Infrared thermography and ulcer prevention in the high-risk diabetic foot: data from a single-blind multicentre controlled clinical trial.

AIM: To assess the usefulness of monthly thermography and standard foot care to reduce diabetic foot ulcer recurrence. METHODS: People with diabetes (n = 110), neuropathy and history of ≥ 1 foot ulcer participated in a single-blind multicentre clinical trial. Feet were imaged with a novel thermal imaging device (Diabetic Foot Ulcer Prevention System). Participants were randomized to intervention (active thermography + standard foot care) or control (blinded thermography + standard foot care) and were followed up monthly until ulcer recurrence or for 12 months. Foot thermograms of participants from the intervention group were assessed for hot spots (areas with temperature ≥ 2.2°C higher than the corresponding contralateral site) and acted upon as per local standards. RESULTS: After 12 months, 62% of participants were ulcer-free in the intervention group and 56% in the control group. The odds ratios of ulcer recurrence (intervention vs control) were 0.82 (95% CI 0.38, 1.8; P = 0.62) and 0.55 (95% CI 0.21, 1.4; P = 0.22) in univariate and multivariate logistic regression analyses, respectively. The hazard ratios for the time to ulcer recurrence (intervention vs control) were 0.84 (95% CI 0.45, 1.6; P = 0.58) and 0.67 (95% CI 0.34, 1.3; P = 0.24) in univariate and multivariate Cox regression analyses, respectively. CONCLUSIONS: Monthly intervention with thermal imaging did not result in a significant reduction in ulcer recurrence rate or increased ulcer-free survival in this cohort at high risk of foot ulcers. This trial has, however, informed the design of a refined study with longer follow-up and group stratification, further aiming to assess the efficacy of thermography to reduce ulcer recurrence.

Developing a foot ulcer risk model: what is needed to do this in a real-world primary care setting?

AIM: To determine how routinely collected data can inform a risk model to predict de novo foot ulcer presentation in the primary care setting. METHODS: Data were available on 15 727 individuals without foot ulcers and 1125 individuals with new foot ulcers over a 12-year follow-up in UK primary care. We examined known risk factors and added putative risk factors in our logistic model. RESULTS: People with foot ulcers were 4.2 years older (95% CI 3.1-5.2) than those without, and had higher HbA1c % (mean 7.9 ± 1.9 vs 7.5 ± 1.7) / HbA1c mmol/mol (63 ± 21 vs 59 ± 19) (p<0.0001) concentration [+0.45 (95% CI 0.33-0.56), creatinine level [+6.9 µmol/L (95% CI 4.1-9.8)] and Townsend score [+0.055 (95% CI 0.033-0.077)]. Absence of monofilament sensation was more common in people with foot ulcers (28% vs 21%; P<0.0001), as was absence of foot pulses (6.4% vs 4.8%; P=0.017). There was no difference between people with or without foot ulcers in smoking status, gender, history of stroke or foot deformity, although foot deformity was extremely rare (0.4% in people with foot ulcers, 0.6% in people without foot ulcers). Combining risk factors in a single logistic regression model gave modest predictive power, with an area under the receiver-operating characteristic curve of 0.65 (95% CI 0.62-0.67). The prevalence of ulceration in the bottom decile of risk was 1.8% and in the top decile it was 13.4% (compared with an overall prevalence of 6.5%); thus, the presence of all six risk factors gave a relative risk of 7.4 for development of a foot ulcer over 12 years. CONCLUSION: We have made some progress towards defining a variable set that can be used to create a foot ulcer prediction model. More accurate determination of foot deformity/pedal circulation in primary care may improve the predictive value of such a future risk model, as will identification of additional risk variables.

Barriers to foot care in patients with diabetes as identified by healthcare professionals.

AIMS: To seek the views of healthcare professionals as to the barriers to foot care that they perceive as having an impact on clinical outcomes and contributing to the number of amputations. METHODS: The study involved healthcare professionals from the UK attending our 2015 and 2016 Masterclass diabetic foot conferences. Admission to these conferences was open to all members of the multidisciplinary spectrum who provide care of people with diabetes and foot problems. Attendees were asked to write down concerns that they considered to constitute barriers to foot care for people with diabetes. RESULTS: A total of 425 responses were received (90.8% of the total attendance at the 2015/2016 conferences). Analysis of the responses produced eight key subject areas in which barriers to care were identified: patient referrals, communication between disciplines, access to specialist services, patient care, funding, organization of care, education and infection. Within these key areas, respondents reported poor recognition and diagnosis of foot problems, lack of awareness of the need for referral both by the person with diabetes and healthcare professionals, difficulties in the referral pathway, lack of access to multidisciplinary care, shortage of resources and lack of education of both people with diabetes and healthcare professionals. The respondents identified these barriers as contributing to delay in people with diabetes receiving specialist help. Such a delay can lead to amputation. CONCLUSIONS: The crucial barrier to diabetic foot care is delay in accessing specialist care. Until this is addressed, care will be less than optimum and amputations will continue.

Minor amputation does not negatively affect health-related quality of life as compared with conservative treatment in patients with a diabetic foot ulcer: An observational study.

BACKGROUND: Health-related quality of life (HRQoL) is poor in patients with persistent diabetic foot ulcers and poor HRQoL predicts worse outcomes in these patients. Amputation is often considered a treatment failure, which is why conservative treatment is generally preferred over amputation. However, it is unclear whether minor amputation negatively affects HRQoL compared with conservative treatment in patients with diabetic foot ulcers. METHODS: In the cohort of the multicenter, prospective, observational Eurodiale study, we determined difference in change of HRQoL measured by EQ-5D between patients with a diabetic foot ulcers that healed after conservative treatment (n = 676) and after minor amputation (n = 145). Propensity score was used to adjust for known confounders, attempting to overcome lack of randomization. RESULTS: Baseline HRQoL was not significantly different between patients treated conservatively and undergoing minor amputation. In addition, there was no difference in the change of HRQoL between these groups. In patients who healed 6 to 12 months after the first visit, HRQoL on the anxiety/depression subscale even appeared to improve more in those who underwent minor amputation. CONCLUSIONS: Minor amputation was not associated with a negative impact on HRQoL in patients with a diabetic foot ulcers. It may therefore not be considered treatment failure in terms of HRQoL but rather a viable treatment option. A randomized controlled trial is warranted to further examine the influence of minor amputations on health-related quality of life.

Acute Charcot neuro-osteoarthropathy.

Charcot neuro-osteoarthropathy (CN) is one of the most challenging foot complications in diabetes. Common predisposing and precipitating factors include neuropathy and increased mechanical forces, fracture and bone resorption, trauma and inflammation. In the last 15 years, considerable progress has been made in the early recognition of the acute Charcot foot when the X ray is still negative (stage 0 or incipient Charcot foot). Recent advances in imaging modalities have enabled the detection of initial signs of inflammation and underlying bone damage before overt bone and joint destruction has occurred. Casting therapy remains the mainstay of medical therapy of acute CN. If timely instituted, offloading can arrest disease activity and prevent foot deformity. In cases with severe deformity, modern surgical techniques can correct the unstable deformity for improved functional outcome and limb survival. Emerging new studies into the cellular mechanisms of severe bone destruction have furthered our understanding of the mechanisms of pathological bone and joint destruction in CN. It is hoped that these studies may provide a scientific basis for new interventions with biological agents.

Undiagnosed severe sleep apnoea and diabetic foot ulceration - a case series based hypothesis: a hitherto under emphasized factor in failure to heal.

BACKGROUND: Although great progress has been made in managing diabetic foot disease, it continues to carry significant morbidity and mortality. Obstructive sleep apnoea (OSA) and diabetes frequently coexist and recent studies suggest significant under-recognition of OSA in those with diabetes. There are no current reports on the direct clinical impact of OSA on acute or chronic diabetic foot ulcer healing. CASE REPORT: We describe three cases with Type 2 diabetes and a mean BMI of 50 kg/m(2) in whom we believe undiagnosed severe OSA may have impeded the rate of recovery of acutely infected foot ulcers. Despite standard care whilst in hospital with optimization of glycaemia, daily wound care, ulcer offloading techniques including casting, it was difficult to achieve satisfactory granulation in the first two cases with previously unrecognized and hence untreated severe OSA (Apnoea-Hypopnea Index > 30) until correction had been achieved through continuous positive airway pressure therapy (CPAP). In the third case, despite all optimization techniques, healing has not been achieved and individuals' reluctance to consider CPAP may be one possible factor. DISCUSSION: We observe in three severely obese individuals with diabetes that untreated severe OSA may have contributed to delayed wound healing. We also observed an improvement in two individuals after institution of CPAP therapy. Clinicians managing the diabetic foot should consider investigating the presence of OSA in non-healing or slowly progressive foot ulcers when all other factors have been fully optimized.

Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute Charcot osteoarthropathy.

AIMS: To assess markers of inflammation and bone turnover at presentation and at resolution of Charcot osteoarthropathy. METHODS: We measured serum inflammatory and bone turnover markers in a cross-sectional study of 35 people with Charcot osteoarthropathy, together with 34 people with diabetes and 12 people without diabetes. In addition, a prospective study of the subjects with Charcot osteoarthropathy was conducted until clinical resolution. RESULTS: At presentation, C-reactive protein (P = 0.007), tumour necrosis factor-α (P = 0.010) and interleukin-6 (P = 0.002), but not interleukin-1ß, (P = 0.254) were significantly higher in people with Charcot osteoarthropathy than in people with and without diabetes. Serum C-terminal telopeptide (P = 0.004), bone alkaline phosphatase (P = 0.006) and osteoprotegerin (P < 0.001), but not tartrate-resistant acid phosphatase (P = 0.126) and soluble receptor activator of nuclear factor-κß ligand (P = 0.915), were significantly higher in people with Charcot osteoarthropathy than in people with and without diabetes. At follow-up it was found that tumour necrosis factor-α (P = 0.012) and interleukin-6 (P = 0.003), but not C-reactive protein (P = 0.101), interleukin-1ß (P = 0.457), C-terminal telopeptide (P = 0.743), bone alkaline phosphatase (P = 0.193), tartrate-resistant acid phosphatase (P = 0.856), osteoprotegerin (P = 0.372) or soluble receptor activator of nuclear factor-kß ligand (P = 0.889), had significantly decreased between presentation and the 3 months of casting therapy time point, and all analytes remained unchanged from 3 months of casting therapy until resolution. In people with Charcot osteoarthropathy, there was a positive correlation between interleukin-6 and C-terminal telopeptide (P = 0.028) and tumour necrosis factor-α and C-terminal telopeptide (P = 0.013) only at presentation. CONCLUSIONS: At the onset of acute Charcot foot, serum concentrations of tumour necrosis factor-α and interleukin-6 were elevated; however, there was a significant reduction in these markers at resolution and these markers may be useful in the assessment of disease activity.

Charge transfer doping of silicon.

We demonstrate a novel doping mechanism of silicon, namely n-type transfer doping by adsorbed organic cobaltocene (CoCp2*) molecules. The amount of transferred charge as a function of coverage is monitored by following the ensuing band bending via surface sensitive core-level photoelectron spectroscopy. The concomitant loss of electrons in the CoCp2* adlayer is quantified by the relative intensities of chemically shifted Co2p components in core-level photoelectron spectroscopy which correspond to charged and neutral molecules. Using a previously developed model for transfer doping, the evolution in relative intensities of the two components as a function of coverage has been reproduced successfully. A single, molecule-specific parameter, the negative donor energy of -(0.50±0.15) eV suffices to describe the self-limiting doping process with a maximum areal density of transferred electrons of 2×1013 cm-2 in agreement with the measured downward band bending. The advantage of this doping mechanism over conventional doping for nanostructures is addressed.

Treating comorbid insomnia in patients enrolled in therapist-assisted transdiagnostic internet-delivered cognitive behaviour therapy for anxiety and depression: A randomized controlled trial.

Transdiagnostic Internet-delivered cognitive behaviour therapy (ICBT) for patients experiencing anxiety and depression can produce large improvements in symptoms. Comorbid insomnia is common among individuals seeking treatment for anxiety and depression, yet transdiagnostic ICBT rarely targets insomnia and many ICBT patients report that symptoms of insomnia remain after treatment. This trial explored the impact of including a brief intervention for insomnia alongside an existing transdiagnostic ICBT course that included brief weekly therapist assistance. Patients were randomly assigned to receive either the Standard transdiagnostic (n = 75) or a Sleep-Enhanced course (n = 142), which included information on sleep restriction and stimulus control. Intent-to-treat analyses using generalized estimating equation (GEE) showed significant, large reductions in all primary outcomes (insomnia: d = 0.96, 95 % CI [0.68, 1.24]; depression: d = 1.04, 95 % CI [0.76, 1.33]; and anxiety: d = 1.23, 95 % CI [0.94, 1.52]) from pre-treatment to post-treatment, with changes maintained at 3-months. Patients assigned to the Sleep-Enhanced course reported larger reductions in insomnia than patients in the Standard transdiagnostic course (Cohen's d = 0.31, 95 % CI [0.034, 0.60]) at post-treatment but no significant between-group differences in any of the primary outcomes were found at follow-up. Patient-reported adherence to sleep restriction guidelines (p = .03), but not stimulus control instructions (p = .84) was associated with greater reductions in insomnia symptoms during the course. Overall, patients who received the Sleep-Enhanced course were satisfied with the materials and most patients reported making sleep behaviour changes. The trial results demonstrate that including a brief intervention targeting insomnia can be beneficial for many patients who enroll in ICBT primarily for symptoms related to anxiety and depression.

Simulating an interacting gauge theory with ultracold Bose gases.

We show how density dependent gauge potentials can be induced in dilute gases of ultracold atoms using light-matter interactions. We study the effect of the resulting interacting gauge theory and show how it gives rise to novel topological states in the ultracold gas. We find in particular that the onset of persistent currents in a ring geometry is governed by a critical number of particles. The density-dependent gauge potential is also found to support chiral solitons in a quasi-one-dimensional ultracold Bose gas.

Importance of factors determining the low health-related quality of life in people presenting with a diabetic foot ulcer: the Eurodiale study.

AIM: To identify the factors responsible for the low health-related quality of life associated with foot ulcers and the relative importance of these factors. METHODS: A total of 1232 patients with a new foot ulcer, who presented at one of the 14 centres in 10 European countries participating in the Eurodiale study, were included in this cross-sectional study. Patient and ulcer characteristics were obtained as well as results from the Euro-Qol-5D questionnaire, a health-related quality of life instrument with five domains (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). To analyse the relative importance of comorbidities and ulcer- and patient-related factors for health-related quality of life, linear regression models were used to calculate the relative contributions of each factor to the fit (R(2) ) of the model. RESULTS: Patients reported poor overall health-related quality of life, with problems primarily in the mobility and pain/discomfort domains. Among the comorbidities, the inability to stand or walk without help was the most important determinant of decreased health-related quality of life in all five domains. Among ulcer-related factors, ulcer size, limb-threatening ischaemia and elevated C-reactive protein concentration also had high importance in all domains. The clinical diagnosis of infection, peripheral arterial disease and polyneuropathy were only important in the pain/discomfort domain. CONCLUSIONS: The factors that determine health-related quality of life are diverse and to an extent not disease-specific. To improve health-related quality of life, treatment should not only be focused on ulcer healing but a multifactorial approach by a specialized multidisciplinary team is also important.

Medical management of Charcot arthropathy.

Charcot arthropathy is a major complication of diabetes and it poses management challenges to health care professionals. Early diagnosis and timely intervention are essential for improved outlook of these patients. Casting therapy has been accepted as the mainstay treatment of the acute Charcot foot, although there are still controversies regarding its duration, the choice of removable and non-removable device and weight-bearing casts vs. non-weight-bearing casts. Two groups of antiresorptive therapies have been evaluated in the treatment of the acute Charcot foot, bisphosphonates (intravenous and oral) and calcitonin. These therapies have clearly shown a reduction of bone turnover, although, they have not shown a significant effect on temperature reduction. Current evidence to support their use is weak. An anabolic agent to speed up clinical resolution and fracture healing may be helpful and a clinical trial to evaluate the possible benefit of 1-84 recombinant human parathyroid hormone on fracture healing in the acute Charcot foot is in progress. This paper summarises the current approach to medical management of acute Charcot arthropathy with specific emphasis on casting and pharmacological therapy. Emerging new studies of the pathogenesis of this condition are also discussed.

Five-year follow-up of a cohort of people with their first diabetic foot ulcer: the persistent effect of depression on mortality.

AIMS/HYPOTHESIS: Depressive disorders are associated with mortality within 18 months of presentation of diabetic foot ulcers (DFU). The main aim of this study was to determine whether depressive disorder is still associated with increased mortality in people with their first foot ulcer at 5 years. METHODS: This is a 5-year follow-up of a cohort of 253 patients presenting with their first DFU. At baseline, the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) 2.1 was used to define those who met DSM-IV (Diagnostic and Statistical Manual 4th edition) criteria for depressive disorder. Cox regression analysis controlled for potential covariates: age, sex, marital status, socioeconomic status, smoking, mean HbA(1c), diabetes complications and ulcer severity. The main outcome was mortality at 5 years. RESULTS: The prevalence of DSM-IV depressive disorder at baseline was 32.2% (n = 82). There were 92 (36.4%) deaths over the 5 years of follow-up. In the Cox regression (n = 246), after adjusting for covariates, baseline DSM-IV depressive disorder was significantly associated with a twofold increased risk of mortality for any depressive episode (HR 2.09, 95% CI 1.34, 3.25), minor (HR 1.93, 95% CI 1.00, 3.74) or major depressive disorders (HR 2.18, 95% CI 1.31, 3.65), compared with patients who were not depressed. CONCLUSIONS/INTERPRETATION: Depression is associated with a persistent twofold increased risk of mortality in people with their first DFU at 5 years.

Audit of acute Charcot's disease in the UK: the CDUK study.

AIMS/HYPOTHESIS: We studied factors associated with the development and resolution of acute Charcot foot using a web-based observational study. METHODS: Clinicians managing cases of acute Charcot foot in the UK and Ireland between June 2005 and February 2007 were invited to register anonymised details on a secure website. RESULTS: A total of 288 cases (age 57.0 ± 11.3 years [mean ± SD]; 71.2% male) were registered from 76 centres. Of these, 36% of patients recalled an episode of relevant trauma in the preceding 6 months, while 12% had had surgery to the affected foot. In 101 (35%) cases, ulceration was present at registration and 20% of these had osteomyelitis. Non-removable off-loading devices were used at presentation in 35.4% of cases, with removable off-loading used in 50%. Data on resolution were available for 219 patients. The median time to resolution was 9 months in patients whose initial management included the use of non-removable off-loading, compared with 12 months in the remainder (p = 0.001). Bisphosphonates were administered intravenously in 25.4% and orally in 19.4% of cases. The median time to resolution in patients who received bisphosphonates was 12 months and was longer than in those who did not (10 months, p = 0.005). CONCLUSIONS/INTERPRETATION: The median time to resolution was longer than in earlier series. Although limited by being observational and non-randomised, these data suggest that the use of non-removable off-loading at presentation may shorten the time to resolution. They provide no evidence to indicate that the use of bisphosphonates is beneficial.

Osteoprotegerin gene polymorphism in diabetic Charcot neuroarthropathy.

AIMS: Recently, an association between two polymorphisms (1181G>C and 245T>G) of the osteoprotegerin (OPG) gene and diabetic Charcot neuroarthropathy was suggested on the basis of studies of a limited number of samples derived from subjects from one geographical region (Italy). The aim of this study was to assess the presence of various osteoprotegerin gene polymorphisms in patients with diabetes and Charcot neuroarthropathy compared with subjects with diabetic neuropathy but no Charcot foot and healthy controls from another geographical region (Poland). METHODS: DNA was isolated from 54 patients with Charcot neuroarthropathy, 35 subjects with diabetic neuropathy but no Charcot foot, and 95 healthy controls to evaluate OPG gene polymorphisms and their possible contribution to the development of Charcot neuroarthropathy. RESULTS: Statistically significant differences between the group of subjects with neuropathy but no Charcot neuroarthropathy and the control group were found for 1217C>T, 950T>C and 245T>G polymorphisms, between the group of patients with Charcot neuroarthropathy and the control group for 1181G>C and 950T>C polymorphisms, and between the group of subjects with neuropathy but no Charcot neuroarthropathy and the group of patients with Charcot neuroarthropathy for 1217C>T and 245T>G polymorphisms. CONCLUSION: We suggest that genetic factors, particularly OPG gene polymorphisms, may play a role in the development of diabetic Charcot neuroarthropathy.

Surface transfer doping of hydrogen-terminated diamond by C60F48: energy level scheme and doping efficiency.

Surface sensitive C1s core level photoelectron spectroscopy was used to examine the electronic properties of C(60)F(48) molecules on the C(100):H surface. An upward band bending of 0.74 eV in response to surface transfer doping by fluorofullerene molecules is measured. Two distinct molecular charge states of C(60)F(48) are identified and their relative concentration determined as a function of coverage. One corresponds to ionized molecules that participate in surface charge transfer and the other to neutral molecules that do not. The position of the lowest unoccupied molecular orbital of neutral C(60)F(48) which is the relevant acceptor level for transfer doping lies initially 0.6 eV below the valence band maximum and shifts upwards in the course of transfer doping by up to 0.43 eV due to a doping induced surface dipole. This upward shift in conjunction with the band bending determines the occupation of the acceptor level and limits the ultimately achievable hole concentration with C(60)F(48) as a surface acceptor to values close to 10(13) cm(-2) as reported in the literature.

Study protocol for a multicentre comparative diagnostic accuracy study of tools to establish the presence and severity of peripheral arterial disease in people with diabetes mellitus: the DM PAD study.

INTRODUCTION: Peripheral arterial disease (PAD) is a key risk factor for cardiovascular disease, foot ulceration and lower limb amputation in people with diabetes. Early diagnosis of PAD can enable optimisation of therapies to manage these risks. Its diagnosis is fundamental, though challenging in the context of diabetes. Although a variety of diagnostic bedside tests are available, there is no agreement as to which is the most accurate in routine clinical practice.The aim of this study is to determine the diagnostic performance of a variety of tests (audible waveform assessment, visual waveform assessment, ankle brachial pressure index (ABPI), exercise ABPI and toe brachial pressure index (TBPI)) for the diagnosis of PAD in people with diabetes as determined by a reference test (CT angiography (CTA) or magnetic resonance angiography (MRA)). In selected centres, we also aim to evaluate the performance of a new point-of-care duplex ultrasound scan (PAD-scan). METHODS AND ANALYSIS: A prospective multicentre diagnostic accuracy study (ClinicalTrials.gov Identifier NCT05009602). We aim to recruit 730 people with diabetes from 18 centres across the UK, covering primary and secondary healthcare. Consenting participants will undergo the tests under investigation. Reference tests (CTA or MRA) will be performed within 6 weeks of the index tests. Imaging will be reported by blinded consultant radiologists at a core imaging lab, using a validated scoring system, which will also be used to categorise PAD severity. The presence of one or more arterial lesions of ≥50% stenosis, or tandem lesions with a combined value of ≥50%, will be used as the threshold for the diagnosis of PAD. The primary outcome measure of diagnostic performance will be test sensitivity. ETHICS AND DISSEMINATION: The study has received approval from the National Research Ethics Service (NRES) (REC reference 21/PR/1221). Results will be disseminated through research presentations and papers. TRIAL REGISTRATION NUMBER: NCT05009602.

Differences in minor amputation rate in diabetic foot disease throughout Europe are in part explained by differences in disease severity at presentation.

OBJECTIVES: The incidence of minor amputation may vary significantly, and determinants of minor amputation have not been studied systematically. We evaluated minor amputation rate, the determinants of minor amputation and differences in amputation rate between European centres. METHODS: In the Eurodiale study, a prospective cohort study of 1232 patients (1088 followed until end-point) with a new diabetic foot ulcer were followed on a monthly basis until healing, death, major amputation or up to a maximum of 1 year. Ulcers were treated according to international guidelines. Baseline characteristics independently associated with minor amputation were examined using multiple logistic regression modelling. Based on the results of the multivariable analysis, a disease severity score was calculated for each patient. RESULTS: One hundred and ninety-four (18%) patients underwent a minor amputation. Predictors of minor amputation were depth of the ulcer (odds ratio 6.08, confidence interval 4.10-9.03), peripheral arterial disease (odds ratio 1.84, confidence interval 1.30-2.60), infection (odds ratio 1.56, confidence interval 1.05-2.30) and male sex (odds ratio 1.42, confidence interval 0.99-2.04). Minor amputation rate varied between 2.4 and 34% in the centres. Minor amputation rate in centres correlated strongly with disease severity score at the moment of presentation to the foot clinic (r=0.75). CONCLUSIONS: Minor amputation is performed frequently in diabetic foot centres throughout Europe and is determined by depth of the ulcer, peripheral arterial disease, infection and male sex. There are important differences in amputation rate between the European centres, which can be explained in part by severity of disease at presentation. This may suggest that early referral to foot clinics can prevent minor amputations.

Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression.

AIMS: Thiazolidinediones (TZDs) are associated with a higher risk of bone fracture in women compared with men. The aim of the present study was to investigate whether TZDs could influence osteocyte behaviour and contribute to the skeletal phenotype observed in TZD-treated patients. METHODS: The murine MLO-Y4 cell line was used as a source of osteocytes. These cells were cultured for 24 h with 0, 10(-8) m, 10(-7) m, 10(-6) m, 10(-5) m or 10(-4) m of pioglitazone, rosiglitazone or troglitazone in the presence or absence of 17beta-oestradiol. The extent of osteocyte apoptosis was assessed, as was the expression of the bone formation inhibitor sclerostin and receptor activator for nuclear factor kappaB ligand (RANKL) also. RESULTS: In the absence of 17beta-oestradiol, pioglitazone, rosiglitazone and troglitazone induced osteocyte apoptosis dose-dependently even at the lowest concentration of 10(-8) m. Furthermore, the expression of sclerostin but not RANKL was significantly increased in TZD-treated cultures compared with untreated cultures. The presence of 17beta-oestradiol significantly reduced TZD-induced osteocyte apoptosis and also sclerostin up-regulation. CONCLUSIONS: These findings therefore raise the potential concern of using TZDs in post-menopausal women where the lack of oestrogen would not prevent osteocyte apoptosis and sclerostin up-regulation and may aggravate the reduction in bone mass in these patients.