Michael Edmonds

Medial Localization of Mineralization-Regulating Proteins in Association With Mönckeberg’s Sclerosis Evidence for Smooth Muscle Cell–Mediated Vascular Calcification

BACKGROUND Calcification of the media of peripheral arteries is referred to as Mönckebergs sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media. METHODS AND RESULTS In situ hybridization, immunohistochemistry, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the expression of mineralization-regulating proteins in human peripheral arteries with and without MS. MS occurred in direct apposition to medial vascular smooth muscle cells (VSMCs) in the absence of macrophages or lipid. These VSMCs expressed the smooth muscle-specific gene SM22alpha and high levels of matrix Gla protein but little osteopontin mRNA. Compared with normal vessels, vessels with MS globally expressed lower levels of matrix Gla protein and osteonectin, whereas alkaline phosphatase, bone sialoprotein, bone Gla protein, and collagen II, all indicators of osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs derived from MS lesions exhibited osteoblastic properties and mineralized in vitro. CONCLUSIONS These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs.

High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study

Aims/hypothesisLarge clinical studies describing the typical clinical presentation of diabetic foot ulcers are limited and most studies were performed in single centres with the possibility of selection of specific subgroups. The aim of this study was to investigate the characteristics of diabetic patients with a foot ulcer in 14 European hospitals in ten countries.MethodsThe study population included 1,229 consecutive patients presenting with a new foot ulcer between 1 September 2003 and 1 October 2004. Standardised data on patient characteristics, as well as foot and ulcer characteristics, were obtained. Foot disease was categorised into four stages according to the presence or absence of peripheral arterial disease (PAD) and infection: A: PAD −, infection −; B: PAD −, infection +; C: PAD +, infection −; D: PAD +, infection +.ResultsPAD was diagnosed in 49% of the subjects, infection in 58%. The majority of ulcers (52%) were located on the non-plantar surface of the foot. With regard to severity, 24% had stage A, 27% had stage B, 18% had stage C and 31% had stage D foot disease. Patients in the latter group had a distinct profile: they were older, had more non-plantar ulcers, greater tissue loss and more serious comorbidity.Conclusions/interpretationAccording to our results in this European cohort, the severity of diabetic foot ulcers at presentation is greater than previously reported, as one-third had both PAD and infection. Non-plantar foot ulcers were more common than plantar ulcers, especially in patients with severe disease, and serious comorbidity increased significantly with increasing severity of foot disease. Further research is needed to obtain insight into the clinical outcome of these patients.

The Charcot Foot in Diabetes

The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity.

Blood flow in the diabetic neuropathic foot

SummaryThe mechanisms which underlie the development of Charcot joints and foot ulceration are poorly understood. The present study using non-invasive Doppler techniques demonstrates that in the neuropathic leg, the arteries are rigid, peripheral blood flow is increased and associated with arteriovenous shunting. We studied 10 diabetics with severe neuropathy (including five with Charcot changes), 16 diabetics without neuropathy and 10 control subjects. Markedly abnormal blood velocity profiles (sonograms) were demonstrated only in those patients with severe neuropathy. They showed increased diastolic flow (indicated by a reduced Pulsatility Index of 2.88 ±0.8 (mean ±SD) compared with 9.53±4.0 (p<0.001) in the diabetics without neuropathy and 10.8±3.7 (p<0.001) in the control subjects) suggesting arteriovenous shunting. Increased rigidity was indicated by decreased transit times -57±6.3 ms (mean±SD) in the diabetics with neuropathy compared with 66 ±7.6ms (p<0.01) in the diabetics without neuropathy and 67±9.1 ms (p<0.05) in the control subjects. This was accompanied by raised ankle systolic pressures -199±22 mmHg (mean +SD) in the diabetics with neuropathy compared with 151±15 mmHg, (p<0.001) in the diabetics without neuropathy and 146±18 mmHg (p<0.001) in the control subjects. Medial wall calcification occurred almost exclusively in the neuropathic subjects. These alterations in blood flow which include arteriovenous shunting may be important in the pathogenesis of complications of the neuropathic leg.

A Cohort Study of People With Diabetes and Their First Foot Ulcer The role of depression on mortality

OBJECTIVE—The aim was to evaluate over 18 months whether depression was associated with mortality in people with their first foot ulcer. RESEARCH DESIGN AND METHODS—A prospective cohort design was used. Adults with their first diabetic foot ulcer were recruited from foot clinics in southeast London, U.K. At baseline, the Schedules for Clinical Assessment in Neuropsychiatry 2.1 was used to define those who met DSM (Diagnostic and Statistical Manual of Mental Disorders)-IV criteria for minor and major depressive disorders. Potential covariates were age, sex, marital status, socioeconomic status, smoking, antidepressant use, A1C, macro- and microvascular complications, and University of Texas classification–based severity and size of ulcer. The main outcome was mortality 18 months later, and A1C was the secondary outcome. The proportion who had an amputation, had recurrence, and whose ulcer had healed was recorded. RESULTS—A total of 253 people with their first diabetic foot ulcer were recruited. The prevalence of minor and major depressive disorder was 8.1% (n = 21) and 24.1% (n = 61), respectively. There were 40 (15.8%) deaths, 36 (15.5%) amputations, and 99 (43.2%) recurrences. In the adjusted Cox regression analysis, minor and major depressive disorders were associated with an approximately threefold hazard risk for mortality compared with no depression (3.23 [95% CI 1.39–7.51] and 2.73 [1.38–5.40], respectively). There was no association between minor and major depression compared with no depression and A1C (P = 0.86 and P = 0.43, respectively). CONCLUSIONS—One-third of people with their first diabetic foot ulcer suffer from clinical depression, and this is associated with increased mortality.

Resource utilisation and costs associated with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale Study

Aims/hypothesisThe aim of the present study was to investigate resource utilisation and associated costs in patients with diabetic foot ulcers and to analyse differences in resource utilisation between individuals with or without peripheral arterial disease (PAD) and/or infection.MethodsData on resource utilisation were collected prospectively in a European multicentre study. Data on 1,088 patients were available for the analysis of resource use, and data on 821 patients were included in the costing analysis. Costs were calculated for each patient by multiplying the country-specific direct and indirect unit costs by the number of resources used from inclusion into the study up to a defined endpoint. Country-specific costs were converted into purchasing power standards.ResultsResource use and costs varied between outcome groups and between disease severity groups. The highest costs per patient were for hospitalisation, antibiotics, amputations and other surgery. All types of resource utilisation and costs increased with the severity of disease. The total cost per patient was more than four times higher for patients with infection and PAD at inclusion than for patients in the least severe group, who had neither.Conclusions/interpretationImportant differences in resource use and costs were found between different patient groups. The costs are highest for individuals with both peripheral arterial disease and infection, and these are mainly related to substantial costs for hospitalisation. In view of the magnitude of the costs associated with in-hospital stay, reducing the number and duration of hospital admissions seems an attractive option to decrease costs in diabetic foot disease.

Delivery of care to diabetic patients with foot ulcers in daily practice: results of the Eurodiale Study, a prospective cohort study

Aims  To determine current management and to identify patient‐related factors and barriers that influence management strategies in diabetic foot disease.

Sympathetic nerve failure in diabetes

SummarySympathetic damage is a striking feature of diabetic neuropathy, probably much more common and important than previously suspected. Degeneration of arterial medial smooth muscle with subsequent medial calcification is a feature of diabetic neuropathy and represents a structural abnormality probably resulting from sympathetic denervation. Loss of vasomotor control is responsible not only for postural hypotension but also for the remarkable increase of peripheral blood flow and arteriovenous shunting in the neuropathic foot. Demineralisation of bones and neuroarthropathic bone and joint destruction may result. Intractable oedema is another consequence of these haemodynamic abnormalities, while in other cases there is a close association of sympathetic defects with painful neuropathies. The possibility of new treatments using sympathomimetic agents to reverse these abnormalities now exists, and ephedrine has already been shown to be highly effective in reducing neuropathic oedema.

Measurement of Markers of Osteoclast and Osteoblast Activity in Patients with Acute and Chronic Diabetic Charcot Neuroarthropathy

Excess osteoclast activity is believed to be responsible for the early bone changes associated with Charcot neuroarthropathy in diabetes mellitus. Markers of osteoclast and osteoblast activity were measured in four groups of patients: 16 with an acute Charcot foot, 16 with a chronic Charcot foot, 10 diabetic controls, and 10 non‐diabetic controls. Serum carboxyterminal telopeptide of type 1 collagen (1CTP), a marker of osteoclastic bone resorption, was significantly raised in the dorsal venous arch of the acute Charcot foot, 6.1 ± 1.5 μg l−1 (mean ± SD) compared with the chronic Charcot foot 4.1 ± 1.4, diabetic controls 3.3 ± 1.4, and non‐diabetic controls 2.8 ± 1.4, p < 0.0001. This local increase in 1CTP was also reflected systemically in a study subgroup of 6 patients with acute Charcot neuroarthropathy, in whom peripheral antecubital vein 1CTP was 9.2 ± 2.6 compared with 9.0 ± 3.1 in the foot. In 6 chronic Charcot neuroarthropathy patients, foot (3.8 ± 1.3) and systemic (4.0 ± 1.5) 1CTP values were similar. Serum procollagen carboxyterminal propeptide (P1CP), an indicator of osteoblastic bone formation, was not significantly different between the feet of patients with acute Charcot neuroarthropathy 112 ± 1.5 μg l−1, patients with chronic Charcot neuroarthropathy 109 ± 1.5 μg l−1, diabetic controls 93.5 ± 2.3 μg l−1, and non‐diabetic controls 90.1 ± 1.5 μg l−1. These results suggest that the acute Charcot foot demonstrates excess osteoclastic activity without concomitant increase in osteoblastic function. This may be important in its pathogenesis. © 1997 John Wiley & Sons, Ltd.

Changes in the Incidence of Lower Extremity Amputations in Individuals With and Without Diabetes in England Between 2004 and 2008

OBJECTIVE To describe recent trends in the incidence of nontraumatic amputations among individuals with and without diabetes and estimate the relative risk of amputations among individuals with diabetes in England. RESEARCH DESIGN AND METHODS We identified all patients aged >16 years who underwent any nontraumatic amputation in England between 2004 and 2008 using national hospital activity data from all National Health Service hospitals. Age- and sex-specific incidence rates were calculated using the total diabetes population in England every year. To test for time trend, we fitted Poisson regression models. RESULTS The absolute number of diabetes-related amputations increased by 14.7%, and the incidence decreased by 9.1%, from 27.5 to 25.0 per 10,000 people with diabetes, during the study period (P > 0.2 for both). The incidence of minor and major amputations did not significantly change (15.7–14.9 and 11.8–10.2 per 10,000 people with diabetes; P = 0.66 and P = 0.29, respectively). Poisson regression analysis showed no statistically significant change in diabetes-related amputation incidence over time (0.98 decrease per year [95% CI 0.93–1.02]; P = 0.12). Nondiabetes-related amputation incidence decreased from 13.6 to 11.9 per 100,000 people without diabetes (0.97 decrease by year [0.93–1.00]; P = 0.059). The relative risk of an individual with diabetes undergoing a lower extremity amputation was 20.3 in 2004 and 21.2 in 2008, compared with that of individuals without diabetes. CONCLUSIONS This national study suggests that the overall population burden of amputations increased in people with diabetes at a time when the number and incidence of amputations decreased in the aging nondiabetic population.