[Diabetic foot: new insights into pathophysiology and treatment]. / Diabetische voet: nieuwe inzichten in pathofyrsiologie en behandeling.

A foot ulcer is a complication that is difficult to treat in people with diabetes mellitus. Over the past few years, both clinicians and scientists have been showing more interest in this condition. A number of factors are involved in the development and maintenance of a diabetic foot ulcer, including: polyneuropathy, mechanical overload, peripheral arterial disease and infection. The cornerstones of treatment are: relief of pressure, the restoration of perfusion ofthe foot, treatment of infection, wound care, optimum glucose regulation and education. New and effective methods of treatment have become available. These include a non-removable plaster cast that is modelled to the form of the foot (a 'total contact cast'), endovascular revascularisation procedures in the lower leg, and topical application of negative pressure.

Progressive vertebral deformities despite unchanged bone mineral density in patients with sarcoidosis: a 4-year follow-up study.

UNLABELLED: To evaluate the incidence of new and/or progressive vertebral deformities and changes in bone mineral density, we re-examined 66 patients with sarcoidosis after a follow-up period of four years. In 17 subjects (26%) new and/or progressive vertebral deformities were found, though BMD did not change significantly. INTRODUCTION: Previous studies from our group have shown that morphometric vertebral deformities suggestive of fractures can be found in 20% of patients with sarcoidosis, despite a normal bone mineral density (BMD). The aim of this study was to determine the incidence of new and/or progressive vertebral deformities and the evolution of BMD during the course of this disease. METHODS: BMD of the hip (DXA) and vertebral fracture assessment (VFA) with lateral single energy densitometry was performed at baseline and after 45 months in 66 patients with sarcoidosis. Potential predictors of new/ progressive vertebral deformities were assessed using logistic regression analysis. RESULTS: The BMD of the total group was unchanged after follow-up. The prevalence of vertebral deformities increased from 20 to 32% (p < 0.05); in 17 subjects (26%) new or progressive vertebral deformities were diagnosed. A lower T-score of the femoral neck [(OR = 2.5 (CI: 1.0-5.9), p < 0.05)] and mother with a hip fracture [(OR = 14.1 (CI: 1.4-142.6), p < 0.05)] were independent predictors of new/progressive deformities. CONCLUSIONS: In subjects with sarcoidosis the number of vertebral deformities increases in the course of this disease, despite unchanged BMD. The combination of low normal BMD and family history of fragility fractures confers an increased risk of the incidence of these deformities.

Intracranial multiple midline germinomas: is histological verification crucial for therapy?

In this report we present two patients with intracranial multiple midline tumours in the suprasellar region and pineal gland. We postulate that in a patient with multiple midline tumours and normal values of the tumour markers human chorionic gonadotropin and alpha-fetoprotein in serum and cerebrospinal fluid, the only possible diagnosis is a germinoma. In such a situation no histological confirmation is required to start low-dose radiotherapy.

Health-related quality of life of diabetic foot ulcer patients and their caregivers.

AIMS/HYPOTHESIS: The effect of a foot ulcer on health-related quality of life (HRQoL) of patients with diabetes mellitus and their caregivers is unclear, and was therefore evaluated prospectively in this multicentre study. METHODS: HRQoL according to the 36-item health-related quality of life questionnaire (SF-36) of 294 patients (ulcer duration > or = 4 weeks) and 153 caregivers was analysed at baseline (time-point zero [T0]), once the ulcer was healed or after 20 weeks (time-point 1 [T1]), and 3 months later (time-point 2 [T2]). Patients with severe ischaemia were excluded. RESULTS: The mean age of the patients was 60 years, 72% were male, and time since diagnosis of diabetes was 17 years. Patients reported a low HRQoL on all SF-36 subscales. At T1, HRQoL scores in physical and social functioning were higher in patients with a healed vs a non-healed ulcer (p<0.05). At T2, these differences were larger, with higher scores for physical and social functioning, role physical and the physical summary score (all p<0.05). Within-group analysis revealed that HRQoL improved in different subscales in patients with a healed ulcer and worsened in patients with a persistent ulcer from T0 to T2 (all p<0.05). The caregivers of patients with a persisting ulcer had more emotional difficulties at T2. CONCLUSIONS/INTERPRETATION: Diabetic patients with a healed foot ulcer had a higher HRQoL than patients with a persisting ulcer. Healing of a foot ulcer resulted in a marked improvement of several SF-36 subscales 3 months after healing (from T0 to T2). HRQoL declined progressively when the ulcer did not heal. A diabetic foot ulcer appeared to be a large emotional burden on the patients' caregivers, as well.

[Disorders of lipid metabolism in 3 patients with diabetes mellitus type 2]. / Gestoorde vetstofwisseling bij 3 patiënten met diabetes mellitus type 2.

Three patients with diabetes mellitus (type 2) and cardiovascular disease had disturbed lipid concentrations: two women aged 60 and 73 years and one man aged 47 years. The lipid levels were normalised during the 9-18 years of treatment with medication and in this period the patients experienced no cardiovascular events. Disturbances in plasma lipid levels play a major role in the increased risk of cardiovascular disease in patients with diabetes mellitus (type 2). Cholesterol-lowering treatment should be aggressive and based on the lipid profile. Statins reduce cardiovascular events by lowering the concentration of both the total cholesterol and low-density lipoprotein cholesterol whereas fibrates reduce cardiovascular events by increasing high-density lipoprotein cholesterol concentrations and lowering triglyceride concentrations.

Rosiglitazone.

Type 2 diabetes mellitus is characterised by impaired insulin secretion, diminished peripheral insulin action and increased hepatic glucose production. Clinical trials have indicated that near-normal glucose control may reduce the risk for microvascular and - to a lesser extent - macrovascular complications in Type 2 diabetic patients. Thiazolidinediones improve insulin action by activating a nuclear receptor, PPARgamma. Therefore, these drugs are often referred to as 'insulin sensitisers'. Rosiglitazone is the second compound of this group. Clinical studies with rosiglitazone have shown that it is effective in lowering blood glucose levels in Type 2 diabetic patients treated with either diet alone, sulphonylurea or metformin. Preliminary studies suggest that rosiglitazone also improves glycaemic control in insulin-treated patients while even slightly decreasing insulin dose. The magnitude of the effects is, however, moderate. In diet-treated patients, the reduction of HbA1c levels amounted on average 0.5 - 1.5% and addition to existing sulphonylurea therapy decreased HbA1c by 1.0 - 1.2%. The clinical relevance of additional beneficial effects, i.e., on blood pressure and microalbuminuria, needs to be determined further. Rosiglitazone does not cause hypoglycaemia or gastrointestinal side effects. There is however some concern related to fluid retention, which seems to be an effect of all PPARgamma agonists. In patients treated with rosiglitazone, no severe hepatotoxic side effects have been noticed until now. In the treatment of our patients with Type 2 diabetes, drugs like rosiglitazone which directly reduce insulin resistance are very welcome but more data on its combined use with insulin are needed. Additional studies will also explore its long-term effects in sparing beta-cell function and reducing diabetes-related complications and atherosclerosis.

Peripheral vascular disease and type 2 diabetes mellitus.

Patients with Type 2 diabetes mellitus frequently have peripheral vascular disease, with a predilection for the lower legs. In this review potential mechanisms for this high prevalence and altered distribution are explored. It is hypothesised that the metabolic abnormalities in the prediabetic phase predispose to a more distal and aggressive atherosclerosis. Once diabetes has developed this process is accelerated due to chronic hyperglycaemia. Furthermore, endothelial damage, non-enzymatic glycosylation and polyneuropathy could lead to impaired vascular remodelling and collateral formation.

Miglitol, a new alpha-glucosidase inhibitor.

Miglitol (Bay m 1099, Bayer) is a second generation alpha-glucosidase inhibitor. It is a derivative of 1-desoxynojirimycin, and binds reversibly to the brushborder alpha-glucosidase enzymes. In contrast to its parent drug (acarbose, Bay g 5421, Bayer), miglitol is almost completely absorbed in the small intestine. It has to be taken with each main meal, and through its effect on carbohydrate digestion it blunts the postprandial blood glucose increase. Miglitol has no or a very small effect on fasting blood glucose levels. The blood-glucose lowering effects of miglitol in patients with Type 2 diabetes are lower than those of the frequently-used sulphonylurea compounds. Long-term studies show that a moderate average reduction of HbA1c of 0.3-0.7% point from baseline can be achieved. An advantage over sulphonylurea is the effect on serum insulin levels: miglitol therapy leads to slightly lower postprandial levels of serum insulin, whereas chronic sulphonylurea treatment usually increases serum insulin levels. This insulin-sparing effect may, in theory, lead to a lesser weight gain or even no weight gain and reduced risk of hypoglycaemia during chronic treatment. Long-term experience in Type 1 diabetic patients is limited. Similarly, miglitol may lead to reduced postprandial glucose excursions, slightly reduced insulin requirements and perhaps, as a consequence, a lower risk of hypoglycaemia. More long-term data are needed to fully assess to the clinical use of miglitol in these patients.

Breakers of advanced glycation end products restore large artery properties in experimental diabetes.

Glucose and other reducing sugars react with proteins by a nonenzymatic, posttranslational modification process called nonenzymatic glycation. The formation of advanced glycation end products (AGEs) on connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal aging and which occurs at an accelerated rate in diabetes, leading to an increase in arterial stiffness. A new class of AGE crosslink "breakers" reacts with and cleaves these covalent, AGE-derived protein crosslinks. Treatment of rats with streptozotocin-induced diabetes with the AGE-breaker ALT-711 for 1-3 weeks reversed the diabetes-induced increase of large artery stiffness as measured by systemic arterial compliance, aortic impedance, and carotid artery compliance and distensibility. These findings will have considerable implications for the treatment of patients with diabetes-related complications and aging.

Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozotocin-diabetic rats.

Advanced glycation end-product-formation is thought to play a role in the development of diabetic angiopathy. By altering the structure of different extracellular matrix components advanced glycation end-products might affect vascular and glomerular permeability. In this study we investigated the effect of treatment with an inhibitor of advanced glycation end-product-formation, aminoguanidine, on vascular permeability and the development of albuminuria in streptozotocin-induced diabetic rats. Male Wistar Rp rats were randomized into a control group, a diabetic group, and an aminoguanidine-treated diabetic group. After 8 weeks, 24-h urine collections were taken and rats were implanted with an arterial and a venous catheter. mean arterial blood pressure was determined by intra-arterial measurement. Regional albumin clearances were assessed in the eye, ileum, lung, skeletal muscle and skin using an isotope technique. Mean arterial pressure in the diabetic group was significantly lower in the control and aminoguanidine-treated groups (p < 0.02). Regional albumin clearances were significantly increased in all tissues of diabetic rats compared to control rats (p < 0.05). Aminoguanidine treatment of diabetic rats resulted in a significant decrease of regional albumin clearance in all tissues except the lung (p < 0.05, lung p = 0.07). The development of albuminuria in diabetic rats however, was not affected by aminoguanidine.

Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats.

The accumulation of advanced glycosylation end-products (AGEs) on collagen and the subsequent stiffening of this matrix protein in diabetes has been described many years ago. Structural modification of collagen in the arterial wall might have important effects on arterial elasticity. Aminoguanidine is known to decrease the formation of AGEs. In this study we evaluated the effects of aminoguanidine treatment on different parameters reflecting arterial wall elasticity in diabetic rats. We demonstrated that treatment of diabetic rats with aminoguanidine resulted in a significant increase in carotid static compliance (+39%, P < 0.01 under control conditions, and +27%, P < 0.01 after abolition of vascular tone by KCN), and a decrease in characteristic aortic input impedance (-40%, P < 0.01). The arterial pulse pressure in aminoguanidine-treated rats was decreased (-15%, P < 0.05) and the pulsatile component of left ventricular power output was relatively diminished (-35%, P < 0.05). In addition, we observed a lower fluid filtration across the carotid wall. These results indicate an increased vascular elasticity, an improved left ventricular-arterial coupling, and a decreased vascular permeability in diabetic rats after aminoguanidine treatment, suggesting that AGE-accumulation on collagen negatively affects arterial wall properties in experimental diabetes.

The microcirculation and hypertension.

AIM: To review published evidence on the effects of arteriolar changes in primary and secondary hypertension. BACKGROUND: Pressure profile analyses have shown that the microcirculation is a major site of vascular resistance. With the recent refinement of intravital microscopy techniques detailed information has become available on mechanisms of the microvascular resistance increase in hypertension. Three mechanisms play an important role: (1) a decrease in arteriolar diameter; (2) arteriolar vessel wall hypertrophy; and (3) small arteriolar and capillary rarefaction. METHOD: The evidence was synthesized into a hypothesis on the role of the microcirculation in primary forms of hypertension. HYPOTHESIS: The hypothesis formulated contains two important elements in that (1) diminished outgrowth of the microvascular bed in different tissues is seen as an important early pathogenic mechanism; and (2) the decreases in arteriolar diameter and vessel wall hypertrophy are seen as adaptive mechanisms that maintain a constant wall stress. The three factors together maintain the increase in vascular resistance that is common to all established forms of primary hypertension.

Effects of bepridil on conduction properties of the isolated rabbit sinus node and atrial myocardium.

In the isolated rabbit sinus node and right atrial myocardium, the effects of bepridil (1-6 x 10(-6) M) on impulse formation, impulse conduction, and tissue refractoriness were examined. In the sinus node, drug concentrations between 1 and 3 x 10(-6) M were tested. In the border zone of the sinus node, bepridil (3 x 10(-6) M) reduced impulse conduction velocity by 65% and prolonged the effective refractory period by 81% (n = 11). In the center of the sinus node, bepridil in a concentration of 2.5 x 10(-6) M decreased impulse conduction velocity by 78% and prolonged effective refractory period by 77% (n = 9), whereas a drug concentration of 3 x 10(-6) M blocked impulse conduction systematically. Despite these marked effects on nodal conduction properties, only limited effects on sinus rate were found. Conduction properties in the atrium were affected by bepridil as well, but higher concentrations (4-6 x 10(-6) M) were needed. Impulse conduction velocity was decreased by 57%, and the effective refractory period was prolonged by 73% (6 x 10(-6) M; n = 8). At these higher drug concentrations, sinus automaticity decelerated and ceased abruptly, after which only subthreshold oscillations were detectable. From these findings, we concluded that (a) bepridil reduces impulse conduction velocity and prolongs refractoriness in the sinus node, less markedly in the atrial myocardium; (b) bepridil affects nodal impulse conduction prior to nodal impulse formation; and (c) bepridil possesses both "fast channel" and "slow channel" inhibitory properties.