Who Owns the Data? Open Data for Healthcare.

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.

Glomerular endothelial glycocalyx constitutes a barrier to protein permeability.

Glycocalyx, composed of glycoproteins including proteoglycans, coats the luminal surface of the glomerular capillaries. Human heparanase degrades heparan sulphate glycosaminoglycans and is up-regulated 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.

Maximum skin hyperaemia induced by local heating: possible mechanisms.

BACKGROUND: Maximum skin hyperaemia (MH) induced by heating skin to > or = 42 degrees C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH. METHODS: MH was achieved by local heating of skin to 42-43 degrees C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H1 receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, NG-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP). RESULTS: MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small. CONCLUSION: NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating.

Endothelial dysfunction and insulin resistance.

In this article, we review several mechanisms by which insulin resistance is related to endothelial dysfunction. The mechanisms we discuss may explain the high prevalence of cardiovascular disease found in people with the metabolic syndrome and diabetes mellitus.

Capillary pressure in subjects with type 2 diabetes and hypertension and the effect of antihypertensive therapy.

Raised capillary pressure has been implicated in the formation of diabetic microangiopathy in type I diabetes, in which it is elevated in those with the earliest signs of diabetic kidney disease but remains normal in those without complications. In subjects with type 2 diabetes without complications, capillary pressure is normal, although alterations in the pressure waveforms suggested enhanced wave reflections. The nature of skin capillary pressure in subjects with type 2 diabetes and hypertension remains to be elucidated, as does the effect of blood pressure-lowering therapy on capillary pressure in these subjects. Three studies were performed in well-matched groups. First, capillary pressure was elevated in hypertensive subjects with type 2 diabetes compared with normotensive subjects with type 2 diabetes (20.2 [17.4 to 22.7] mm Hg versus 17.7 [16.1 to 18.9] mm Hg, respectively, P<0.03, Mann-Whitney U test). Second, no significant difference was detected between hypertensive subjects with type 2 diabetes and hypertensive subjects without type 2 diabetes (19.4 [15.8 to 21.3] mm Hg versus 17.2 [15.1 to 19.8] mm Hg, respectively, P=0.5, Mann-Whitney U test). Finally, patients with type 2 diabetes were recruited to a case-control study. Seven subjects received blood pressure-lowering therapy and 8 did not. Therapy reduced capillary pressure from 18.2 [15.8 to 20.1] mm Hg to 15.9 [15.4 to 17.0] mm Hg (P=0.024 ANOVA), in contrast to the lack of effect of time alone. Mean arterial pressure was reduced from 110 [102 to 115] mm Hg to 105 [101 to 111] mm Hg (P=0.006, ANOVA). These findings provide a plausible mechanism by which reducing arterial hypertension may reduce the risk of microangiopathy in type 2 diabetes.

Endothelial dysfunction and inflammation in asymptomatic proteinuria.

BACKGROUND: Proteinuria is associated with vascular risk and a systemic increase in vascular permeability. Endothelial dysfunction occurs early in atherosclerosis and modulates vascular permeability. Vascular risk and chronic inflammation are associated. This study investigates whether the increased vascular permeability in proteinuria reflects systemic endothelial dysfunction and chronic inflammation. METHODS: Twenty-one patients with asymptomatic proteinuria (1.29 g/24 h; range 0.18 to 3.17) and 21 matched controls were studied. Microvascular endothelial function was assessed using acetylcholine iontophoresis. Maximum microvascular hyperemia (MMH) was assessed by flux response to local skin heating. Macrovascular endothelial function was assessed by flow-associated dilation (FAD) in the brachial artery using ultrasound. von Willebrand factor (vWF) was measured as a marker of endothelial activation. Low-grade inflammation was assessed by measurement of circulating C-reactive protein (CRP) values using a high sensitivity assay. RESULTS: FAD was impaired in proteinuric subjects (AP) compared to controls [1.8 (0.2 to 5.3) AP vs. 3.8 (1.5 to 6.2) C %; P = 0.014]. There was no significant difference between groups in MMH or in the response to acetylcholine iontophoresis. The AP group had a higher CRP [4.0 (0.5 to 39.0) AP vs. 0.2 (0.1 to 21.3) C mg/L; P < 0.001] and tendency to higher vWF [101.5 (67.0 to 197.0) AP vs. 77.5 (45.0 to 185.0) C IU/dL; P = 0.046] compared to controls. In the AP, but not control, group there was an inverse correlation between CRP and microvascular function as determined by acetylcholine iontophoresis (r = -0.509; P = 0.018). CONCLUSIONS: In AP subjects there is evidence of macrovascular endothelial dysfunction remote from the kidney and of low-grade inflammation that is associated with microvascular endothelial dysfunction.

Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is abundantly expressed by podocytes, but its role in glomeruli is unknown. Angiopoietins are endothelial cell growth factors that function in concert with VEGF but have not previously been observed in human glomeruli. Angiopoietin 1 (Ang1) acts via the endothelial receptor Tie2 to promote maturation and stabilization of blood vessels, resisting angiogenesis and opposing some actions of VEGF. Ang1, Ang2, Tie2, and VEGF expression in normal human renal cortex was examined with immunofluorescence and immunohistochemical analyses. High-power, multiple-color, immunofluorescence analyses and additional antibodies (specific for particular components of the glomerular filtration barrier) were used to determine the exact locations of Ang1 and Tie2 in the glomerular capillary wall. Immuno-electron-microscopic analysis of rat glomeruli was used to further localize endothelial Tie2 expression. RNA and protein extracted from human glomeruli, cultured human podocytes, and cultured human endothelial cells were analyzed for Ang1, Ang2, and Tie2 by using reverse transcription-PCR and Western blotting. Ang1 was detected in podocytes in normal glomeruli and, with VEGF, was concentrated in podocyte foot processes. Tie2 was demonstrated on glomerular capillary endothelial cells, particularly on the abluminal surface. Reverse transcription-PCR and Western blotting analyses confirmed the expression of Ang1 and Tie2 in glomeruli and of Ang1 in cultured podocytes. These findings suggest a role for Ang1 in the maintenance of the glomerular endothelium and make it a good candidate to be a regulator of the actions of VEGF on glomerular permeability, resisting angiogenesis while allowing the induction of high permeability to water and small solutes.