POINT: podiatry for international diabetic foot teams.

FOREWORD: The Point Project is an initiative between the two organisations: D-Foot International and the International Federation of Podiatrists (FIP-IFP). Both organisations promote the role of evidence-based foot care for patients with and at risk of diabetes. This collaborative work highlights the podiatric skills needed in order to deliver comprehensive evidence-based care to patients with diabetic foot disease. The statements along with the relevant skills and behaviours are based upon the guidance documents produced by the International Working Group on the Diabetic Foot (IWGDF), thus meaning while this is a consensus document it is also evidence-based. Representatives from both organisations with a multidisciplinary membership met early in 2017 to discuss the different areas of practice and to define which skills and behaviours were required at different levels of practice. Using the TRIEpodD-document (UK) and IWGDF guidance as the basis for discussion, the team identified which knowledge, skills and behaviours could be considered podiatric in nature. Once identified as podiatric, we discussed at which level of podiatric practice they could apply. The members of the team came from a variety of locations which represented practice at the different levels. Following the initial meeting, further discussions took place via email in order to consolidate initial discussions and complete the document. Cognisant of the large volume of guidance in relation to all areas of practice, this document is aimed to assist clinicians by pointing them in the direction in which they need to develop services rather than being a set of rules which must be followed. The POINT team feels that this document supports clinicians globally on three levels: As a benchmarking tool for existing teams to critically reflect upon their practice and identify where quality improvements can be made As a tool for clinicians who wish to establish a diabetic foot team to highlight the skills needed in order to provide care across the breadth of diabetic foot practice highlighting the specific roles in which podiatrists can help For national and local decision makers, to identify which skills can be provided by podiatrists to promote the development of the profession. While this is a consensus relating to podiatric skills, the team is aware that, in the absence of podiatrists, skills will be provided by other health professionals. We support this practice and while such professionals can not be considered podiatrists, they are providing podiatric skills to the diabetic foot team. The delivery of the relevant skill to the patient is the important factor, not the health professional is delivering it. The development of this document is merely the first step to identifying areas where skills need to be developed. Both D-Foot and FIP-IFP are committed to developing podiatric skills further across the globe. The aims and objectives of the two organisations are mutually beneficial to those suffering from diabetic foot disease. People with diabetes deserve the best care that they can receive, irrespective of the resources available. By working together we have been able to identify the podiatric knowledge, skills and behaviours required to provide evidence-based care. The next step is to work together to ensure consistent delivery of these globally for the benefit of those suffering the debilitating consequences of diabetic foot disease.

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.

Formation of the ZnFe2O4 phase in an electric arc furnace off-gas treatment system.

To better understand the phenomena of ZnFe2O4 spinel formation in electric arc furnace dust, the dust was characterized with particle size analysis, X-ray fluorescence (XRF), electron backscatter diffraction (EBSD), and electron probe micro-analysis (EPMA). Different ZnFe2O4 formation reaction extents were observed for iron oxide particles with different particle sizes. ZnO particles were present as both individual particles and aggregated on the surface of larger particles. Also, the slag particles found in the off-gas were shown not to react with the zinc vapor. After confirming the presence of a ZnFe2O4 formation reaction, the thermodynamic feasibility of in-process separation - a new electric arc furnace dust treatment technology - was reevaluated. The large air intake and the presence of iron oxide particles in the off-gas were included into the thermodynamic calculations. The formation of the stable ZnFe2O4 spinel phase was shown to be thermodynamically favorable in current electric arc furnace off-gas ducts conditions even before reaching the post combustion chamber.

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.

Reporter gene expression from LTR-circles as tool to identify HIV-1 integrase inhibitors.

Early HIV-1 integrase inhibitors, such as compounds containing a ß-diketo acid moiety, were identified by extensive high-throughput screening campaigns. Traditionally, in vitro biochemical assays, measuring the catalytic activities of integrase, have been used for this purpose. However, these assays are confounded by the absence of cellular processes or cofactors that play a role in the integration of HIV-1 DNA in the cellular genome. In contrast to regular cell-based virus inhibition assays, which targets all steps of the viral replication cycle, a novel cellular screening assays was developed to enable the specific identification of integrase inhibitors, employing a readout that is linked with the inhibition of integrase activity. Therefore, a HIV-1 lentiviral vector equipped with the enhanced green fluorescent protein (eGFP) reporter gene was used to detect expression from extrachromosomal viral DNA (1- or 2-long terminal repeat circles), formed when integration of vector DNA into the cellular genome is prevented by an integrase inhibitor. In this assay, eGFP expression from the low residual level of transcriptional activity of extrachromosomal DNA was measured via high-throughput flow cytometry. An algorithm for analysis of eGFP expression histograms enabled the specific identification of integrase inhibitors. This assay is amenable for high throughput screening to identify inhibitors of HIV-1 integrase.

A novel high-throughput cellular screening assay for the discovery of HIV-1 integrase inhibitors.

The discovery of HIV-1 integrase inhibitors has been enabled by high-throughput screening and rational design of novel chemotypes. Traditionally, biochemical assays focusing on the strand transfer activity of integrase have been used to screen compound libraries for identification of novel inhibitors. In contrast, cellular screening assays enable a phenotypic or multi-target approach, and may result in identification of compounds inhibiting integrase in its natural context, the pre-integration complex. Furthermore, a cellular assay encompassing 3' processing, strand transfer and nuclear import may lead to the identification of compounds with novel mechanisms of action targeting cellular and viral factors. Therefore, a cellular screening assay was developed, which focused on integrase activity, where infection of MT4 cells with an HIV-1 based lentiviral vector was synchronized by temporary arrest at the reverse transcriptase step and subsequent release to enable integration. The assay was validated using a panel of antivirals and proved to be a robust cellular screening assay for the identification of novel integrase inhibitors.

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.

Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics.

AIMS: Diabetic polyneuropathy (DPN) without or with neuropathic pain (DPN-P) is one of the most frequent complications of diabetes. To better delineate their respective prevalences, we conducted a cross-sectional study that included 1111 patients (767 type 2 and 344 type 1 diabetic patients) followed up in diabetic outpatients clinics. The association of DPN and DPN-P with other diabetic complications, the impact on quality of life (QoL) and pain management were also investigated. METHODS: Two validated tools (Neuropen) and the DN4 questionnaire) were used to diagnose the two conditions. Pain intensity was measured using a visual analogue scale, and participants completed the 12-item Short-Form Health Survey to evaluate the physical and mental components of QoL. Univariate and multivariate models were used for the statistical analyses. RESULTS: The prevalence of DPN was 43% (95% CI 40.1-45.9), and was higher in type 2 (50.8%) than in type 1 (25.6%) diabetic patients. The prevalence of DPN-P was 14% (95% CI 12.1-16.2) which, again, was higher in type 2 (17.9%) than in type 1 (5.8%) patients. These prevalences both increased with age and diabetes duration. Nephropathy, obesity, low HDL cholesterol and high triglyceride levels were independently associated with DPN and/or DPN-P. Physical and mental components of QoL were significantly altered by DPN-P, but not DPN. Only half of the DPN-P patients were using analgesic treatment, while 28% were using anticonvulsants or antidepressants. CONCLUSION: DPN and DPN-P are frequent complications of diabetes, especially in type 2, and can be identified with inexpensive and easy-to-use screening tools. Despite its profound impact on QoL, DPN-P remains undertreated.

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

AIMS/HYPOTHESIS: The 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. METHODS: Data 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. RESULTS: Resource 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/INTERPRETATION: Important 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. METHODS: The Eurodiale Study is a prospective cohort study of 1232 consecutive individuals presenting with a new diabetic foot ulcer in 14 centres across Europe. We determined the use of management strategies: referral, use of offloading, vascular imaging and revascularization. RESULTS: Twenty-seven percent of the patients had been treated for > 3 months before referral to a foot clinic. This varied considerably between countries (6-55%). At study entry, 77% of the patients had no or inadequate offloading. During follow-up, casting was used in 35% (0-68%) of the plantar fore- or midfoot ulcers. Predictors of use of casting were male gender, large ulcer size and being employed. Vascular imaging was performed in 56% (14-86%) of patients with severe limb ischaemia; revascularization was performed in 43%. Predictors of use of vascular imaging were the presence of infection and ischaemic rest pain. CONCLUSION: Treatment of many patients is not in line with current guidelines and there are large differences between countries and centres. Our data suggest that current guidelines are too general and that healthcare organizational barriers and personal beliefs result in underuse of recommended therapies. Action should be undertaken to overcome these barriers and to guarantee the delivery of optimal care for the many individuals with diabetic foot disease.

Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study.

AIMS/HYPOTHESIS: Outcome data on individuals with diabetic foot ulcers are scarce, especially in those with peripheral arterial disease (PAD). We therefore examined the clinical characteristics that best predict poor outcome in a large population of diabetic foot ulcer patients and examined whether such predictors differ between patients with and without PAD. METHODS: Analyses were conducted within the EURODIALE Study, a prospective cohort study of 1,088 diabetic foot ulcer patients across 14 centres in Europe. Multiple logistic regression modelling was used to identify independent predictors of outcome (i.e. non-healing of the foot ulcer). RESULTS: After 1 year of follow-up, 23% of the patients had not healed. Independent baseline predictors of non-healing in the whole study population were older age, male sex, heart failure, the inability to stand or walk without help, end-stage renal disease, larger ulcer size, peripheral neuropathy and PAD. When analyses were performed according to PAD status, infection emerged as a specific predictor of non-healing in PAD patients only. CONCLUSIONS/INTERPRETATION: Predictors of healing differ between patients with and without PAD, suggesting that diabetic foot ulcers with or without concomitant PAD should be defined as two separate disease states. The observed negative impact of infection on healing that was confined to patients with PAD needs further investigation.

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

AIMS/HYPOTHESIS: Large 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. METHODS: The 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 +. RESULTS: PAD 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/INTERPRETATION: According 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.

[Intracellular calcium-releasing channels as cellular targets for immunophilins: a molecular, functional and structural analysis]. / Intracellulaire calcium-vrijzettingskanalen als cellulaire doelwitten voor immunofilines: een moleculaire, functionele en structurele analyse.

In this study, the FKBP12-binding properties of IP3Rs and RyRs were compared. Although the primary sequence of IP3Rs en RyRs contained a putative FKBP12-binding site, the functional, molecular and structural properties of these sites appeared to be completely different. For RyRs, FKBPs appear to function as associated proteins that are important for the functional regulation of the channel, thereby stabilizing the RyR complex. For IP3Rs, FKBPs might be involved in the de novo protein synthesis of the IP3Rs and the folding of the peptide chain to a functional IP3R protein, thereby functioning as helper enzymes. Hence, it is very unlikely that they function as associated regulatory proteins of the IP3R. In addition, we provided evidence that FKBP 12 is also an important regulating protein of the Ca(2+)-flux properties of the RyR3. FKBP12 clearly modulated both RyR3-mediated global and local Ca(2+)-responses.

Calcium release from the Golgi apparatus and the endoplasmic reticulum in HeLa cells stably expressing targeted aequorin to these compartments.

Extracellular agonists mobilize Ca2+ from SERCA-comprising intracellular Ca2+ stores located in both the Golgi apparatus and the endoplasmic reticulum. Ca2+ release from both these compartments was studied in HeLa cells stably expressing the luminescent Ca2+ indicator aequorin specifically targeted to these compartments. Changes in lumenal [Ca2+] as detected by the aequorin measurements were correlated with parallel changes in total Ca2+ content of the stores. The latencies and initial rates of Ca2+ release from the Golgi apparatus and the endoplasmic reticulum were quite similar. However, maximal Ca2+ release measured with Golgi-targeted aequorin terminated faster than that from the endoplasmic reticulum. The rate and extent of Ca2+ depletion from both compartments correlated well with the peak amplitude of the cytosolic [Ca2+] rise. Time-course experiments further revealed that the peak of the cytosolic Ca2+ response occurred before the lumenal [Ca2+] reached its lowest level. We conclude that both the Golgi apparatus and the endoplasmic reticulum contribute to the rise in cytosolic [Ca2+] upon agonist stimulation, but the kinetics of the Ca2+ release are different.

IP(3)-mediated Ca(2+) signals in human neuroblastoma SH-SY5Y cells with exogenous overexpression of type 3 IP(3) receptor.

Human neuroblastoma SH-SY5Y cells, predominantly expressing type 1 inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R), were stably transfected with IP(3)R type 3 (IP(3)R3) cDNA. Immunocytochemistry experiments showed a homogeneous cytoplasmic distribution of type 3 IP(3)Rs in transfected and selected high expression cloned cells. Using confocal Ca(2+) imaging, carbachol (CCh)-induced Ca(2+) release signals were studied. Low CCh concentrations (< or = 750 nM) evoked baseline Ca(2+) oscillations. Transfected cells displayed a higher CCh responsiveness than control or cloned cells. Ca(2+) responses varied between fast, large Ca(2+) spikes and slow, small Ca(2+) humps, while in the clone only Ca(2+) humps were observed. Ca(2+) humps in the transfected cells were associated with a high expression level of IP(3)R3. At high CCh concentrations (10 microM) Ca(2+) transients in transfected and cloned cells were similar to those in control cells. In the clone exogenous IP(3)R3 lacked the C-terminal channel domain but IP(3)-binding capacity was preserved. Transfected cells mainly expressed intact type 3 IP(3)Rs but some protein degradation was also observed. We conclude that in transfected cells expression of functional type 3 IP(3)Rs causes an apparent higher affinity for IP(3). In the clone, the presence of degraded receptors leads to an efficient cellular IP(3) buffer and attenuated IP(3)-evoked Ca(2+) release.

Helicobacter pylori, parietal cell antibodies and autoimmune gastropathy in type 1 diabetes mellitus.

BACKGROUND: Fifteen to 20% of type 1 diabetic patients exhibit parietal cell antibodies (PCA), which are associated with autoimmune gastritis, hypochlorhydria, iron deficiency and pernicious anaemia. AIM: To examine whether Helicobacter pylori infection could explain the high prevalence of PCA and autoimmune gastropathy in diabetes. If so, H. pylori eradication could prevent autoimmune gastritis. METHODS: In 229 type 1 diabetics (M/F: 135/94; age: 41 +/- 12 years) PCA were measured. H. pylori infection was assessed by serology, urea breath test in all and by histology (updated Sydney system) in 88 subjects. Pentagastrin tests were performed in 42 patients. RESULTS: Sixty-nine patients were PCA-positive. H. pylori infection was present in 72 patients and was negatively associated with HLA-DQA1*0103-B1*0603 (OR=0.12, P=0.015) and positively with DQA1*0501-B1*0201 (OR=1.9, P=0.032). PCA-positivity was linked to HLA-DQA1*0501-B1*0301 (OR=3.9, P=0.017). A link between H. pylori and PCA was observed when PCA-positivity was defined as a titre > or = 1/20 (OR=2.0, P=0.03), but not if > or =1/40 was the cut-off point. PCA-positivity, but not H. pylori infection, was associated with iron deficiency anaemia (OR=2.7, P=0.008), pernicious anaemia (OR= 33.5, P < 0.0001), hypochlorhydria (OR=12.1, P=0.0008) and autoimmune gastritis (OR=12.5, P < 0.0001). CONCLUSIONS: The HLA-bound susceptibility of H. pylori and PCA differed. PCA-positivity but not ongoing H. pylori infection is associated with autoimmune gastritis. Low titres of PCA might reflect H. pylori infection rather than autoimmune gastropathy.

Ethical aspects of cardiopulmonary resuscitation in premature neonates: where do we stand?

Advances in diagnosis, techniques, therapeutic interventions, organisation of perinatal care, and socio-economic factors have all contributed to the survival after resuscitation and intensive care of neonates with extremely low birth weight and gestational age. While morbidity during the first years of life in those infants does not increase, at school age multiple dysfunctions may become apparent. What are the limits of intensive care for the newborn? Is it right to use extreme technical and economic measures for neonates with a borderline chance of survival? What is justifiable for the neonate, the family, the society and how does legislation interfere in a decision process which involves starting, stopping or continuing intensive care? A short historical overview for the care of the newborn is given, followed by the outcome after resuscitation and treatment of the very low birth weight infant. Published management strategies and recommendations are discussed.

Baseline cytosolic Ca2+ oscillations derived from a non-endoplasmic reticulum Ca2+ store.

Cytosolic Ca(2+) oscillations can be due to cycles of release and re-uptake of internally stored Ca(2+). To investigate the nature of these Ca(2+) stores, we expressed the Pmr1 Ca(2+) pump of Caenorhabditis elegans in COS-1 cells and pretreated the cells with thapsigargin to prevent Ca(2+) uptake by the sarco(endo)plasmic reticulum Ca(2+)-ATPase. Pmr1 co-localized with the Golgi-specific 58K protein and was targeted to a Ca(2+) store that was less leaky for Ca(2+) than the endoplasmic reticulum and whose inositol trisphosphate receptors were less sensitive to inositol trisphosphate and ATP than those in the endoplasmic reticulum. ATP-stimulated Pmr1-overexpressing cells responded after a latency to extracellular Ca(2+) with a regenerative Ca(2+) signal, which could be prevented by caffeine. They also produced very stable ilimaquinone-sensitive baseline Ca(2+) spikes, even in the presence of thapsigargin. Such responses never occurred in non-transfected cells or in cells that overexpressed the type-1 sarco(endo)plasmic reticulum Ca(2+)-ATPase. Abortive Ca(2+) spikes also occurred in histamine-stimulated untransfected HeLa cells pretreated with thapsigargin, and they too were inhibited by ilimaquinone. We conclude that the Pmr1-induced Ca(2+) store, which probably corresponds to the Golgi compartment, can play a crucial role in setting up baseline Ca(2+) spiking.

Repaglinide improves blood glucose control in sulphonylurea-naive type 2 diabetes.

The prandial glucose regulator repaglinide has a rapid onset of action, a short half-life and is metabolised mainly by the liver. Here we report the findings of a 10-week, double-blind, parallel, placebo controlled, randomised trial with repaglinide in 25 diet-treated, sulphonylurea-naïve patients with Type 2 diabetes. Repaglinide was titrated, based on capillary blood glucose, from 0.5 mg to a maximum of 4 mg, preprandially with breakfast and dinner. After 10 weeks, repaglinide was associated with a decrease in HbA(1c) of 2.3%Hb relative to the placebo group (P=0.018). This reflected a 30% decrease within the repaglinide group from a mean HbA(1c) of 7.0 to 4.9%Hb (P<0.002). Repaglinide was also associated with a decrease in fructosamine, by 0.88 mmol/l, relative to placebo (P<0.001), with a 20% decrease (from 3.80 to 3.04 mmol/l) within the repaglinide group (P<0.001). Fasting and postprandial blood glucose concentrations decreased in association with repaglinide by 3.6 and 6.4 mmol/l, respectively, relative to placebo (P<0.001 in each case). Within the repaglinide group fasting and postprandial blood glucose decreased by 3.9 and 6.2 mmol/l, respectively (P<0.001 in each case). The number of patients reporting hypoglycaemia in the repaglinide group was similar to placebo (15 vs. 20, respectively; NS). Test meal assessments confirmed that repaglinide effectively controls glucose levels by stimulating mealtime insulin secretion. Fasting serum insulin concentration was not raised compared to baseline or placebo during repaglinide therapy, albeit that fasting glucose levels were decreased by repaglinide. Twice-daily meal-related insulin secretagogue therapy with repaglinide, a new short and rapid-acting prandial glucose regulator, is capable of improving all measures of glycaemic control without increased hypoglycaemia or fasting hyperinsulinaemia.

The Diabetic Foot Project of Flanders, the northern part of Belgium: implementation of the St Vincent consensus. Sensibilisation and registration in diabetes centres.

As a result of the St Vincent declaration, a Belgian "task force" was installed in 1992 and consequently 16 working groups were formed. They presented their objectives in 1995. The working group "prevention and treatment of diabetic foot lesions" started the implementation of a screening program to obtain an overview of the presentation of diabetic foot lesions, the amputation rate and the prevalence of patients with a foot at risk. This study reports the results from 43 out of 73 Flemish diabetes centres. 1653 patients were enrolled in this study (53% women, 47% men, median age 61). 34.6% were type 1 and, 65.4% type 2. One or more arterial pedal pulses were absent in 28%, 30.5% had an abnormal monofilament test, 35% skin lesions and 28% malformations. Still 19% smoked, 15.8% had visual problems and 11% had already developed an ulcer previously. Ulcers were reported in 8.7% of which almost 2/3 belonged to Wagner class I. 69 (3.87%) of the patients had had amputations. According to the four-risk categories-scale 46.3% of the patients belonged to the highest one; peripheral vascular disease, previous amputations, previous ulcers, and Charcot joints. In our region we didn't have previous data on the prevalence and morbidity of the amputation rate with diabetes patients. We observed 3.87% amputations, which is rather high in comparison with international data (0.44% - 2.4%). The general follow-up of diabetic foot problems can be organised in co-operation with other care providers. A national program therefore is going to start in the next months. We all have to be aware of the size of the problem to offer the best possible prevention. As we have seen, the use of inlay soles and podiatrist-made ortheses for example is very low. We hope that all care providers will participate in this important project, so that they will acquire a specific attitude towards these patients. In daily clinical practice there are some key-roles to be respected by all health care providers. In our opinion the next are of the utmost importance: take off your diabetic patient's shoes when they visit you; give specific education if your patient has a foot at risk; if an ulcer is present, carefully follow-up is mandatory and if no good evolution of the ulcer is seen, an early referral to a diabetic foot clinic is obvious. Together we can lower down the amputation rate of diabetic foot lesions. And that would be a marvelous implementation of the St Vincent declaration in Belgium.