Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants.Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology

The Carotid Artery Plaque Size and Echogenicity are Related to Different Cardiovascular Risk Factors in the Elderly

Carotid plaques can be characterised by ultrasound by size and echogenicity. Both size and echogenicity are predictors of cardiovascular events. The aim of this study was to examine whether traditional risk factors and markers of inflammation and oxidation were associated with plaque size and echogenicity. Computerised analysis of carotid plaque size and echogenicity (grey scale median, GSM) were performed by ultrasound in a population-based health survey in 1,016 subjects aged 70 years (PIVUS study). Information on cardiovascular risk factors was collected, together with markers of inflammation and oxidation. Increased Framingham risk score, systolic blood pressure, higher BMI and decreased HDL, lower glutathione levels were related to echolucent plaques. Previous or present smoking was common with significantly more pack-years related to the echorich plaques. Plaque size was associated with increased Framingham risk score, systolic blood pressure, blood glucose levels, smoking, ApoB/A1 ratio, OxLDL, TNF alpha, HOMA insulin resistance, leucocyte count, decreased BCD-LDL and low levels of l-selectin. Low HDL, increased BMI and decreased glutathione levels were associated with the echolucency of carotid plaques, implying metabolic factors to play a role for plaque composition. Markers of inflammation were related to plaque size alone, implying inflammation to be predominantly associated with the amount of atherosclerosis. These results suggest that plaque size and echogenicity are influenced by different risk factors

Attentional capture for tool images is driven by the head end of the tool, not the handle

Tools afford specialized actions that are tied closely to object identity. Although there is mounting evidence that functional objects such as tools capture visuospatial attention relative to non-tool competitors, this leaves open the question of which part of a tool drives attentional capture. Here, we used a modified version of the Posner cueing task to determine whether attention is oriented towards the head versus the handle of realistic images of common elongated tools. We compared cueing effects for tools with control stimuli that consisted of images of fruit and vegetables of comparable elongation to the tools. Critically, our displays controlled for lower-level influences on attention that can arise from global shape asymmetries in the image cues. Observers were faster to detect low-contrast targets positioned near the head end versus the handle of tools. As expected, no lateralized performance bias was observed for the control stimuli. In a follow-up experiment we confirmed that the bias towards tool heads was not due to inhibition of return as a result of early attentional orienting towards tool handles. Finally, we confirmed that real-world exemplars of the tools in the cueing studies were associated more strongly with specific grasping patterns than the elongated fruits and vegetables. Together, our results demonstrate that affordance effects on attentional capture are driven by the head end of a tool. Prioritizing the head end of a tool is adaptive because it ensures that the most relevant region of the object takes priority in selecting an effective motor plan

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation

Identification of bacterial biofilm and the Staphylococcus aureus derived protease, staphopain, on the skin surface of patients with atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by an impaired epidermal barrier, dysregulation of innate and adaptive immunity, and a high susceptibility to bacterial colonization and infection. In the present study, bacterial biofilm was visualized by electron microscopy at the surface of AD skin. Correspondingly, Staphylococcus aureus (S. aureus) isolates from lesional skin of patients with AD, produced a substantial amount of biofilm in vitro. S. aureus biofilms showed less susceptibility to killing by the antimicrobial peptide LL-37 when compared with results obtained using planktonic cells. Confocal microscopy analysis showed that LL-37 binds to the S. aureus biofilms. Immuno-gold staining of S. aureus biofilm of AD skin detected the S. aureus derived protease staphopain adjacent to the bacteria. In vitro, staphopain B degraded LL-37 into shorter peptide fragments. Further, LL-37 significantly inhibited S. aureus biofilm formation, but no such effects were observed for the degradation products. The data presented here provide novel information on staphopains present in S. aureus biofilms in vivo, and illustrate the complex interplay between biofilm and LL-37 in skin of AD patients, possibly leading to a disturbed host defense, which facilitates bacterial persistence