Retinal vessel diameters and reactivity in diabetes mellitus and/or cardiovascular disease

Background: Retinal vessel calibre and vascular dilation/constriction in response to flicker light provocation may provide a measure distinguishing patients suffering from diabetes mellitus and/or cardiovascular disease. Methods: One hundred and sixteen age and sex matched patients with diabetes mellitus (DM), cardiovascular disease (CVD) and both DM and CVD (DM+CVD) underwent systemic and intraocular pressure measurements. Retinal vessel calibres were assessed using a validated computer-based program to compute central retinal artery and vein equivalents (CRVE) from monochromatic retinal images. Vessel dilation and constriction responses to flicker light provocation were assessed by continuous retinal vessel diameter recordings. Plasma endothelial markers von Willebrand factor (vWf) and soluble E selectin (sEsel) were measured by ELISA. Results: Retinal vessel calibres were comparable across groups but CRVE correlated significantly with disease duration in DM patients (r=0.57, p<0.001). Patients suffering DM only exhibited reduced arterial vasomotion at rest and reduced arterial constriction following flicker light induced vessel dilation compared to patients with CVD and those suffering both CVD+DM (p=0.030). Patients suffering from CVD+DM exhibited significant differences between each flicker cycle in regards to arterial maximum constriction (p=0.006) and time needed to reach arterial maximum dilation (p=0.004), whereas the other two groups did not show such inconsistencies between individual flicker cycles. vWf was raised in CVD+DM compared to the other two groups (p≤0.02), whilst sEsel was raised in CVD+DM compared to DM alone (p=0.044). Conclusions: Dynamic retinal vascular calibres as obtained by continuous diameter measurements using flicker light provocation can reveal subtle differences between groups suffering from CVD with and without DM. This difference in reaction pattern and lack of arterial constriction in DM may provide a suitable marker to monitor progression

Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia

BACKGROUND: Inflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα). METHODOLOGY/PRINCIPAL FINDINGS: Expression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE(-/-)) and TNFα deficient (TNFα(-/-), ApoE(-/-)/TNFα(-/-)) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE(-/-) than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE(-/-) mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides. CONCLUSIONS/SIGNIFICANCE: Hyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE(-/-) mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes

Constant slip‐rate on the Doruneh strike‐slip fault, Iran, averaged over Late Pleistocene, Holocene, and decadal timescales

Varying estimates of both present‐day strain accumulation and long‐term slip‐rate on the Doruneh left‐lateral strike‐slip fault, NE Iran, have led to suggestions that it exhibits large along‐strike and/or temporal changes in activity. In this paper, we make and compare estimates of slip‐rate measured using both geodesy and geomorphology, and spanning time periods ranging from decadal to 100 ka. To image the present‐day accumulation of strain we process seven years (2003‐2010) of data from six ENVISAT tracks covering the fault, with interferograms produced for 400 km‐long strips of data in order to image the long‐wavelength signals associated with interseismic strain accumulation across the locked fault. Our analysis shows that less than 4 mm/yr – and likely only 1‐3 mm/yr ‐ of slip accumulates across the fault. Using high‐resolution optical satellite imagery we make reconstructions of displacement across six alluvial fans whose surfaces cross the fault, in four separate river catchments. We determine the ages of these fans using infra‐red‐stimulated luminescence dating combined with U‐series dating of pedogenic carbonates. The six fans vary in age from ∼10‐100 kyr, and a regression line fitted to four of these yields a slip rate of 2.5 ± 0.3 mm/yr. We conclude that within the uncertainty of our measurements the slip‐rate has remained constant over the last ∼100 ka and is representative of the strain accumulation at the present‐day. The slip‐rate that we measure is consistent with the E‐W left‐lateral Doruneh fault accommodating N‐S right‐lateral faulting by 'bookshelf' faulting, with clockwise rotation about a vertical axis

Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation

Advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) have a pathogenetic role in the development and progression of different oxidative-based diseases including diabetes, atherosclerosis, and neurological disorders. AGEs and ALEs represent a quite complex class of compounds that are formed by different mechanisms, by heterogeneous precursors and that can be formed either exogenously or endogenously. There is a wide interest in AGEs and ALEs involving different aspects of research which are essentially focused on set-up and application of analytical strategies (1) to identify, characterize, and quantify AGEs and ALEs in different pathophysiological conditions ; (2) to elucidate the molecular basis of their biological effects ; and (3) to discover compounds able to inhibit AGEs/ALEs damaging effects not only as biological tools aimed at validating AGEs/ALEs as drug target, but also as promising drugs. All the above-mentioned research stages require a clear picture of the chemical formation of AGEs/ALEs but this is not simple, due to the complex and heterogeneous pathways, involving different precursors and mechanisms. In view of this intricate scenario, the aim of the present review is to group the main AGEs and ALEs and to describe, for each of them, the precursors and mechanisms of formation