No abstract

Glycocalyx, composed of glycoproteins including proteoglycans, coats the luminal surface of the glomerular capillaries. Human heparanase degrades heparan sulphate glycosaminoglycans and is upregulated in proteinuric states. In this study, we analyze the structure of the human glomerular endothelial cell glycocalyx in vitro and examine its functional relevance, especially after treatment with human heparanase. Electron microscopy of conditionally immortalized glomerular endothelial cells revealed a 200-nm thick glycocalyx over the plasma membrane, which was also demonstrated by confocal microscopy. Neuraminidase treatment removed the majority of glycocalyx, reduced trans-endothelial electrical resistance by 59%, and increased albumin flux by 207%. Heparinase III and human heparanase specifically cleaved heparan sulphate: this caused no change in trans-endothelial electrical resistance, but increased the albumin passage across the monolayers by 40% and 39%, respectively. Therefore, we have characterized the glomerular endothelial cell glycocalyx and have shown that it contributes to the barrier to flux of albumin across the cell layer. These results suggest an important role for this glycocalyx in the restriction of glomerular protein passage in vivo and suggest ways in which human heparanase levels may be linked to proteinuria in clinical disease.

The late complications of diabetes represent in large part microvascular dysfunction. The development of techniques to measure microvascular function has resulted in a clearer picture of the stages of development of microangiopathy and the key pathophysiological processes involved. Considerable evidence supports the hemodynamic hypothesis of pathogenesis, which argues that early insulin-dependent diabetes is characterized by increased microvascular pressure and flow. Resultant injury to the microvascular endothelium causes adaptive microvascular sclerosis contributing to a loss of vasodilatory reserve and autoregulatory capacity with increasing disease duration. High susceptibility to microangiopathy appears to be characterized by both high capillary pressure and increased permeability, although the interrelationship between these variables needs to be better defined. In normotensive non-insulin-dependent diabetes subjects, a different pattern of microvascular functional abnormalities is apparent; it is hypothesized that these differences represent the impact of a prediabetic insulin-resistant phase on microvascular behavior and may in part explain the differential expression of vascular pathology in the two major types of diabetes. The physiological framework that has been defined reveals those pivotal processes upon which scientific attention should be centered and facilitates the generation of plausible molecular and cellular mechanisms that fit the physiological facts.

Research on large shared medical datasets and data-driven research are gaining fast momentum and provide major opportunities for improving health systems as well as individual care. Such open data can shed light on the causes of disease and effects of treatment, including adverse reactions side-effects of treatments, while also facilitating analyses tailored to an individual’s characteristics, known as personalized or “stratified medicine.” Developments, such as crowdsourcing, participatory surveillance, and individuals pledging to become “data donors” and the “quantified self” movement (where citizens share data through mobile device-connected technologies), have great potential to contribute to our knowledge of disease, improving diagnostics, and delivery of ­healthcare and treatment. There is not only a great potential but also major concerns over privacy, confidentiality, and control of data about individuals once it is shared. Issues, such as user trust, data privacy, transparency over the control of data ownership, and the implications of data analytics for personal privacy with potentially intrusive inferences, are becoming increasingly scrutinized at national and international levels. This can be seen in the recent backlash over the proposed implementation of care.data, which enables individuals’ NHS data to be linked, retained, and shared for other uses, such as research and, more controversially, with businesses for commercial exploitation. By way of contrast, through increasing popularity of social media, GPS-enabled mobile apps and tracking/wearable devices, the IT industry and MedTech giants are pursuing new projects without clear public and policy discussion about ownership and responsibility for user-generated data. In the absence of transparent regulation, this paper addresses the opportunities of Big Data in healthcare together with issues of responsibility and accountability. It also aims to pave the way for public policy to support a balanced agenda that safeguards personal information while enabling the use of data to improve public health.

Normal healthy subjects show a reflex rise in precapillary resistance in the skin of the foot when they rise from lying to standing. To investigate the integrity ofthis reflex in patients with diabetes mellitus blood flow in the plantar region of the big toe was measured, using a laser Doppler flowmeter. The responses of diabetic patients with and without peripheral sensory neuropathy and healthy control subjects matched for age and sex were studied, with the foot at heart level and the foot passively lowered to 50 cm below the heart.In normal subjects mean blood flow recorded during the third to fourth minute of dependency fell to 18-1 (SD 11-9)% of the preceding resting flow determined with the foot at heart level. In the diabetic patients without neuropathy blood flow fell to 28.9 (18-6)% ofthe preceding resting flow. In the diabetic patients with neuropathy blood flow fell to 53-5 (23-7)% of the preceding resting flow, which was significantly different from the value achieved by the diabetics without neuropathy (p<0-02) and the healthy controls (p<0002). Six normal subjects were indirectly heated to release sympathetic tone and achieve the same mean skin temperature of the foot as the diabetic patients with neuropathy, and blood flow fell to 38-7 (24-3)% of the preceding resting flow, a value not significantly different from the response seen in the patients with neuropathy.These findings suggest that the postural control of blood flow in the foot is disturbed in patients with diabetic neuropathy, and this disturbance is compatible with a loss of sympathetic vascular tone. The resultant hyperperfusion on dependency may account for the oedema seen in some patients with neuropathy and may also act as a stimulus for the thickening of capillary basement IntroductionThe precapillary resistance in the skin of the foot rises on standing, thereby limiting the rise in capillary pressure resulting from the vertical column of blood between the heart and the foot.' Evidence suggests that this vasoconstriction is mediated by a sympathetic axon reflex.2 We examined this reflex in patients with diabetes for

Nail-fold capillary hypertension may develop early in the course of diabetes, before the emergence of microvascular disease, and may be influenced by changes in metabolic control.

The microvascular response of foot skin to minor thermal injury and the skin of the anterior abdominal wall to injury from a needle was assessed by laser Doppler flowmetry in 23 patients with type I diabetes and 21 healthy control subjects. After minor thermal injury mean (SD) maximum skin blood flow was significantly lower in the diabetic group than the control group (0.53 (0-11) v 0-72 (0.10) V, in arbitrary units of flow, respectively, p<0001) and was negatively correlated with the duration of diabetes (r= -0-60; p<0-01). After needle injury a similar pattern of impairment was seen, the peak flow value recorded being significantly lower in the diabetic group than the control group (0.28 (0-10) v 0-41 (0-09) V, respectively; p<0-001) and also negatively correlated with the duration of diabetes (r=-0-61; p<0-01). There was a significant relation between the response obtained at the two sites of injury in the diabetic group (r= + 0-72, p<0O001) but not in the control group. The impairment in response was not related to diabetic control and was not explicable in terms of a reduction in superficial skin capillary density.

1. The mechanism of postural vasoconstriction in the skin of the foot was examined in 102 healthy subjects by using laser Doppler flowmetry. 2. In 45 subjects, when one foot was lowered 50 cm below heart level and the other foot kept horizontal, blood flow was progressively reduced in the dependent foot (by 79%) with a concomitant, but less pronounced, reduction in flow in the horizontal foot (by 18%), indicating that a central mechanism is involved. After lumbar sympathetic blockade (in 10 patients with epidural anaesthesia), the flow in the horizontal foot remained virtually constant, indicating that the central component is mainly mediated via efferent sympathetic nerves, whereas the postural fall in flow in the dependent foot, though partially attenuated, was preserved, indicating that a local mechanism is mainly involved. 3. On lowering one foot below heart level in 12 subjects, there was a small but significant reduction in systolic and mean arterial pressures during the first minute of dependency. During the fourth minute, systolic pressure decreased, diastolic pressure and heart rate increased, but the mean arterial pressure was maintained. 4. In 19 subjects postural vasoconstriction was nearly abolished during local nervous blockade (lignocaine 3.7 x 10(-4)-7.4 x 10(-2) mol/l), indicating that the local mechanism mediating the vasoconstriction is mainly neurogenic in nature. However, there was still a small fall (19%) in flow in the dependent foot during blockade, probably indicating a minor contribution of a local myogenic mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)