathogenesis of the syndrome, the identification of individuals at risk of vascular disease, and the measures that can be used to treat patients at increased risk of complications.

References

1. Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 1595–1607.
2. Kaplan NM: The deadly quartet. Upper-body obesity,glucose intolerance, hypertriglyceridemia, and hypertension. Arch.Intern.Med. 149:1514–1520, 1989.
3. World Health Organization Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications, part 1: diagnosis and classification of diabetes mellitus. 1999. Geneva, WHO.
4. Balkau B, Charles MA: Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet. Med. 16: 442–443, 1999
5. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285: 2486–2497, 2001
6. Wild SH, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for 2000 and projections for 2030. Diabetes Care. 2004 27: 1047–53.

Omega-3 fatty acids from fish oil and cardiovascular disease
Philip C. Calder, Institute of Human Nutrition, University of Southampton, Bassett Crescent East, Southampton SO16 7PX

Long chain omega-3 polyunsaturated fatty acids (-3 PUFAs) are found in fatty fish and in fish oils. Substantial evidence from epidemiological and case-control studies indicates that consumption of fish, fatty fish and long chain -3 PUFAs reduces risk of cardiovascular mortality. Secondary prevention studies using long chain -3 PUFAs in patients post-myocardial infarction have shown a reduction in total and cardiovascular mortality with an especially potent effect on sudden death. Long chain -3 PUFAs have been shown to decrease blood triacylglycerol concentrations, to decrease production of chemoattractants, growth factors, adhesion molecules, inflammatory eicosanoids and inflammatory cytokines, to lower blood pressure, to increase nitric oxide production, endothelial relaxation and vascular compliance, to decrease thrombosis and cardiac arrhythmias and to increase heart rate variability (see Calder 2004 for a review). These mechanisms most likely explain the primary and secondary cardiovascular protection afforded by long chain -3 PUFA consumption. A recent study (Thies et al. 2003) suggests that long chain -3 PUFAs might also act to stabilise advanced atherosclerotic plaques, perhaps through their anti-inflammatory effects. As a result of the robust evidence in their favour a number of recommendations to increase intake of long chain -3 PUFAs have been made.

References:
Calder, P.C. (2004) N-3 fatty acids and cardiovasculardisease: evidence explained and mechanisms explored. Clinical Science 107, 1–11.

Thies, F., Garry, J.M.C., Yaqoob, P., Rerkasem, K., Williams, J., Shearman, C.P., Gallagher, P.J., Calder, P.C. and Grimble, R.F. (2003) Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 361, 477–485.

Ultrasound – what is its rôle in wound healing?
Alison Chumley1 and Raj Mani2. Bone Centre1 and Vascular Medicine Research Group2, Southampton University Hospitals Trust NHS, Tremona Road, Southampton SO16 6YD.

Ultrasound is commonly used as a diagnostic tool in obstretic and cardiovascular medicine. In managing diabetes and its complications, ultrasound has widespread applications in diagnosis, therapy as well as research. This paper will examine the current evidence in this context.

In its Duplex imaging mode, the current generation of ultrasound scanners offers imaging and blood velocity waveform measurements that are very reliable for the diagnosis of peripheral vascular disease. Ultrasound also offers safe and accurate diagnosis of deep vein thrombosis above and below the knees. Optimal frequencies for these applications are in the bandwidth 5–8 MHz.

At 0.6MHz, ultrasound scanners may be used to measure the velocity of transit (speed of sound) through bone and using this, bone ultrasonic attenuation (BUA) calculated which closely reflects bone mineral density. In this mode, ultrasound may be used to determine the risk of hip fractures reliably. Ultrasonic assessment of fracture risk is as good as that obtained using more complex techniques such bone densitometry.1 It has immense potential to unlock the mysteries surrounding the pathogenesis of the Charcot Foot.

Low frequency ultrasound (in the KHz range) is a safe and effective debridement tool. Debridement leads to granulation and this in turn, to wound healing. At higher frequencies, the evidence of wound healing efficacy is equivocal.2

Exciting developments in this field include measurements of intima media thickness (Centre frequency 5–8 MHz),
wound imaging. High-resolution ultrasound probes (Centre frequency 13-20 MHz, typical resolution 120 microns)
have the potential to perform non-invasive biopsies.

References:
1. Marshall D, Johnell O and Wedel H. Meta-analysis of how well measures of bone mineral density predicts occurrence of osteoporotic fractures. BMJ 1996; 312: 1254–59.
2. Uhelmann C, Heinig B and Wollina U. Therapeutic ultrasound in lower extremity wound management. IJLEW 2003;2(3): 152–158.

Diabetic Foot Infections Are Different in the Neuroischaemic Foot compared with the Neuropathic Foot
Michael Edmonds, Elizabeth Hampton. Diabetic Foot Clinic, King’s College Hospital, London, UK

Background and aims:
Much of the literature on the diabetic foot infections refers to the neuropathic foot. There is very little information on neuroischaemic foot infections. The aim of this study was to compare infection between the neuroischaemic foot and neuropathic foot.

Patients and methods:
We studied 88 patients presenting to the foot clinic with infection severe enough to require in-patient hospital treatment. There were two groups: Group 1- 61 patients with infected neuroischaemic ulcers and Group 2- 27 patients with infected neuropathic foot ulcers. Mean age was 73±10 years (mean±SD) for group 1 and 56±11 years for group 2, (p<0.001) and mean duration of diabetes was 17.5±10 years for group 1 and 20±12 years for group 2 (p>0.05). Initial organisms from a deep wound swab, C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR) and white blood cell count (WBC) taken on the day of admission were compared between groups 1 and 2.

Results:
The spectrum of organisms was different between groups 1 and 2. In group 1, coliforms were the most common organisms, being present in 26% of patients, whereas in group 2, methicillin sensitive Staph aureus (MSSA) was the most common organism, which was isolated in 35% of patients. The number of coliforms was significantly greater in group 1 compared with group 2 (26% vs 8%, p<0.05). Furthermore, there was a significant difference in the number of MSSA in group 1 compared with group 2 (15% vs 35%, p<0.05). The number of methicillin resistant Staph aureus (MRSA) was not significantly different in group 1 compared with group 2 (16% vs 15%). The number of anaerobes was also not significantly different, 3% in group 1 compared with 4% in group 2 (p>0.05). There was a similar inflammatory response to infection in group 1 and in group 2. When we compared group 1 with group 2, there was no significant difference in the levels of CRP (50±53 mg/l vs 48±58 mg/l, p>0.05), ESR (61±25 mm/hr vs 58±34 mm/hr, p>0.05) and WBC (8.6±3.0 10\S\9/ l vs 9.4±3.8 10\S\9/l, p>0.05).

Conclusion:
These results indicate that there should be a different approach in the initial treatment of neuroischaemic compared with neuropathic foot infections. Antibiotic therapy should cover gram-negative bacteria in the neuroischaemic foot.

Autologous Platelet Concentrate enriched with Growth Factors (APC+) Treatment for Handling Chronic Diabetic Foot Ulcerations – Implementing Growth Factors as a New Treatment Modality
Gerd Friese1, Tarek Othman1, Monika Herten2, Achim Hübinger1, Werner Scherbaum1. 1. German Diabetes Center, Leibniz-Institute at the Heinrich-Heine-University, Düsseldorf. 2. Kieferklinik, Heinrich-Heine- University, Düsseldorf, Germany.

Introduction:
Diabetic foot syndrome is a difficult to treat, cost intensive complication resulting from diabetes mellitus, quite often leading to amputation. The pathogenesis is multifactorial in nature. The therapeutic management typically encompasses pressure relief, infection control, vascular diagnostics and therapy, oxygen exchange, education as well as an individually tailored wound management. Despite optimal therapeutic treatment, many wounds fail to heal. A promising new approach is the application of Autologous Platelet Concentrate (APC+) in the wound management therapy.

Methods:
Sixteen consecutive patients with non-healing, no longer infected foot lesions (Wagner Stage I-III) previously treated for a minimum of six weeks of standardized therapy congruent with the international consensus of the diabetic foot were treated with APC+.The production of the APC+ was derived from a small sample of patient’s whole blood and processed via the SmartPReP™ System (Harvest Technologies).

After proper wound bed preparation and debridement, APC+ application, occlusion with polyurethane foam, the APC+ remained undisturbed on the wound for seven days, followed by an additional seven days of conservative moist dressing treatment. A new APC+ cycle was initiated every two weeks.

Results:
The treatment period ranged from 3–28 weeks with 2–14 APC+ cycles resulting in complete wound closure of 11/ 16 wounds (69%). 15/16 patients (94%) showed a significant benefit from the therapy in that wound size was markedly reduced or increased area of granulation tissue. The treatment of one heal fistula showed no marked sign of improvement to the therapy. 2/16 wounds (12%) resulted in infection that required treatment. Ischemic disturbances were present in all patient diagnosis where epithelialization was not achieved.

Discussion:
The application of APC+ as part of a therapy regimen indicates that the release of growth factors is a safe method to initiate and accelerate healing of chronic, non-healing wounds. Questions regarding the routine use and efficiency as
well as patient collection and wound circumstances require further evaluation.

The pathogenesis of the acute Charcot foot: a unifying hypothesis
William Jeffcoate, Dept of Diabetes and Endocrinology, City Hospital, Nottingham, UK

The pathogenesis of the acute Charcot foot in diabetes is complex and there has been no clear delineation of the relative significance of the different factors involved. It is recognised that the condition occurs only in those with severe distal symmetrical neuropathy, and that loss of protective sensation, hyperaemia from sympathetic denervation and reduction in pre-morbid bone density may play a part, but to a varying extent in different cases. However, some features remain unexplained, including the facts that
(i) acute Charcot foot is such a rare complication of neuropathy,
(ii) the hyperaemia is asymmetrical, is self-limiting and responds to immobilisation, and
(iii) the clinical features are indistinguishable in those with type 1 and type 2 diabetes – despite the differing prevalence of pre-morbid osteopenia in the two. Of these various processes, it is the marked asymmetrical inflammation of the acute Charcot foot which is pivotal and which, paradoxically, has been least studied. If the rôle of local hyperaemia is taken into account, it is possible to construct a unifying hypothesis based on a cycle of aggravation between inflammation, worsening osteolysis and increasing bone disorganisation. This process is initiated and maintained by motor, sensory and vasomotor neuropathy, possibly associated with abnormal release of circulating and nerve-derived hormones and altered expression of local cytokines such as RANKL and TNF-_. Recognition of the components of this model allows a more structured approach to evaluating therapeutic interventions. While there may be a place for reducing bone lysis by using bisphosphonates and calcitonin, treatment should hinge on measures taken to reduce local hyperaemia. Effective immobilisation is crucial, but other approaches should be considered: including the use of antihypertensives and agents such as antagonists of RANKL (I_B) and TNF-_ (infliximab and etanercept).

Assessment of viability of the critical foot
Finn Gottrup, Professor of Surgery, University of Southern Denmark, University Center of Wound Healing, Department of Plastic Surgery, Odense University Hospital, Odense, Denmark

All living cells need energy to provide structural and functional capacity. Assessment of the tissue viability is for this reason needed in case of critical situations for the tissue. The critical foot refers to problems with vascular supply of nutrition’s and in case of diabetes also increased risk of infection.

Assessment demands:
Assessment of the variability of the critical foot can be performed different ways. In clinical daily life subjective methods like ‘The clinical look’, evaluation of foot pulses, capillary response etc. provides a rough evaluation of the tissue vitality. This type of assessment is totally dependable on the experience of the investigator. To obtain optimal results both in treatment and research of the critical foot objective and quantitative methods are of vital importance. The methods must be simple, easy to perform and quick with high stability and degree of reproducibility.

Methods:
No assessment method fulfils all these demands, but some methods are useful for evaluation of the critical foot. These methods relates to tissue perfusion and oxygenation. Detection of poor tissue perfusion and oxygenation is crucial in clinical life in order to avoid complications related to the ischemic tissue. Tissue perfusion can evaluate by use of skin perfusion methods or wash-out of radiated tracers (Xe, In etc). Methods to assess oxygenation focus on measuring the tissue oxygen tension (PtO2) (defined as the partial pressure of the physiological dissolved oxygen in the cellular environment). PtO2 can be measured by indirect as well as direct monitoring systems and using different types of techniques. In the critical foot the indirect (atraumatic) methods measures PtO2 through the skin (transcutaneous measurement), while the direct (traumatic) methods the measuring devise is placed in the tissue (subcutaneous).

Conclusions:
Methods for evaluation tissue viability are of crucial importance in the critical foot. The methods should be stable and reproducible. Different methods focusing on the viability of skin and subcutaneous tissue are available.

Some mechanical properties of skin in the diabetic studied non-invasively
Lina Hammad1, Geoff Roberts and Raj Mani. Vascular Medicine Research Group, Southampton University Hospitals Trust NHS, Southampton SO16 6YD. 1. Present affiliation: Assistant Professor, Department of Radiological Sciences, King Saud University, Saudi Arabia.

Increased unrelieved plantar pressure leads to callus formation and ulcers in patients with diabetic neuropathy. Since these changes in dermal tissues consequent to pressure imply changes in stiffness and elasticity, reliable means of assessing these changes may be valuable in pre-selecting patients for targeted therapy. In order to achieve this aim, we chose to study some mechanical properties in patients with diabetes mellitus.

The site selected for study was the distal third of the leg as this was more easily accessible. We chose to study controlled extension/relaxation and hardness as separate measurements to quantify elasticity and tissue hardness respectively. We chose Extensometry and Durometry and a previously validated protocol 1 to achieve our aims.

Thirty-two diabetic patients with foot ulcers and 35 age matched controls were with prior informed consent were included in this study that was approved by the Local Ethics Committee for this hospital Trust. Patients were lying semi recumbent in a temperature and draught controlled room. Extensometry was measured midway between the medial malleolus and the medial condyles of the tibia. Durometry was measured on three sites viz 5 and 10 cms superior to the medial malleolus and midway between the medial malleolus and the tibial condyles.

Patients had significantly less Relaxation times compared with controls (mean +/- 1SD 17 +/- 12.1 versus 20.6 +/- 12.7 seconds, p = 0.013) though the Force at maximum extension (Fpeak) was not significantly different. Patients also had higher hardness values at all sites (34.5 +/- 11.1, 34.03 +/- 11.1, 27.2+/- 9) compared with controls. The differences were highly statistically significant (p < 0.0001 between measurements at all sites).

We had previously detected impaired venous refilling times in these patients. This study shows that the lower third of the legs were harder possibly because of unrelieved oedema that has been shown to affect oxygen diffusion as well as tissue perfusion that would impair wound healing.

References:
Hammad L. A study of some mechanical and microcirculatory parameters in skin subject to venous ulceration. Ph D thesis, University of Southampton 2000.

Mani R. From the wound healing laboratory: any evidence for change? In Chronic Wound Management – the evidence for change. Mani R. CRC Parthenon Press, 2002, London pp 135–144.

Diagnosis of Human Diabetic Neuropathy
R A Malik, Department of Medicine, Manchester Royal Infirmary, Manchester, UK

The neuropathies are amongst the commonest of the longterm complications of diabetes, affecting up to 50% of patients. There is increasing evidence that measures of neuropathy such as electrophysiology and quantitative sensory tests are not only predictors of endpoints including foot ulceration, but also of mortality. Therefore the accurate detection, characterization and quantification of human diabetic neuropathy are important to define at risk patients, anticipate deterioration, and assess new therapies.

QST: Quantitative sensory testing which includes the assessment of vibration, thermal and pain thresholds has proven valuable.

Electrophysiology: Multiple consensus panels have recommended the inclusion of electrophysiology in the evaluation of diabetic neuropathy and as a surrogate efficacy measure in clinical trials.

Nerve Biopsy: The use of nerve biopsy, typically of the sural nerve when undertaken at a center with sufficient expertise, is a useful diagnostic procedure in patients with neuropathy of a known origin, or in diabetic patients with atypical neuropathies

Skin Biopsy: Quantification of epidermal nerve fibres has been applied to the study of patients with diabetic neuropathy, HIV-associated neuropathy and idiopathic small fiber sensory neuropathy and recently has been used to assess early neuropathic changes in patients with IGT.

Magnetic Resonance Imaging: MRI of the spinal cord has demonstrated that patients with DPN have a lower crosssectional cord area than healthy controls in the cervical and thoracic regions.

Corneal Confocal Microscopy: This is a completely noninvasive technique which quantifies corneal nerve damage and repair, which correlates with the severity of diabetic neuropathy. It has been proposed it may be used in the diagnosis and assessment of treatment efficacy in human diabetic neuropathy.

The relationship between Plantar Pressure Loading and Cutaneous Perfusion in the Diabetic Foot
Mr DR Miller MRCS1, Prof PE Price PhD1, Prof EFJ Ring DS2, DR R von Deursen3, Prof KG Harding FRCS1. 1. Wound Healing Research Unit, Department of Surgery and 3. Research Centre for Kinaesiology, Cardiff University, Wales, UK. 2. Medical Imaging Group, School of Computing, University of Glamorgan, Wales, UK

Background
Diabetic neuropathy and microvascular disease are inextricably linked in the development of diabetic foot disease. We have recently presented findings to support the hypothesis that the plantar hyperaemic response to loading appears to be impaired in diabetics but only when sensory neuropathy is present. As part of this study the role of quantified plantar pressure loading was also examined and we now seek to present this portion of the data. Our hypothesis being, increasing plantar loading would have the effect of diminishing the hyperaemic response on off-loading.

Method
Fifty diabetic subjects (with and without sensory neuropathy) and twenty five controls were studied. Ulceration, deformity, macrovascular disease and smoking were excluded. High resolution thermal imaging (<0.1°C) was used as an
indirect measure of blood flow at four plantar sites (heel, medial midfoot, medial metatarsal heads and hallux) before (baseline) and at intervals up to 20 minutes after a standard treadmill walking test. Two dynamic plantar pressure variables, mean peak pressure (MPP) and pressure time integral pressure (PTI), were assessed for the same four sites using both force platform and in-shoe techniques.

Results
Comparing the four plantar sites studied, the lowest magnitude of temperature change from baseline occurred in the medial midfoot. However when the degree of association between the two variables was statistically tested (using the Pearson correlation coefficient), no consistent correlation was found between magnitude of temperature rise and either plantar pressure variable studied for diabetics or controls. In the minority of occasions where a significant relationship arose, it was of a negative linear nature.

Conclusion
The effect of increasing plantar loading might be to decrease the hyperaemic response; however our hypothesis has not been consistently supported and warrants further study. Despite their limitations, our findings have alarming implications about the effect of elevated plantar loading on cutaneous perfusion in the diabetic foot.

Plantar pressures and neuropathic ulcers: from histology to clinical findings
Alberto Piagessi MD, Dept of Endocrinology and Metabolism, University of Pisa, Pisa, Italy

Neuropathic ulceration is the most prevalent type of chronic lesion of the diabetic foot. Its pathogenesis is mainly related to the abnormally increased pressure under the foot secondary both to lack of sensation and deformities induced by peripheral sensory – motor neuropathy, associated with an abnormal gait.

The maintenance and chronicization of the ulcerative state is secondary to the repetition of postural trauma, which sustains a chronic inflammatory state, both characterised by hypertrophy of skin layers and diffuse, intense inflammatory infiltrate all over the ulcer.

The off-loading of the ulcer is, per se, sufficient to restore the healing process, with a switch to a reparative phase evident both from histological and biochemical point of view.

Does podiatry alter patient’s perception of risk of diabetic foot ulceration?
Elizabeth Mudge and Professor Patricia Price, Wound Healing Research Unit (WHRU), Cardiff University, Cardiff Medicentre, Heath Park, Cardiff CF14 4UJ.

Prevention of diabetic foot ulceration requires the patient to have appropriate knowledge and understanding, and a realistic perception of their personal risk. Patient education has been shown to dramatically reduce the number of episodes of diabetic foot ulceration. However, there are few studies in the literature demonstrating an association between visits to a podiatrist and decreased foot lesions.

The aim of this study was to investigate the perception of risk of diabetic foot ulceration among 200 diabetic patients in a city population, by comparing 100 diabetic patients who were regularly attending a podiatrist (‘existing patients’) with 100 diabetic patients who had not previously attended a podiatrist (‘new patients’). Participants were excluded if they had a history of previous foot ulceration or amputation as a result of diabetes. The respondents completed a structured, five-point Likert scale questionnaire, which consisted of twenty statements, and seven general questions. The statements allowed the participant to accept or reject established views of diabetic foot care relating to peripheral vascular disease, neuropathy and selfcare.

A combination of both positive and negative statements was used to prevent an acquiescence response. Quantitative analysis using a between-groups design demonstrated a higher level of knowledge in existing patients compared to new patients (Mann-Whitney U = 3656, p<0.001). This result suggests that diabetic foot care information from a podiatrist does improve a patient’s perception of risk of diabetic foot ulceration. However, the median scores in both groups reflected a general misunderstanding or misconception of risk of diabetic foot ulceration in 79% of the new patients and 64% of the existing patients (X 2 = 6.95, p< 0.008)). The participants who used Insulin as their method of diabetic control scored highest overall (Kruskal Wallis X 2 = 32.97, p<0.001). Specific areas of misunderstanding/misperception of basic foot care, neuropathy and vascular disease were highlighted by the study which can be used as the basis for future information interventions by this professional group.

Impact of Peripheral Vascular Disease on Plantar Pressure in type 2 Diabetic patients with Neuroischaemic Feet
Zoltan Pataky1, Jean-Philippe Assal2, Alain Golay2, Pierre Conne1 and Hubert Vuagnat1
1. General Medical Rehabilitation Service, Loëx Hospital, Rehabilitation and Geriatrics Dept, Geneva’s
University Hospitals, Route de Loëx 151, CH – 1233 Bernex/Geneva, Switzerland.
2. Service of Therapeutic Education for Chronic Diseases, Dept of Community Medicine, Geneva’s University Hospitals, Switzerland.

Background:
The high plantar pressure in diabetic patients plays a crucial role in plantar ulcer development. However, about twothirds of patients with chronic foot ulcers have arterial insufficiency. The direct impact of vascular impairment on plantar pressure has not yet been evaluated. The purpose of our study was to analyse the relationship between foot arterial pressures and plantar pressures in diabetic patients with neuro-ischaemic feet.

Methods:
Foot arterial pressures and plantar pressure parameters (Peak Plantar Pressure: PPP, Foot-Floor Contact time: FFC,
and Plantar Pressure Integral: PPI) were measured in eleven type 2 diabetic patients with both peripheral neuropathy
and peripheral vascular disease (PVD). Peripheral neuropathy was defined as a tuning fork score < 4/8 (measured at the big toe and internal malleolus; Tuning fork 128 Hz Rydel-Seiffer“), the absence of both patellar and ankle reflexes and with a temperature discrimination more than +5°C (Thermocross“). The PVD was evaluated by Doppler technique. Both PPP and FFC were measured by Force- Sensing Resistive„ (FSR 174„) sensors under the 1st, 3rd and 5th metatarsal heads as well as under the heel and big toe of both feet. The PPI was defined by the integral of the pressure over the time.

Results:
We have found significant relationship between plantar pressure parameters (PPP, FFC, and PPI) under the first metatarsal heads and Doppler arterial pressures of both tibial posterior and dorsalis pedis artery (p < 0.001). There was no relationship between arterial pressures and plantar pressure parameters under 3rd and 5th metatarsal heads or under both the heel and the big toe. The results were similar and comparable on both feet.

Conclusions:
According to our results, plantar pressure could be higher in diabetic patients with more severe PVD, which could contribute to an increased risk of foot ulceration. In terms of prevention, even more attention should be paid in such patients to diminish the risk of foot lesions and consecutive lower-extremity amputations.

Microvascular reactivity and anglogenic potential in diabetic patients with and without risk of foot ulceration.
Christian Qualtrini1, Rayaz Malik1, Maria Jeziorska2, David Gawkrodger3, Solomon Tesfaye4.
1. Department of medicine, Manchester Royal Infirmary, Oxford Road, M13 9NL, Manchester, UK.
2. Labrotory Medicine Academic Group, University of Manchester, Oxford Road, M13 9PT Manchester, UK.
3. Dermatology Outpatients, Royal Hallamshire Hospital, Glossop Road, Sheffield.
4. Diabetes Centre, Royal Hallanshire Hospital, Glossop Road, Sheffield, S10 2JF, UK.

Diabetic patients with elevated vibration perception threshold (VPT) have increased the risk of foot ulceration and impaired ulcer healing. We studied 7 control suspects (C) and 18 patients grouped into 6 at high risk (HR, VPT=99 pc) and 12 at low risk (LR, VPT£99 pc) to assess factors which may influence wound healing (C v LR v HR). Electrophyslology (nerve conduction velocity) confirmed the grater severity of neuropathy in HR (Median motor 53±4, 53±12, 42±19, Median sensory 61±8, 53±12, 42±19; Personal motor 46±4, 43±11, 40±15; Sural sensory 48±4, 42±13, 39±11 m/sec). Vasodilatation following iontophoresis with ACh (endothelium dependent) was significantly reduced (C 797±520, LR 493±400, HR 185±222%) (ANOVA, P=0.04, post-hoc C vs, HR p,0.05); with SNP (endothelium dependant) was reduced but failed to achieve significance (1055±985, 1000±1404, 194±153% (NS). Sympathetic vasoconstrictor response (VR) was reduced (-48±21, -43±19, -21±17% (P=0.04, post-hoc NS). A biopsy from the dorsum of the foot was immunostained for nerve fibre density (NFD) (PGP 9.5). blood vessels density (BVD) (vWF), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR2) and hypoxia inducible factor 1-alpha (HIF1a) intensity, NFD was reduced even in LR patients; 406 ±251. 98±69, 70±71 (Kruskal-Wallis, P=0.003, post-hoc C vs. HR p,0.01). Whilst there was no significant difference for BVD (C-205±62, LR-188±91, HR-259±101, VEGF: 304±340, 76±75, 212±253, VEGFR2; 104±121, 63±64, 142±155 or HIF1: 21±22. 73±102, 97±109) there appeared to be an upregulation of all parameters in the HR group. HIF1 correlated significantly with VR (Spearman’s r=0.44, p=0.03), BVD (r=0.48, p=0.01), VEGF (r=0.40, p=0.05), and VEGFR2 (r=O.54, p=0.007). NFD correlated to VEGF expression (r=0.44, p=0.03).

Small fibre precedes large fibre loss in patients deemed to be at low risk of ulceration. HR show endothelial dysfuction and abnormal vasoconstriction, associated with increased expression of HIF1 and VEGF. VEGF expression may regulate nerve fibre integrity.

The Efficacy of Poly Hydrated Ionogens in achieving stable wound closure in Recalcitrant Diabetic Foot Ulcers: a multicentre phase-1 pilot study
A. Pirayesh1, F. Rogge1, L Dessy1, H Hoeksema1, A. Spano1, A. D’all Antonia2, A. Mosahebi3, R. Lobmann4, M.J. Hoekstra5, S. Monstrey1, and PHI Study Group.
1. Department of Plastic Surgery Ghent, Belgium,
2. Departments of Plastic Surgery, Sassari and Verona, Italy,
3. Department of Plastic Surgery, East Grinstead, United Kingdom,
4. Department of Endocrinology, Magdenburg, Germany,
5. Burns Research Institute, Beverwijk, The Netherlands

Introduction:
Diabetic Foot Ulcers (DFU) continue to present a formidable challenge in terms of morbidity and health care costs. Increasing evidence ascertains the important role of Matrix Metallo-Proteinases (MMPs) and their tissue inhibitors TIMPS in wound healing. Imbalance of MMPs in the DFU microenvironment has been associated with poor wound healing. Current research is directed towards therapeutic agents that could redress the imbalance of MMPs/ TIMPs. Poly Hydrated Ionogens (PHIs) formulation is based on metallic ions and citric acid. PHI application aims to positively restore MMP ratios within chronic wounds. This initial multi-centre pilot study aimed to investigate the efficacy of the PHI formulation in achieving stable wound closure in recalcitrant DFUs.

Methods:
Twenty patients with therapy resistant DFUs of at least 2cm2 and three months duration were treated with PHI formulation in an acetate carrier dressing. Wound debridement, digital imaging and wound perimeter tracing was performed weekly. Serum samples and punch biopsies were taken from random ulcers for quantitative MMP/TIMP analysis at three time points to assess feasibility of this method. Patient satisfaction was assessed with a questionnaire.

Results:
Stable wound closure with high patient satisfaction was achieved in 15 (75%) DFUs. MMP/TIMP ratios within different healing phases were delineated. Discussion: This pilot study’s encouraging results prompt us to further investigate the PHI efficacy in DFU treatment in a web-based, multi-centre, randomised controlled trial.

Diabetes in India-what can we do to stem the tide?
A. Rekha and A. Ravi. Sri Ramachandra Medical College and Research Institute, Chennai–600116, India. 14 Sabari Nagar Extension, No 1/756, Mugallivakkam, Porur, Chennai–116, India

Introduction:
The incidence of diabetes in India has grown alarminglywhat was 2% in the early 1970s is a whopping 13.2%. India has the dubious distinction of having the largest number of diabetics, followed by China. The WHO has predicted that by the year 2005, India will have 57.2 million diabetics.Yet only 3.6 million receive pharmacological treatment.

Aims of the presentation:
To highlight the common complications of diabetes mellitus To stress the need for lifestyle modification To study the rôle of alternate medicines for treatment of diabetes To briefly discuss the role of botanicals and nutraceuticals
in the treatment of diabetes

Discussion:
The common long-term complications of diabetes include ophthalmopathy, neuropathy, nephropathy and vasculopathy leading to critical limb ischemia. Life style modifications include: a) dietary modifications (with emphasis on low sugar, low fat diet); b) the need for regular appropriate exercise; c) cessation of smoking; and d) stress management.

Avenues that need to be pursued include gene therapy, islet cell transplantation and cloning of insulin secreting cells. Botanical agents which are useful in glycaemic control include bitter melon (karela-Mormordica), fenugreek (Trigonella), garlic (Allium ), gurmar (Gymnema sylvestre) and aloe vera. Nutraceuticals include vitamins like Vitamin
C and E; trace elements like vanadium, chromium, magnesium, selenium and zinc; and agents like lipoic acid,
L-arginine and niacin.

Conclusion:
Those who can see the invisible can do the impossible. While allopathy remains the yardstick for comparison, alternate solutions are available for glycaemic control. We have moved away from the paths of our forefathers, thanks to urbanisation and modernisation. This is reflected in our attitudes, our social behaviour, our dietary patterns and consequently in our disease patterns. A re-look at our past, to re-assess the relevant, will be the way ahead.

The Mechanics of Wound Healing: The Ultrasonic Biopsy
Geoff Roberts and Raj Mani. Vascular MedicineResearch Group, Southampton University Hospitals Trust, Southampton, SO16 6YD.

Angiogenesis, the formation of granulation tissue and epithelisation characterise wound healing. In other words,
markers of these events provide a reliable commentary on healing and hence form the basis of our understanding of the healing process.

Our Group has been examining tissue structure in and around the wound using high-resolution ultrasound with an aim to characterise healing tissue. This process permits tissues to be imaged but more importantly preserves radio frequency data so that robust analytical techniques can be used to derive the mechanical properties of wound tissue and its constituent parts.

The system uses a reciprocating mechanism to provide linear scanning of a focused transducer housed in a water bath. A frame rate of 2 s-1 is achieved. The transducer is pulsed 256 times per traverse generating an image 256 AScans by 1024 samples. Sample rate is variable and both piezoelectric (PZT) and polyvinylidene difluoride (PVDF) transducers can be used. As the aim of the project is to measure the physical properties of tissue, 2D images are generated in real time merely to identify regions of interest.

We have scanned normal tissue as control and the perimeter and surface of chronic lower extremity wounds with prior informed consent of subjects and with Local Ethics approval. The data is being analysed using Fast Fourier Transforms to
(a) determine the reproducibility
(b) the stiffness of structures within the dermis. These data will be presented from this work in progress project.

Venous disease in diabetes – what is the evidence?
Raj Mani1, Geoff Roberts1, Jenny Deagle2, Chris Rosevere2 and Jas Dulay2. Vascular Medicine Research Group1 and Hospital at Home2, Southampton University Hospitals Trust NHS, Tremona Road, Southampton, SO16 6YD.

The prevalence and effects of peripheral arterial disease in patients with diabetes mellitus (DM) are well described and accepted. Sincere attempts to improve the management of this condition are also being implemented. Boulton described venous insufficiency in patients with diabetic neuropathy1 and more recently Sumpio mentioned this a risk factor for foot ulcers2. We present two sets of observations on venous disorders on patients with diabetes. In a study of diabetic foot ulcers (N = 30, median age 59.5 years, 23M, 7F) we examined the prevalence of venous incompetence using calf vein plethysmography in the first visit. We used a laser Doppler flowmeter and a protocol previously validated by us and found a majority (85%) of the ulcerated limbs had shorter venous refilling times (< 20 seconds, median = 9.5 seconds) compared to their contralateral limbs. A longer venous refilling time was associated with better likelihood of healing (p = 0.008). Should we test for venous function in wound clinics? A prospective of audit of patients (N = 1100) presenting
with symptoms of deep vein thrombosis (DVT) over a twelve-month period (mid 2002–3) was done. It was observed that out of 480 patients with a positive diagnosis of DVT, only 16 were also diabetic that is approximately 3.3%. These were above and below knee DVTs. All local Primary Care Trusts have open access this service that has been functioning for some years. This simple observation does not permit further comment. However, Prandoni et al investigated the relationship between atherosclerosis and venous thrombosis in patients by comparing the prevalence of carotid plaques in patients with spontaneous as well as secondary thrombosis and suggested a link between arterial and venous disorders.3 Future research in the diabetic population should tease out the possibilities of such a link in order to prevent the major complications known in patients with DM.

References
1. Boulton AJM and Van Schie CHM. Measurements in the neuropathic foot. In Chronic Wound Healing – Clinical Measurements and Basic Science. Eds. Mani R, Falanga V, Shearman CP and Sandeman DS. WB Saunders, 1999, pp. 26–49.
2. Sumpio BE. Foot ulcers. New England Journal of Medicine 2000; 343: 1257–64.
3. Prandoni P, Bilora F, Marchiori A et al. An association between atherosclerosis and venous thrombosis. New England Journal of Medicine 2003; 348 (15): 1435–1440.

Systemic management of necrotizing fasciitis in lower extremity of the diabetes mellitus
Sadanori Akita1, Kozo Akino2 and Akiyoshi Hirano1.
1: Division of Plastic and Reconstructive Surgery,
2: Division of Anatomy and Neurobiology, Dept of Developmental and Reconstructive Medicine Nagasaki University, Graduate School of Biomedical and Sciences, 1-7-1 Sakamoto, Nagasaki, 852, Japan

Necrotizing fasciitis is a rare but rapidly progressive infectious disease mainly involving the fascia and subcutaneous tissue, causing the disruption of the skin microcirculation, and life-threatening. The application of an artificial dermis is sometimes controversial since the artificial dermis may cause the local infection even in the cleaner wounds. Since we have experienced the usefulness and applicability of the artificial dermis, the clinical trials were attempted in compromised lower extremities. The underlying disease such as diabetes mellitus sometimes worsened the progression and the extent. In four lower extremities of diabetic patients, ranging from 42- year-old to 74-year-old, average 59-year-old) thee was a rush and extensively-developed necrotizing fasciitis. The two of these demonstrated the secondary diabetes due to higher (more than 30 mg per day) oral steroid-intake for controlling the primary diseases such as idiopathic thrombocytopenic purpura (ITP) and systemic lupus erythematosus (SLE). All cases demonstrated the bacterial causative organisms such as group A streptococcus and methicillin- resistant staphylococcus aureus (MRSA). With multi-disciplinary management by bacteriologists, internists and surgeons, all cases salvaged limbs even
though there were the initial exotoxin-induced shock states. The extensive surgical debridement included the discolored skin, subcutaneous tissues and fascia and the simultaneously application of an artificial dermis (porcine tendon-derived) and subsequent secondary thin splitskin grafting (0.001 inches) successfully replaced the necrotized tissues in both functionally and aesthetically, and the donor site wound healing was excellent in follow- up of 2 to 7 years, average 5.3 years.

New Method of Diabetic Ulcers Treatment using Sodium Hyaluronate and an Iodine Complex
Lubos Sobotka1 and Vladimir Velebny2.
1: Department of Metabolic Care and Gerontology, Medical Faculty, Charles University, 50005 Hradec Kralove.
2: CPN, Usti nad Orlici, Czech Republic.

Diabetic ulcers are difficult to heal due to defects in local microvasculature, and simultaneous microbial contamination. These defects frequently results in leg amputation. We have developed a new and unique system for wound treatment, which is based on combination of high molecular weight sodium hyaluronate with an iodine complex - Hyiodine‚ (patent No: WO 03/059404). The aim of our study was to assess the effect of this new method of wound dressing on healing of infected diabetic ulcers. The effect of Hyiodine‚ was studied on 18 patients suffering from complicated foot diabetic wounds. Hyiodine‚ was either spread directly over the wound, or (more frequently) gauze was immersed in Hyiodine‚ and then put on/into the wound. Then several layers of dry gauze covered the wound. This dressing was changed each 24 hours. Wound healing was monitored daily, and wound pictures were taken by digital camera (Camedia–Olympus) each second week. Within 2–6 weeks after the onset of treatment all but three defects were filled with granulation tissue. Complete healing was evident in 15 patients within 9–20 weeks after the start of treatment, depending on the wound character, localization and extent. One patient is still being treated by Hyiodine and significant improvement is apparent on his wound. Treatment was not successful in three subjects with ischemic defects due to simultaneous arterial occlusion.

We can conclude that the hyaluronan-iodine complex Hyiodine‚ is at present time efficient method for treatment of difficult to heal diabetic defects without complete arterial occlusion.

The Collagenolytic Activity of Blood Plasma in Diabetic Patients with Foot Ulcers
Strakhova G. Yu., Arbuzova M. I., Tokmakova A. Yu. National Research Centre for Endocrinology, Moscow, Russia.

The aim of our study was to evaluate the collagenolytic activity of blood plasma in diabetic patients with foot ulcers.

Objective and methods:
We studied 27 patients with type 1 and type 2 diabetes mellitus (15 males and 12 females, mean age of 46.2 ± 17.3 years, diabetes duration of 12.6 ± 8.6 years), which were divided into two groups: the 1st group included 16 patients with neuropathic foot ulcers; the control group – 11 diabetic patients without foot ulcer. Patients of both groups did not differ significantly (p>0.05) in sex, age, duration and treatment of diabetes, HbA1c, prevalence of diabetic retinopathy and renal insufficiency. The collagenolytic activity of blood plasma was measured by photometry. The standard solutions of collagenase (‘Sigma’, USA) and blood samples were incubated with the solution of azocollagen (‘Sigma’, USA) in 0.05 M tris-HCl buffer containing 1 mM CaCl2 and were centrifuged for 22 hours at 37°C. Specificity of hydrolysis of the substrate was estimated in reaction in the presence of 0.1 M EDTA. To examine the accuracy of difference between groups Mann-Whitney test was used for parametric values and Fisher’s exact criterion test for nonparametric values.

Results and conclusions:
The average collagenolytic activity of blood plasma was 62.38 ± 15.52 ng/ml in diabetic patients with foot ulcers and 36.55 ± 12.83 ng/ml in control patients, that is authentically higher (p = 0.0001). Thus, we suggest that the increased level of the collagenolytic activity of blood plasma may have an important role on the healing of diabetic foot ulcers, but its value in wound treating still remain an open question and require further investigations.

Aggressive Interventional Management of the Ischemic Diabetic Foot Candidate to Lower Limb Amputation
L.Uccioli1, R. Gandini2, A. Ascoli Marchetti3, A. Caselli1, R. Leo1, S. Fabiano2, S. Di Carlo1, L. Giurato1 and G. Simonetti2
1: Department of Internal Medicine,
2: Department of Diagnostic Imaging and Interventional Radiology, and 3: Department of Surgery, University of Tor Vergata, Roma, Italy

Diabetic foot is a serious complication of diabetes mellitus and the risk of lower extremity amputation is very high in this population when compared with people without diabetes. Patients with threatening ischemia of the lower extremities constitute a steadily increasing patient population owing to the increasing age of the general population and the growing incidence of diabetes.

CLI almost always concerns pattern of accelerated, extensive, multilevel arterial occlusive disease of lower limb vessels. There is increasing evidence that distal arterial revascularisation offers the best chance for limb salvage. Patients with gangrene and ischemic infected deep ulcers (Texas stage C or D and grade 2 or 3) that are candidate to major amputation, to save the legs, require aggressive distal, infrapopliteal revascularisation on the basis of foot runoff, despite any kind of lesion (obstructions and /or stenosis ) found in the vascular tree There still exists some controversy on the appropriate management of limb-threatening ischemia. PTA is becoming the option of choice in several conditions because is less invasive and therefore suitable also for very compromised patients.

To achieve the best results it is necessary to develope a specific protocol for limb salvage that includes the best available techniques of lower extremity endovascular procedures like extensive endoluminal or subintimal PTA with or without stenting, aggressive surgical debridment to remove all necrotic and infected tissues, including minor amputation, heavy antibiotic therapy with broad spectrum i.v. antibiotics. These frail patients may be severely affected in presence of fever and gangrene and may receive the best assistance in special hospital units where nutritional and metabolic control, water and electrolytes balance and the cardiovascular condition are under strict supervision. When the flow to the lower limb has been restored and the gangrene removed it is very important to have a specific treatment protocol in order to speed the healing of the wounds.

One option is the skin draft with autologous fibroblasts and keratinocytes previously cultured in laboratories and prepared as dermal and epidermal sheets ready for transplantation. This approach allows to heal wounds with extensive tissue loss that would require very long time to recover. Outcomes must be evaluated in terms of technicalsuccess, persistence of viability, limb salvage and ulcer healing.

This multidisciplinary approach with a very motivated and updated team allows to get the best results in terms of limb salvage. In our unit it has allowed to enrich the 82% of limb salvage of the affected legs that otherwise would have been amputated.

Microcirculation in the Diabetic Foot – Its Rôle in Impaired Healing of Foot Wounds
Aristidis Veves, Harvard Medical School, Boston, USA

The microcirculation in diabetic feet is impaired and this may play an important role in the impaired wound healing capacity that is observed in diabetic patients. The most prominent findings are impaired endothelium dependent and independent vasodilation and reduced or absent nerve axon reflex- related vasodilation. This renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury and makes it functionally ischemic even in the presence of satisfactory blood flow under normal conditions. Furthermore, it is currently realized that substances that are secreted by healthy C-nociceptive fibers play a role in angiogenesis, a major component of the wound healing process.

PARP activation and increased nitrosative stress, along with oxidative stress, are currently considered as major contributors to the skin microvascular abnormalities. Intervention with various modalities, including ACE inhibitors, insulin sensitizers (troglitazone), statins and exercise did not have any effect on skin microcirculation. However, recent studies in our unit have suggested that treatment with valsartan, an angiotensin II receptor blocker, increases resting skin blood flow and reduces PARP activity in type 2 diabetic patients. Strategies that can reverse microvascular abnormalities and increase angiogenesis may prove pivotal in improving wound healing in the diabetic foot and further research in this area will be required.

A Case Study showing the use of a Kerraboot™ for a patient with numerous ulcers on the lower limb
I. Wilson1 and S. Butterly.
1: Podiatory manager, Selly Oak Hospital, Raddlebarn Road, Selly Oak, Birmingham, B29

The Kerraboot is a relatively new and novel product for the management of wounds on the lower limb. It has been used in a limited number of clinical situations. This case study demonstrates its use in an 81 year old patient with type one diabetes and multiple neuro-ischaemic ulcers on her left foot. She has previously had a femoral popliteal bypass graft which was known to have occluded. Further surgery to the leg was inappropriate and the vascular surgeon had suggested amputation, the patient and her consultant were reluctant to agree to this.

A variety of standard dressings were found to be ineffective. The authors determined that Kerraboot might be more effective in the promotion of autolysis, additionally providing a simpler, relatively painfree dressing regime. After one week of use there was considerable autolysis of necrotic tissue on all of the ulcers (the precise measurements will be presented) and further sharp debridement was possible. This progress has continued. After 8 weeks treatment with Kerraboot the wounds are now granulating and have reduced in size as seen in the table below.

Initially concern was raised due to the infrequency of dressing changes leading to an accumulation of exudate and excessive maceration. Also,the shape of the forefoot of the Kerraboot did cause additional digital lesions. Reinforcement of the method of application and increased frequency of changing the boot reduced the impact of these initial problems.

Outcome:
The Kerraboot has been easy to use, has produced marked improvements in a short period of time, allieviated the pain of dressing changes and has so far preserved a patient’s leg. Frequency of dressing change has been an issue as in the first instance the ward nurses failed to change the boot daily, resulting in accumulation of exudate in the bottom of the boot resulting excessive pressure and maceration over the toes. As a consequence the patient developed ulcers on the 1st toe and the 4th and 5th toes. These ulcers subsequently healed once appropriate dressing change regime was enforced.