MD Manfredi ; Rizzo
email: mrizzo@unipa.it

Kaspar Berneis

Spyridon Koulouris

Socrates Pastromas

Battista Giovam

Dimitrios Rini

Antonis Sakellariou

Manolis

Kaspar Koulouris

Spyridon Pastromas

Socrates Rini

Dimitrios Sakellariou

Antonis S Manolis

Socrates Pastromas

Giovam Battista

SHOULD WE MEASURE ROUTINELY OXIDIZED AND SMALL DENSE LOW-DENSITY LIPOPROTEINS IN SUBJECTS WITH TYPE 2 DIABETES?

Keywords: diabetes, oxidized LDL, small, dense LDL, cardiovascular risk, prevention

published or not. The documents may come

Diabetes mellitus (DM) and its vascular complications represent a significant and growing problem in the Western World. Patients with type-2 diabetes develop more frequently accelerated atherosclerosis compared to the general population and mortality for ischemic heart disease is common [START_REF] Beckman | Diabetes and atherosclerosis: epidemiology, pathophysiology, and management[END_REF]. Oxidative stress, as a consequence of the combined effect of various cardiovascular risk factors such as dyslipidemia, hypertension and DM, plays a crucial role in the atherogenic process [START_REF] Navab | The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL[END_REF]. The increase in reactive oxygen species leads to the formation of oxidized (ox) lowdensity lipoproteins (LDL). Nowadays, there is enough evidence supporting the hypothesis that oxLDL are highly immunogenic and atherogenic. Reactive oxygen species (ROS) are generated through several metabolic pathways. These cascades act as modifiers in fatty acids, lipoproteins and amino acids, resulting in the formation of atherogenic particles such as oxLDL [START_REF] Steinberg | Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity[END_REF].

Native LDL particles are characterized by heterogeneity in their physical properties like size and density. Based on various analytical methods such as gradient gel electrophoresis, highperformance gel-filtration chromatography and nuclear magnetic resonance spectroscopy, subclasses of larger, more buoyant or smaller and more dense LDL have been identified. These small, dense LDL particles are more likely to form oxLDL, are less readily cleared and highly atherogenic [START_REF] Rizzo | Atherogenic dyslipidemia and oxidative stress: a new look[END_REF]. Insulin resistance, which is central in type-2 DM, leads to high serum levels of very low density lipoproteins (VLDL) enriched in triglycerides, which are metabolized predominantly to small dense LDL. Thus, small dense LDL particles are an integral part of diabetic dyslipidemia that is also characterized by increased triglyceride and reduced high density lipoproteins (HDL)cholesterol concentrations [START_REF] Mooradian | Dyslipidemia in type 2 diabetes mellitus[END_REF].

Clinical studies have shown that both small, dense LDL and oxLDL may have a distinct predictive role for the presence of vascular atherosclerosis in patients with type-2 DM. However, measurement of these two lipid parameters has not been widely used in daily practice probably due to the limited availability of clinical data and to methodological problems. The aim of the present article is to discuss the most recent clinical evidence about the role of small dense LDL and oxLDL in the development and progression of atherosclerosis and cardiovascular diseases, mainly in patients with type-2 DM. In order to do so, a systematic literature search (by Medline and Scopus) was performed using the following headings: "diabetes", "LDL", "lipoproteins", "oxidized" "small, dense", "size", "subfractions", "subclasses", and "therapy" up to 30 December 2009. The authors also manually reviewed the references of selected articles for any pertinent material.

Oxidation of LDL

LDL can be oxidized by metal ions (e.g. Cu +2 ), lipoxygenases, myeloperoxidase and reactive nitrogen species. Under oxidative stress, lipid molecules containing polyunsaturated fatty acids in LDL are easily oxidized. In vitro, this process includes three phases and a number of changes in lipid composition occur, including the substantial loss of free and esterified cholesterol and the generation of oxidation products, such as oxysterols [START_REF] Heinecke | Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis[END_REF]. Oxysterols seems to have many potent and diverse effects in vitro, several of which may be important in the atherosclerosis process.

The initial phase (lag phase) includes the consumption of the endogenous LDL antioxidants (e.g. vitamin E). The second phase (propagation phase) includes the rapid oxidation of esterified fatty acids to lipid hydroperoxides and up to 90% of the steryl ester acyl groups are modified. In details, in mildly oxidized LDL, cholesteryl hydroxyperoxy-octade-cadienoate (Chol-HPODE) and cholesteryl hydroxyl-octadecadienoate (Chol-HODE) were detected as the main oxidation products.

Chol-HPODE was reported to inactivate platelet-derived growth factor. The third phase is the decomposition phase where the hydroperoxides are converted to reactive aldehydes. These aldehydes react with lysine residues in apolipoprotein (apo) B-100, resulting in oxLDL, which has decreased affinity for the LDL receptor and increased affinity for scavenger receptors of subendothelial macrophages [START_REF] Mertens | Oxidized LDL and HDL: antagonists in atherothrombosis[END_REF]. Oxidized LDL represents a variety of modifications of both the lipid and protein components of LDL that occur when ROS induce lipid peroxidation. This oxidation process is thought to occur mainly in the arterial wall, rather than in plasma. Although fully oxLDL are cleared from the circulation within minutes by the reticuloendothelial system, the presence of small amounts of minimally modified LDL denotes the presence of circulating oxLDL. Therefore, the measurable circulating plasma levels of oxLDL represent only a small fraction of total LDL [START_REF] Tsimikas | Measuring circulating oxidized low-density lipoprotein to evaluate coronary risk[END_REF].

However, oxLDL antibodies are present in the circulation and can be readily measured. In the normal arterial wall without evidence of atherosclerosis, oxLDL levels are very low but in the early stages of atherosclerosis, oxLDL are clearly present. Although concentrations of oxLDL in the arterial wall are not measurable, circulating levels of oxLDL or oxLDL antibodies are theoretically the biomarker of total oxLDL, and consequently of total atherosclerosis burden [START_REF] Tsimikas | In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression[END_REF].

Currently, a directly image oxLDL in human arteries is unavailable [START_REF] Torzewski | Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization[END_REF]. Yet, several specific oxLDL assays based on monoclonal antibodies have been developed since the 1990s, when clinical studies established the strong relationship of circulating oxLDL with cardiovascular diseases. These antibodies can bind unique oxidation-specific epitopes but the methods are not easily comparable, as they have different binding epitopes. More recently enzyme-linked immunoabsorbent assay (ELISA) methods to measure plasma levels of oxLDL are commercially available [START_REF] Holvoet | Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease[END_REF][START_REF] Itabe | Sensitive detection of oxidatively modified low density lipoprotein using a monoclonal antibody[END_REF][START_REF] Palinski | Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma[END_REF]. Oxidized phospatidylcholines (oxPC) are produced after lipid oxidation and promote the expression of monocyte chemoattractant protein-1 (MCP-1) in endothelial cells and oxLDL recognition by macrophage scavenger receptors, mainly cluster of differentiation (CD) 36.

In the first of the above mentioned ELISA methods, the murine immunoglobulin (Ig)M monoclonal antibody DLH3 recognizes oxPC epitopes and uses isolated LDL rather than plasma to measure oxLDL [START_REF] Itabe | A monoclonal antibody against oxidized lipoprotein recognizes foam cells in atherosclerotic lesions. Complex formation of oxidized phosphatidylcholines and polypeptides[END_REF]. Another IgM monoclonal antibody, the E06, recognizes phosphorylcholine, the hydrophilic moiety in phospatidylcholines, and by design this second method is independent of LDL cholesterol or apoB levels [START_REF] Tsimikas | Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes[END_REF][START_REF] Tsimikas | Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long term immunologic responses to oxidized low-density lipoprotein[END_REF]. Finally, the third method uses the antibody 4E6 which binds to aldehydes-modified lysine groups on LDL. OxLDL levels measured with this method are closely correlated with total LDL-cholesterol levels, and this may limit its clinical utility [START_REF] Wu | Is plasma oxidized low-density lipoprotein, measured with the widely used antibody 4E6, an independent predictor of coronary heart disease among U.S. men and women[END_REF]. It is clear that these three assays use antibodies detecting different epitopes and they are set up in different formats and units of measurement. Thus, their results are not easily comparable, limiting the interpretation of the results in clinical studies that assessed plasma levels of oxLDL with different essays. For this reason Tsimikas et al. have suggested that investigators should present their data by linking their antibody to the type of oxLDL they have measured (i.e. "oxLDL-E06" for the E06 antibody) [START_REF] Tsimikas | Measuring circulating oxidized low-density lipoprotein to evaluate coronary risk[END_REF].

Oxidized LDL and cardiovascular risk

The majority of cardiovascular diseases are linked to the atherosclerosis process. One of the most important steps in this cascade is the transfer of oxLDL across the endothelium into the arterial wall [START_REF] Tousoulis | Endothelial function and inflammation in coronary artery disease[END_REF]. This probably takes place at sites of endothelial rupture, induced by oxLDL itself as well as by physical forces and inflammation. OxLDL can damage the continuity of endothelial wall and further induce the expression of adhesion molecules such as MCP-1 and the macrophage colony stimulating factor [START_REF] Cushing | Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells[END_REF]. Therefore, monocytes are activated and attached together with T lymphocytes on the surface of the endothelial cells. Subsequently, leucocytes as well as endothelial and smooth muscle cells secrete growth factors, which cause chemoattraction and, thus, the enhanced migration of monocytes and leucocytes into subendothelium. Modified monocytes form macrophages, which generate ROS that contribute to the conversion of oxLDL into highly oxidized particles.

This form of LDL is considered the most atherogenic and is taken up by macrophages to form the foam cells, which can secrete growth factors and, therefore, inducing smooth muscle cells migration and proliferation into the intima. Thus, the initial lesion, i.e. the fatty streak, is converted to a more advanced lesion with a fibrous cap that covers the lipid rich core. In acute coronary syndromes, some of these plaques (vulnerable plaques) are thinner than the stable plaques, and more prone to rupture. A ruptured plaque is the nidus for thrombus formation and, therefore, for arterial lumen occlusion [START_REF] Madamanchi | Oxidative stress and vascular disease[END_REF][START_REF] Libby | Coronary artery injury and the biology of atherosclerosis: inflammation, thrombosis, and stabilization[END_REF].

Beyond their crucial role in the formation of the atherosclerotic plaque, oxLDL seems to affect other aspect of the atherogenic process. For instance, endothelial dysfunction is clearly promoted by oxLDL. Apoptosis, a process in endothelial and smooth muscle cells that contributes to plaque vulnerability, seems to be affected by oxLDL and their products, such as phospatidylocholine and oxysterols [START_REF] Björkerud | Contrary effects of lightly and strongly oxidized LDL with potent promotion of growth versus apoptosis on arterial smooth muscle cells, macrophages, and fibroblasts[END_REF]. Also, oxLDL promotes thrombus formation by inducing the release of tissue factor by both endothelial cells and smooth muscle cells, and further stimulates the coagulation cascade by reducing thrombomodulin trancription, suppressing protein C activation and modulating tissue factor pathway inhibitor [START_REF] Mertens | Oxidized LDL and HDL: antagonists in atherothrombosis[END_REF]. In addition, oxLDL increases expression of matrix metalloproteinase-9, which causes vascular remodeling and rupture of the fibrous cap in the atherosclerotic lesions [START_REF] Xu | Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages[END_REF].

Elevated plasma oxLDL levels have been reported in patients with coronary artery disease (CAD), carotid atheromatosis, and chronic hemodialysis. However, since oxidation of LDL is mediated by several risk factors and present in both early and late lesions, there is no clear evidence that oxLDL can be used as a marker of preclinical atherosclerosis. Nevertheless, in asymptomatic individuals, elevated oxLDL levels have been associated with increased carotid intima-media thickness and familial hypercholesterolemia [START_REF] Liu | Circulating oxidized low-density lipoprotein and its association with carotid intima-media thickness in asymptomatic members of familial combined hyperlipidemia families[END_REF]. Moreover, some clinical studies have shown an inverse correlation between levels of oxLDL and HDL cholesterol [START_REF] Mertens | Oxidized LDL and HDL: antagonists in atherothrombosis[END_REF].

The association of plasma oxLDL with the presence and the severity of CAD has been established from many clinical studies with the use of the ELISA procedures mentioned above.

Several reports have shown an increase in oxLDL levels in the acute phase immediately after acute myocardial infarction, cerebral infarction, or percutaneous transluminal coronary angiography (PTCA) procedure [START_REF] Itabe | Circulating Oxidized Lipoproteins and Cardiovascular Risk[END_REF]. One possible explanation for this temporal increase is that oxLDL can be demonstrated elevated levels of serum soluble lectin-like oxidized LDL receptor-1 (the endothelial receptor for oxLDL) in patients with acute coronary syndromes, suggesting their potential prognostic role [START_REF] Hayashida | Serum soluble lectin-like oxidized lowdensity lipoprotein receptor-1 levels are elevated in acute coronary syndrome: a novel marker for early diagnosis[END_REF]. Ehara et al. also reported that circulating oxLDL-DLH3 levels were elevated in acute coronary syndromes and that this was correlated with the presence of oxLDL in atherectomy material removed after PTCA [START_REF] Ehara | Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes[END_REF]. In addition, in a follow-up study, Tsimikas et al. suggested that iatrogenic rupture of the plaque during PTCA increases plasma levels of oxLDL-E06 [START_REF] Tsimikas | Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long term immunologic responses to oxidized low-density lipoprotein[END_REF]. In this latter study, a strong correlation was documented between lipoprotein(a) [Lp(a)] and oxLDL-E06 levels, supporting the novel observation from the same group that Lp(a) ultimately binds most of the oxidized phospholipids measured by monoclonal antibody oxLDL-E06. These authors suggested that Lp(a) may be a part of the innate immune system, having a role in clearing proinflammatory oxidized phospholipids; yet, when Lp(a) levels are elevated, as under oxidative stress, this lipoprotein may become an atherogenic molecule in the arterial wall [START_REF] Tsimikas | Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease[END_REF].

The same research group has also recently confirmed the association of circulating levels of oxLDL with stable CAD, a relationship which had been already reported in previous studies [START_REF] Holvoet | Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease[END_REF][START_REF] Suzuki | Diagnostic implications of circulating oxidized low density lipoprotein levels as a biochemical risk marker of coronary artery disease[END_REF][START_REF] Toshima | Circulating oxidized low density lipoprotein levels: A biochemical risk marker for coronary heart disease[END_REF]. In a population of 504 patients undergoing coronary angiography for stable CAD, they reported a close correlation of oxLDL/apoB-100 ratio with the presence and the extent of coronary atherosclerosis [START_REF] Tsimikas | Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease[END_REF]. Interestingly, a close correlation between Lp(a) and the above mentioned ratio was found in this study; nevertheless, in patients under 60 years old, oxLDL/apoB levels were independent of Lp(a), suggesting that oxLDL may mediate atherogenicity beyond its association with Lp(a). In the stent implantation era, restenosis is considered a serious complication, although it has been significantly reduced using drug-eluting stents. There are conflicted results about the usefulness of oxLDL in predicting in stent restenosis and secondary cardiovascular events after a successful PTCA. Naruko et al. enrolled 102 patients with acute myocardial infarction and showed that high levels of oxLDL-DLH3 prior to discharge were correlated with highly percentages of restenosis [START_REF] Naruko | Persistent high levels of plasma oxidized low-density lipoprotein after acute myocardial infarction predict stent restenosis[END_REF]. On the other hand, Braun and colleagues in 687 patients who suffered from unstable and stable angina or myocardial infarction, did not show a significant correlation between oxLDL-4E6 levels and cardiovascular outcomes, including cardiovascular death, myocardial infarction or angiographically-determined restenosis [START_REF] Braun | Lack of association between circulating levels of plasma oxidized low-density lipoproteins and clinical outcome after coronary stenting[END_REF]. In consistent to these findings, Segev et al. have shown that oxLDL-E06 levels, despite an increase after uncomplicated PTCA for stable angina, were not associated with restenosis, in a 6-month angiographic follow-up study [START_REF] Segev | Relationship of a comprehensive panel of plasma oxidized low-density lipoprotein markers to angiographic restenosis in patients undergoing percutaneous coronary intervention for stable angina[END_REF].

Oxidized LDL in patients with type 2 diabetes mellitus

Recent evidences suggest that diabetic atherosclerosis cannot simply be attributed to the adverse lipid profile of these patients, but is mainly an oxidation and inflammation mediated process. It is well known that individuals with type-2 DM exhibit enhanced LDL oxidizability, leading to accelerated atherosclerosis. Glycemia itself induces oxidative stress and advanced glycation end products, formed by glucose-induced modification of proteins, and further acts as ligands for multiple receptors, such as the lectin-like oxidized LDL receptor-1 (LOX-1), inducing oxidative stress, inflammation and vascular dysfunction in diabetes. LOX-1 has been identified as the major oxLDL receptor that is present primarily in the endothelial cells; it has been found upregulated in the vascular endothelium of diabetic animals and seems to play an important role in the pathogenesis of hypertension, diabetes and atherosclerosis (Figure 1). Also, oxLDL interacts with β2-glycoprotein I (β2GPI), and oxLDL/β2GPI complexes have been considered as putative autoantigens in the autoimmune-mediated atherosclerotic vascular [START_REF] Tabuchi | The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis[END_REF] reported a potent interaction of C-reactive protein with oxLDL/β2GPI complexes and its association with arterial inflammation, hyperglycemia and hypercholesterolemia in patients with diabetes mellitus. Further, an increase in the in vivo LDL oxidation has been clearly

shown in patients with type-2 diabetes, as reflected by the higher prevalence of highly oxidized LDL [START_REF] Holvoet | The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort[END_REF]. The association between glycemia and LDL oxidation is in agreement with the observation that even in healthy individuals transiently increased plasma glucose levels correlate with a higher susceptibility of in vitro oxidation of LDL [START_REF] Chen | The relationship between plasma glucose and insulin responses to oral glucose, LDL oxidation, and soluble intercellular adhesion molecule-1in healthy volunteers[END_REF].

Yet, oxLDL themselves may also promote glycemia and the development of diabetes.

Recent data from the CARDIA study showed that in healthy young individuals high concentrations of oxLDL were associated with abdominal obesity, hypertriglyceridemia and hyperglycemia [START_REF] Holvoet | Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome[END_REF], which are essential components of the metabolic syndrome. Notably, subjects at the highest quartile of oxLDL concentrations had a threefold higher risk for the development of metabolic syndrome compared to those who were at lowest quartile during the 5-year follow up. In addition, in a recent clinical study that enrolled women having normal glucose levels, impaired glucose tolerance, impaired fasting glucose or diabetes type-2, levels of oxLDL were independent predictors for the development of type-2 diabetes after the 6-year follow-up [START_REF] Garrido-Sánchez | Anti-oxidized low-density lipoprotein antibody levels are associated with the development of type 2 diabetes mellitus[END_REF]. This may be explained by the fact that oxLDL can reduce the insulin signaling [START_REF] Mazière | Inhibition of insulin signaling by oxidized low density lipoprotein: protective effect of the antioxidant vitamin E[END_REF] as well as the glucose uptake [START_REF] Maddux | Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of alpha-lipoic acid[END_REF].

On clinical grounds, the role of oxLDL as predictor of increased cardiovascular morbidity and mortality in patients with type-2 diabetes has not been clearly delineated. Data from the Health, Aging and Body Composition study, including 3,033 elderly individuals, failed to demonstrate a significant association between oxLDL levels and total cardiovascular risk. Nevertheless, subjects with high oxLDL levels showed a trend to suffer more frequently of acute myocardial infarction [START_REF] Holvoet | Association of high coronary heart disease risk status with circulating oxidized LDL in the well-functioning elderly: findings from the Health, Aging and Body Composition study[END_REF]. Luoma et al. further reported that oxLDL autoantibodies were not predictive of severe chest pain attacks in patients with type-2 diabetes and CAD who were part of this large cohort. By contrast, a predictive role of oxLDL for cardiac events in patients with diabetes type-2 was demonstrated by Shimada et al. [START_REF] Hsu | Autoantibodies to oxidized low-density lipoprotein in patients with type 2 diabetes mellitus[END_REF]. They found in patients with type-2 diabetes and angiographically documented CAD that high levels of oxLDL were an independent and significant predictor of cardiovascular events. In line with these findings, Stephens et al. [START_REF] Shimada | Predictive value of circulating oxidized LDL for cardiac events in type 2 diabetic patients with coronary arterydisease[END_REF] reported a significant association between plasma oxLDL:LDL ratio and CAD status in a cross sectional study of 3,012 middle-aged men with type-2 diabetes Although the correlation with hard clinical end points seems to be weak, the association of with softer end points, such as surrogate markers of atherosclerosis, is more stronger. A clinical study, which included patients with type-2 DM and control subjects, suggested that in patients with long duration of the disease the levels of oxLDL were significantly higher, and that the anklebrachial index was lower than in control or newly diagnosed patients [START_REF] Piarulli | Autoantibodies against oxidized LDLs and atherosclerosis in type 2 diabetes[END_REF]. Similarly, greater intimamedia thickness (IMT) of common carotid artery was correlated with higher levels of oxLDL [START_REF] Piarulli | Autoantibodies against oxidized LDLs and atherosclerosis in type 2 diabetes[END_REF].

Data from the Chennai Urban Rural Epidemiology Study showed a strong association between oxLDL and IMT, even after adjusting for age, sex, and glucose intolerance. Ujihara et al. [START_REF] Gokulakrishnan | Oxidized low-density lipoprotein and intimal medial thickness in subjects with glucose intolerance: the Chennai Urban Rural Epidemiology Study-25[END_REF] further investigated the association between diabetic nephropathy and high levels of oxLDL in patients with type-2 DM. They found that patients with macroalbuminuria had higher values of oxLDL in comparison to the other patients of the cohort with either microalbuminuria or normal renal function. Similar findings were reported by Hsu et al . [START_REF] Ujihara | Association between plasma oxidized low-density lipoprotein and diabetic nephropathy[END_REF]: in comparison to controls, increased titers of oxLDL antibodies were found in patients with type-2 DM and macrovascular disease, but not in those without macrovascular disease.

OxLDL has also been implicated in the hypertrophy of adipocytes from lipid accumulation and proliferation of adipose tissue [START_REF] Nishimura | Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels[END_REF]. It has been also reported that oxLDL may modulate the production of adiponectin, which is able to reduce the excess ROS production in hyperglicemic states, an effect that has implications for vascular protection in diabetes [START_REF] Ouedraogo | Adiponectin suppression of high-glucose-induced reactive oxygen species in vascular endothelial cells: evidence for involvement of a cAMP signaling pathway[END_REF]. In addition, oxLDL may impair triglyceride storage and secretion [START_REF] Krauss | Identification of multiple subclasses of plasma low density lipoproteins in normal humans[END_REF]. To complete this circle of associations between LDL peroxidation and obesity, it has been proposed that the increase in adipose tissue may promote the synthesis of oxLDL, by either increasing production of arachidonate-5-lipoxygenase which catalyzes LDL oxidation, or by decreasing production of superoxide dismutase, which prevents LDL oxidation [START_REF] Nishimura | Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels[END_REF]. However, a more relevant pathophysiologic explanation may be the increased production by the adipose tissue of small dense LDL, which is reputedly more prone to oxidation than buoyant LDL particles [START_REF] Lamarche | Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study[END_REF]. Both diabetes and the metabolic syndrome may promote LDL oxidation through glycemia, development of end-glycation products and increased adiposity. On the other hand, oxLDL may further deteriorate insulin resistance and promote the proliferation of adipocytes. Notably, Scheffer et al . [START_REF] Scheffer | Association of LDL Size with In Vitro Oxidizability and Plasma Levels of In Vivo Oxidized LDL in Type 2 Diabetic Patients[END_REF] have shown that smaller LDL size was associated with increased levels of oxidized LDL, providing additional evidence for the role of small, dense LDL in the etiology of atherosclerosis in diabetes.

Formation of small, dense LDL

LDL comprises multiple subclasses with discrete size and density, different physicochemical composition and metabolic behaviour. Based on their characteristic appearance in analytical ultracentrifugation and gradient gel electrophoresis, up to seven distinct subclasses have been defined. It has been suggested that there are parallel metabolic channels within the delipidation cascade from VLDL to LDL [START_REF] Berneis | Metabolic origins and clinical significance of LDL heterogeneity[END_REF] and a metabolic relationship between large VLDL particles and small LDL particles has been demonstrated using stable isotopes in subjects with a predominance of small, dense LDL [START_REF] Krauss | Altered metabolism of large low density lipoproteins in subjects with predominance of small low density lipoproteins[END_REF]. These studies have not yet identified the specific precursors of individual LDL subclasses; however there are data from animal models suggesting that separate pathways may be responsible for the generation of distinct LDL particles [START_REF] Rizzo | Effects on lipoprotein subclasses of combined expression of human hepatic lipase and human apoB in transgenic rabbits[END_REF]. Dietary intervention studies also demonstrated inverse correlations between changes in large and small LDL, as well as between changes in medium sized and very small LDL, which raise the possibility of precursor-product relationships between distinct LDL subclasses [START_REF] Krauss | Dietary and genetic probes of atherogenic dyslipidemia[END_REF].

Activity of lipolytic enzymes is related to the size of LDL particles. A significant inverse relationship between post-heparin lipoprotein lipase activity and small, dense LDL has been demonstrated and induction of lipoprotein lipase by high fat diet was associated with an increase of 14 large LDL and decrease of small, dense LDL. Reduced activity of lipoprotein lipase and increased activity of hepatic lipase has been shown in subjects with a predominance of small, dense LDL particles [START_REF] Jansen | Hepatic lipase and lipoprotein lipase are not major determinants of the low density lipoprotein subclass pattern in human subjects with coronary heart disease[END_REF]. Hepatic lipase has a higher affinity for LDL than lipoprotein lipase and is positively correlated with plasma triglycerides, apoB, mass of large VLDL and small, dense LDL, but not with the mass of large LDL [START_REF] Campos | Associations of hepatic and lipoprotein lipase activities with changes in dietary composition and low density lipoprotein subclasses[END_REF], suggesting a central role for hepatic lipase in the lipolytic conversion of these particles.

Triglyceridaemia seems to be the main determinant of LDL subclass distribution [START_REF] Deckelbaum | Plasma triglyceride determines structure-composition in low and high density lipoproteins[END_REF]. In fact, the formation of small, dense LDL particles is mostly observed in hypertriglyceridemic state, with an increased transfer of triglycerides from triglyceride-rich lipoproteins to LDL and HDL particles, in exchange of cholesteryl esters through the action of cholesteryl esters transfer protein [START_REF] Guerin | Atherogenic role of elevated CE transfer from HDL to VLDL(1) and dense LDL in type 2 diabetes : impact of the degree of triglyceridemia[END_REF]. This phenomenon leads to the generation of VLDL particles enriched in cholesteryl esters and smaller, triglyceride-rich LDL particles that are good substrates for hepatic lipase. As a consequence, predictive value of small, dense LDL is usually reduced when triglycerides levels are taken into account [START_REF] Rizzo | Who needs to care about small, dense low density lipoproteins?[END_REF]. For example, in a published analysis from the EPIC-Norfolk prospective population study, predictive power for cardiovascular events of LDL particle number and size was lost after adjustment for HDL-cholesterol and triglycerides levels [START_REF] Harchaoui | Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study[END_REF].

Small, dense LDL and cardiovascular risk

Several reasons have been suggested to explain the enhanced atherogenicity of small, dense LDL. These particles are taken up more easily by arterial tissue than larger LDL [START_REF] Bjornheden | Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system[END_REF], suggesting greater transendothelial transport. In addition, small, dense LDL have decreased receptor-mediated uptake and increased proteoglycan binding [START_REF] Galeano | Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity[END_REF]. Sialic acid, due to its exposure at the LDL surface, plays a determinant role in the in vitro association of LDL with the polyanionic proteoglycans [START_REF] Camejo | Interaction of low density lipoproteins with arterial proteoglycans. The role of charge and sialic acid content[END_REF] and it has been shown that sialic acid content of LDL particles of subjects with the predominance of small, dense LDL is reduced. Further, oxidative susceptibility increases and antioxidant concentrations decreases with decreasing LDL size [START_REF] Tribble | Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense lowdensity lipoproteins[END_REF]. Altered properties of the surface lipid layer associated with reduced content of free cholesterol [START_REF] Tribble | Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size[END_REF] and increased content of polyunsaturated fatty acids [START_REF] De Graaf | Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects[END_REF] might also contribute to enhanced oxidative susceptibility of small dense LDL.

To date, the association of LDL size with cardiovascular diseases has been tested in over fifty studies, including cross-sectional and prospective epidemiologic, as well as clinical intervention trials; these studies overall suggest that the quality of LDL exerts a direct influence on cardiovascular risk. Due to previously described atherogenic properties, the predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. It has also been shown that even small increases in the concentration of these particles may substantially contribute to the determination of total cardiovascular risk [START_REF] St Pierre | Low-density lipoprotein subfractions and the longterm risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study[END_REF]. Other studies have investigated if the therapeutic modification of LDL size may be significantly associated with reduced cardiovascular risk. Such investigations used arteriographic changes as outcome variables and have reported that benefit was concentrated in patients with a predominance of small, dense LDL who received treatment that tend to reduce the amount of such particles [START_REF] Rosenson | Relations of lipoprotein subclass levels and lowdensity lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial[END_REF][START_REF] Miller | Predominance of dense lowdensity lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project[END_REF][START_REF] Zambon | Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density[END_REF].

These findings overall suggest that the therapeutic modification of LDL size may be significantly associated with reduced cardiovascular risk, even after multivariate adjustment for confounding factors. In addition, it has been reported [START_REF] Marais | Therapeutic modulation of low-density lipoprotein size[END_REF], although not directly demonstrated, that the modulation of LDL size with fibrates probably contributed to the reduction of cardiovascular risk in large clinical trials [START_REF] Manninen | Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study[END_REF][START_REF] Tenkanen | Some coronary risk factors related to the insulin resistance syndrome and the treatment with gemfibrozil. Experience from the Helsinki Heart Study[END_REF][START_REF] Rubins | Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol: Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trials Study Group[END_REF]. Yet, it cannot be fully excluded that the increased cardiovascular risk associated with smaller LDL size may also be a consequence of the broader pathophysiology of which small, dense LDL are a part (e.g. high triglycerides, low HDL-cholesterol, increased LDL particle number, obesity, insulin resistance, diabetes, metabolic syndrome) [START_REF] Sacks | Low-Density Lipoprotein Size and Cardiovascular Disease: A Reappraisal[END_REF][START_REF] Lamarche | The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects[END_REF][START_REF] Lada | Associations of low density lipoprotein particle composition with atherogenicity[END_REF][START_REF] Cromwell | Low-density lipoprotein particle number and risk for cardiovascular disease[END_REF]. Subjects with a predominance of small dense LDL have a greater than two fold increased risk for developing type-2 diabetes independently of age, sex, glucose tolerance and body mass index, and it has been calculated that an increase in LDL size may be associated with about a 16% decrease in the risk of developing diabetes [START_REF] Austin | Prospective study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women[END_REF]. Subjects with the insulin resistance syndrome have an elevated prevalence of small, dense LDL [START_REF] Reaven | Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles[END_REF] and this has been confirmed in both men and women with type-2 diabetes [START_REF] Selby | LDL subclass phenotypes and the insulin resistance syndrome in women[END_REF][START_REF] Feingold | LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes[END_REF]. In addition, using a euglycemic clamp technique to categorise individuals as insulin-sensitive, insulin-resistant, or with diabetes, more severe states of insulin resistance were associated with smaller LDL size [START_REF] Garvey | Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance[END_REF].

We have investigated the clinical significance of LDL size and LDL subclasses in patients with type-2 diabetes: those with manifest CAD had decreased LDL size and increased small, dense LDL particles as compared to subjects without established CAD. Multivariate analysis revealed that LDL size was the strongest marker of CAD as compared to other established cardiovascular risk factors, including plasma lipids and lipoproteins [START_REF] Berneis | Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes[END_REF]. Increased IMT is considered a reliable surrogate marker of early atherosclerosis and it has been shown to significantly correlate with the presence of CAD and to predict coronary events [START_REF] Chambless | Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993[END_REF][START_REF] Craven | Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. A case-control study[END_REF][START_REF] Wofford | Relation of extent of extracranial carotid artery atherosclerosis as measured by B-mode ultrasound to the extent of coronary atherosclerosis[END_REF]. In the previously mentioned study [START_REF] Berneis | Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes[END_REF] LDL size was significantly associated with carotid IMT and LDL size was the second strongest predictor of IMT when compared to nine other cardiovascular risk factors, and the strongest of all lipid parameters. Thus, small, dense LDL is a key feature of subjects with type-2 diabetes and seems further to represent a strong marker of their clinical and subclinical atherosclerosis.

Hypolipidemic treatments are able to favourably modulate LDL size and subclasses in patients with type-2 diabetes but the effects are varying among the different agents (Table 1).

Notably, in the "Diabetes Atherosclerosis Intervention Study" [START_REF] Vakkilainen | Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS)[END_REF] the therapeutical modulation of LDL size by fenofibrate was significantly associated with reduced cardiovascular risk at univariate analysis; in addition, using multivariate analyses with adjustments for confounding factors, changes in LDL size were strong predictors for cardiovascular events. Yet, although fibrates are more powerful than statins in improving LDL size and subclasses, existing evidence suggest that statins are more powerful agents in reducing hard clinical end points (i.e. cardiovascular morbidity and mortality). In the same context, while fenofibrate seems to be the best fibrate in lowering small dense LDL, the FIELD study [START_REF] Keech | FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial[END_REF] showed no significant reduction in the primary end point in patients with type-2 diabetes who were randomised to receive fenofibrate or placebo.

Conclusions

The most important link between lipid metabolism and inflammation is based on the formation of foam cells (first step of plaque generation) from altered, oxidized LDL [START_REF] Albertini | Oxidation of low-density lipoprotein in atherosclerosis from basic biochemistry to clinical studies[END_REF]. Yet, LDL are very heterogeneous particles, with distinct subclasses that differ in size, density, physicochemical composition, metabolic and oxidative behaviour, as well as atherogenicity [START_REF] Griffin | Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation[END_REF].

Increasing evidence suggests that the ''quality'' of LDL has a direct influence on cardiovascular risk, with smaller, more dense LDL particles being more susceptible to oxidation and greatly atherogenic [START_REF] Rizzo | Should we routinely measure low-density and high-density lipoprotein subclasses?[END_REF].

The inflammation process is induced from oxidized lipoproteins, mainly oxLDL, that are independent predictors of the progression of the atherosclerosis cascade, possibly by binding monocytes to the endothelium [START_REF] Berliner | Minimally modified low density lipoprotein stimulates monocytes endothelial interactions[END_REF]. Additionally, oxLDL seems to be responsible for the expression of pro-inflammatory genes in the subendothelium of vascular bed, including leukocyte adhesion molecules (e.g. intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and Pselectin), chemotactic molecules, (e.g. MCP-1) and mitogenic growth factors, such as the macrophage-colony-stimulating factor, which has a pivotal role in the recruitment and activatation of inflammatory cells in the vessel wall [START_REF] Palinski | Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis[END_REF][START_REF] Berliner | Atherosclerosis: basic mechanisms. Oxidation, inflammation and genetics[END_REF]. Furthermore, oxLDL has a potential role in the formation of reactive aldehyde and phospholipid species with proinflammatory properties, such as the lysophosphatidylcholine [START_REF] Olofsson | Nanomolar concentrations of lysophosphatidylcholine recruit monocytes and induce pro-inflammatory cytokine production in macrophages[END_REF]. In patients with type-2 diabetes hyperglycemia enhances the It has been also demonstrated a positive correlation of IgG autoantibodies to angiographically documented coronary artery disease and an inverse association of IgM with it [106]. Further, in patients with type-2 diabetes high levels of IgG autoantibodies were not associated with subclinical atherosclerosis, but with manifest atherosclerotic lesions [START_REF] Piarulli | Autoantibodies against oxidized LDLs and atherosclerosis in type 2 diabetes[END_REF].

Therefore, oxidized and small, dense LDL seems to have a synergistic impact on cardiovascular risk (Figure 2), with a greater importance in patients at higher-risk, such as those with type-2 diabetes. Increased levels of oxidized and small, dense LDL levels are a feature of patients with type-2 diabetes and small, dense LDL have been shown to be good predictor of future cardiovascular events, even after multivariate adjustment for confounding factors. On the other hand, although the association of oxidized LDL with surrogate markers of atherosclerosis is consistent, the correlation with hard clinical end points seems to be smaller.

In addition, lack of availability of easy, cheap and reproducible essays for measurement of oxidized and, particularly, small, dense LDL have reduced their assessment in large clinical endpoints trials. However, on the basis of available data, the therapeutic modulation of small, dense LDL is significantly associated with reduced cardiovascular risk, even after multivariate adjustment for confounding factors. Since small, dense LDL are difficult to be measured in non-specialized laboratories, in the last years alternative approaches have included the use of lipid indices as their In conclusion, on the basis of available data, the routine measurement of oxidized and small, dense LDL in patients with type-2 diabetes cannot be recommended in daily clinical practice so far.

Yet, their measurement is strongly encouraged, in order to better understand their role on cardiovascular risk of patients with type-2 diabetes.

  ruptured fibrous cap of the atherosclerotic lesions at the time of occurrence of infarction. Moreover, this observation suggests that plasma oxLDL could reflect the conditions of atherosclerotic lesions and vulnerability of the plaque. This association was previously documented in cross-sectional studies showing a correlation among severity of acute coronary syndrome and levels of plasma oxLDL. Hayashida et al.

  et al.

7 .

 7 Small, dense LDL and type-2 diabetesSmall, dense LDL represent one the main dislipidemic features in type-2 diabetes[START_REF] Krauss | Lipids and lipoproteins in patients with type 2 diabetes[END_REF].

  further modifying LDL into oxLDL. In such patients the decreased antioxidant activity is also linked to the lower plasma levels of anticoagulant proteins, as well as to the increased levels of hydroperoxides [100,101]. Yet, the relationship between autoantibodies to oxLDL and atherosclerosis remains controversial. There are studies showing high levels of autoantibodies to oxLDL in subjects with coronary artery disease, carotid atherosclerosis or peripheral arterial disease [102,103]. Current evidences support the concept that IgG autoantibodies are associated with atherogenesis enhancement while IgM have a natural protective role [104]. Circulating IgM autoantibodies have been found in plasma of apparent healthy subjects without any atherosclerosis manifestation [105].

  markers; yet, recent studies have shown that these lipid indices are not good predictors of small, dense LDL [107] and, therefore, their use should be discouraged.

Figure 1 .Figure 2 .

 12 Figure 1. The vicious cycle between glycemia, LDL oxidation, advanced end glycation

AUTHORS' CONTRIBUTIONS


Sonia Lajmi
email: sonia.lajmi@insa-lyon.fr

Johann Stan
email: johann.stan@alcatel-lucent.com

Hakim Hacid
email: hakim.hacid@alcatel-lucent.com

Elöd Egyed-Zsigmond
email: elod.egyed-zsigmond@insa-lyon.fr

Pierre Maret
email: pierre.maret@univ-st-etienne.fr

Extended Social Tags: Identity Tags Meet Social Networks

Keywords: Media tagging, social networks, semantic web, user profile, data mining, optimization

This paper proposes a new approach that uses social networks and common sense deduction rules to adapt the description tags of the photos for the current viewer. We exploit social graphs to enrich the tags associated to the concerned persons in the photo by following the different links between people (i.e. viewer and captured people in the photos). The main contributions of our work are: (i) addition of a more meaningful tagging layer for photos, making tags dynamic and auto-adaptable thanks to the automatic identification of the social context of the visualization. (ii) Due to this dynamics, the search in the social graphs is optimized using a data mining technique.

(iii) we propose a new visualization metaphor for the tagging layer to manage users' feedback. We also describe a system architecture and an experimental study that shows significant improvements of the tagging process and execution times on a dataset containing triples in a FOAF graph.

I. INTRODUCTION

Online communities like Flickr1 , del.icio.us2 , Facebook 3 , or Youtube 4 have established themselves as very popular and powerful services for publishing and searching content. Uploaded data is annotated with information about the content or the context in the form of freely selected keywords, called tags. Among the multimedia data types, images are undoubtedly the most used. Indeed, images are used in various fields like personal usage, medicine, museums, astronomy, etc. A big challenge in this domain is textual semantics association to an image. This can be done by tagging, also called annotation [START_REF] Barnard | Learning the semantics of words and pictures[END_REF] [START_REF] Picard | Vision texture for annotation[END_REF]. Multimedia data tagging is the task of assigning, for each multimedia document, or part of it, a keyword or a list of keywords describing its meaning. In the case of a personal photo, such tags generally concern the captured people, the location, and the event. They have three major objectives: (i) to facilitate later retrieval, (ii) to give sense to the photo when sharing it, and (iii) to make it possible to automatically reason about images since this can't be performed directly on the image's low features (e.g. color and texture).

With the widespread of the Web 2.0 and social networks, manual and semi-automatic tagging have gained lot of interests. In Social Networking Sites (SNS) for example, users can tag people on images with their names. However, this gives the image tag a reduced interpretation range, since the tag will only make sense for those who know the involved person(s). Additional information is then needed for the viewer so that she can understand and interpret the potential relations between her and people in the photo. On the other hand, it is important to consider also the adaptive aspect of these tags: a social relationship only makes sense for a given person. Thus, these tags must adapt for each viewer.

In this paper we consider the case of photos in social networks and we focus our efforts on the tags performed on people (other tags on the photo may exist, e.g. objects, but we are not dealing with this aspect in this paper). We believe that many constraints need to be considered in this context (social networking). We briefly describe in the following the main requirements for such a tagging system that aims at fixing this kind of problems:

• Real-time adaptation: social tags, i.e. tags that are inferred from a social relationship, must adapt in realtime to the viewer. The argument for this is the fact that the path in the social graph between the viewer and actors/witnesses changes with the relationships.

• Scalability: social graphs can reach several millions of nodes. The optimization of social path computation is then an important requirement.

• Relevance feedback management: generally, many paths exist between two nodes in a social graph. Therefore, users should have the possibility to accept or reject an extended social annotation suggestion. If it is rejected, a new suggestion must be computed. 1) Paper contributions: This paper has contributions in social network modeling, multimedia document tagging, and information retrieval optimization. Our contributions can be mapped to the different requirements that have been described before. A first contribution is the addition of a more meaningful tagging layer for photos by exploiting the social relationships that can exist between people in a social network. To support this new layer, an extension of the FOAF vocabulary is also performed. This extension allows a meaningful social dimension label, with terms like friend, colleague, neighbor, partner, parent, etc. Since the social tags become highly selfadaptive, i.e. they must change for each viewer, the search in social graphs must be optimized. Our second contribution is the use of data mining to optimize the retrieval of paths. Finally, we propose a new visualization metaphor for the tagging layer. It is clear that multiple paths can exist between two persons in the social graph. Thus, the identity annotations appear in the form of a list of suggestions. Each suggestion can be associated with a person in the photo with a drag-and-drop operation. If the suggestion does not make sense for the user (too complicated, too long), the algorithm computes another one. It is important to note that the algorithm is designed to always suggest the shortest path. To the best of our knowledge, this is the first work that considers the fact that identity tags must have a social dimension in an environment where it is impossible to anticipate who will view the photo.

2) Paper Organization: The remainder of this paper is organized as follows: Section 2 discusses the new annotation schema that uses social relations to extend the traditional annotation schema. Section 3 introduces our heuristic algorithm that manages rapid access to annotations thanks to a data mining technique. We discuss a system architecture as well as preliminary experimental results in Section 4. Section 5 is dedicated to the study of some related work. Finally, we conclude and give some future directions in Section 6.

II. ENRICHMENT OF IDENTITIY TAGS WITH SOCIAL RELATIONS

A. A new identity annotation schema

In this section we describe the new annotation schema, i.e. strategy, that supports the extended annotation as well as the extension of FOAF. The following terminology is used in the rest of this paper: "Actor" refers to a person present in a photo. A "Witness" is a person who has a social, geographical and temporal proximity with the captured photo, but is not necessarily visible in the photo itself. A person can be both Actor and Witness. An Actor is always a Witness too. The "Tagger" of the photo is the person who currently annotates the photo. The "Viewer" of a photo is the person who currently consults the photo (a Tagger is also a Viewer but the opposite is not necessarily true). For this paper, we focus only on adapting the social dimension to the viewer. We consider the following definition of a social tag:

Definition 1: (Social Tag) A social tag is a label associated by a social community to a multimedia document, e.g. image, that describes its meaning for later interpretation, processing, or distribution.

To illustrate the proposals of this paper, let's consider a simplified case of a scientific conference event. Researchers from different countries meet and exchange ideas and collaborate on projects. A main interest is to meet new or known people and create new or boost existing collaborations. Photos are often taken to memorize a meeting between researchers (See Figure 1(a)). David introduces a number of new researchers, Steven and Edward, to Jennifer who took a photo. Later in, Jennifer tagged it with the names of the persons and put it on her social network site. After this, she shared the photo with David, Steven and Edward (since they are in the photo). When Jennifer viewed the photo, after a while in her social network site, she recognized David but did not remember how she was related to the other persons. The reason for this situation is that Jennifer has followed the traditional annotation schema that we can formalize as follows:

T ags = [P ] ∨ [L] ∨ [E] ∨ [O] ∨ [T ] (1)
Where P stands to persons names, L for location, E for events, O for objects, and T for time. The instanciation of this schema on our example can then produce the following result: One of the most important particularity and weakness related to this annotation schema is that the result is the same for all persons who manipulate this photo, i.e. annotations are static. It becomes clear from this example that there is a missing piece of information, at least from Jennifer's point of view. In fact, since Jennifer has only a direct social relation with David, the annotations about Steven and Edward become meaningless for her. We propose to overcome this problem by enriching the annotations with specific social relationships and by adapting them to the current viewer. Our proposal improves the traditional annotation schema (Formula 1) with the consideration of the social dimension of the tag about a person. It consists in the inclusion of the potential social relationships between the viewer and the annotated person(s). By supposing that Steven has a family relation with David, say his brotherin-law, and Edward is a research colleague, Jennifer would appreciate to have a more meaningful annotation, like: The general form of the new annotation schema becomes then:

T ags = [P ∧ S] ∨ [L] ∨ [E] ∨ [O] ∨ [T ] ( 2
)
Where S is the social dimension associated to people's names. We define then a new concept "extended social tag" as follows:

Definition 2: (Extended social tag) An extended social tag is a social tag enriched with a social dimension describing the social relations between the concerned entities.

It results from Definition 2 a dynamic property that is associated to a social tag. In fact, since the social dimension is exploited and since social relations change from a person to another, the annotations need to be dynamic.

These two annotation schemes can be easily explained from a social network perspective. Consider a graph representation of a social network where nodes represent people and arcs relations between these people. The traditional annotation schema can be viewed as the task of assigning to each node in the graph a semantic annotation. This makes the nodes separate, preventing other nodes, which are not directly concerned by the photo, to interpret it. Our model proposes to build the missing part of the tags, i.e. the connections between the nodes, to improve the meaning of the annotated objects. This makes the annotations more meaningful for all the nodes that have a potential path to people annotated in the photo (See Figure 1).

To make this solution efficient and useful, rich relation representation description and formalisms need to be used. Currently, one of the most used formalism to represent relations is the Friend-Of-A-Friend (FOAF) vocabulary [START_REF] Brickley | The Friend Of A Friend (FOAF) vocabulary specification[END_REF]. FOAF is an XML based vocabulary offering the possibility to describe relations between people. Using FOAF in our context is certainly necessary since we are considering relations between people. However, in its current definition, FOAF seems to be very basic and can not be exploited to describe a set of relations rich enough that can exist between people and which we want to exploit for annotations enrichment. We propose in the following to extend this vocabulary for a better satisfaction of our constraints.

B. Extension of the FOAF vocabulary

We focus here on describing the extensions that we have made on FOAF in order to consider additional types of relations between people. The extension of FOAF, and social ontologies in general, is not particular to our work but is investigated in other research studies [START_REF] Mika | Social networks and the semantic web[END_REF]. The proposed extension is an attempt to address our specific issues. The difference between Relationship Ontology and our proposal called "So-cialSphere Ontology" 5 is that (i) we define a more exhaustive set of relationships, (ii) we categorize those relationships on different Social Network Categories, and (iii) we add common sense rules to perform reasoning about those relationships.

Inspired by the SAUPO model [START_REF] Stan | A User Profile Ontology For Situation-Aware Social Networking[END_REF], we define the "Social Network Category" (SNC) concept as an extension of FOAF and a specialization of the <foaf:Group> concept. From the user's perspective, each member of her social network belongs to a category and therefore the <foaf:Person> concept is connected to the SNC concept by the "belongTo" property. Five different SNCs that specialize the SNC concept are defined: (i) Professional, (ii) Family, (iii) Neighborhoodship, (iv) Friendship, and (v) Intime. For each category, we provide the list of the corresponding relationships hereafter:

• Professional: worksWith, colleagueOf, collaboratesWith, employedBy, mentorOf, apprenticeTo, superviserOf

• Family: parentOf, childOf, grandChildOf, grandParentOf, ancestorOf, descendantOf, siblingOf, uncleOf, cousinOf, nephewOf, nieceOf • Neighbourship: livesWith, neighbourOf. • Friendship: friendOf, lostContactWith, closeFriendOf, hasMet, acquaintanceOf. • Intime: wifeOf, husbandOf, lifePartnerOf, engagedTo,
girlfriendOf, boyFriendOf, husbandOf, wifeOf and each relation with the "ex" prefix (for expressing the unstable aspect of intime relations). This extension, as discussed before, enables the definition of additional relationships that can appear in a social network. This is important in our context to semantically characterize the links of a social network. It should be noted that the relations as defined before are not always symmetric, e.g. if A is the wife of B then B is the husband of A. To prevent the definition of all the alternatives of the relations between people, we make use of some common sense rules for reasoning on the social graph resulting in a higher exploitation of the relationships. Additional implicit rules are defined using four OWL properties: (i) the inverse property <owl:inverseProperty>, (ii) the transitive property <owl:transitiveProperty>, (iii) the symetric property <owl:symetricProperty>, and (iv) the similarity property <owl:sameAs>. Since this is not the main topic of this paper and due to space limitation, this aspect is no longer detailed here.

III. OPTIMIZED SEARCH IN THE SOCIAL GRAPH

In real life, graphs representing social networks can reach a very large size. On Facebook, for example, the graph connecting all users has so far reached over 120 million nodes. To optimize the identity tag suggestion process in large social networks, we propose to optimize the search in the FOAF graph. A query traverses FOAF profiles and returns <foaf:name>, <SocialSphere:Relationship> and <foaf:seeAlso> of the potential actors. Before presenting the optimized algorithm, we consider the following formal definitions:

Let G(V, E) be a directed graph representing the social network. V is the set of n vertices/nodes (|V | = n) and E is the set of all arcs connecting the vertices in V . We consider that G is a connected graph and that it doesn't contain isolated vertices. If v i , v j ∈ V then we denote by (v i , v j ) ∈ E the arc connecting the node v i to the node v j . It should be noted that since the graph is directed, the relations are not symmetric and thus (v i , v j ) = (v j , v i ). The following functions on E are defined:

• N (v i ) → V : defines the direct neighbors of a particular node. • R(v i , v j ) → SocialRelations: defines the relations that link v i to v j For example R(v i , v j ) = SiblingOf . • C(v i , v j ) → RelationCategories: defines the categories of the relation between v i and v j . For example

C(v i , v j ) = F amily
To improve the search, we apply a heuristic optimization of the Breath First Search algorithm [START_REF] Knuth | The art of computer programming[END_REF]. This heuristic is based on the observation that the spatio-temporal context 6 plays an important role to determine social categories of potential actors. For example, if the viewer is located at work and the time is day, it is more likely that she is with her "Professional relationship" than with people belonging to her "Family relationship". In other words, it is more likely that people that are related to a photo taken in this context (actors or witnesses) are members of the social category "Professional relationship". Another heuristic optimization consists in stopping the search when reaching a path of length 2. Indeed longer social paths aren't meaningful for the viewer. This means that all the further relations are presented relatively to the second path of the viewer.

This case represents clearly an association between the user location and her social relations. Thus, we exploit association rule mining [START_REF] Agrawal | Fast algorithms for mining association rules in large databases[END_REF] to handle this part of the problem 7 . The rules are built on data (user context data) gathered with a mobile device for a well defined period (2 months in our testing scenarios). These rules associate a physical context of the user (Location and Time) with a social context (present people). After the extraction of rules, the right-hand-side of the rule is reprocessed in order to have a high-level description of the social context (e.g. a list of names are grouped into a category, like Friends or Family). This is achieved using the extended FOAF profile.

In real life, these rules do not apply for all individuals. This is mainly because there are specific locations where the user can be with people belonging to several categories. For this reason, we have implemented a data mining approach to extract rules that associate a situation (a spatio-temporal context) to a social network category. By using this data mining approach, the following constraints are considered: 1) Each node v i has a list of corresponding set of FOAF attributes, like name, address, etc. 2) The functions R(v i , v j ) and C(v i , v j ) can be associated to each arc (v i , v j ) ∈ E and each arc annotated with R must have a corresponding annotation with C. 3) There exists a dependence between R and C. For example if R represents SiblingOf, then C could represent Family relationship. This dependence is shown in Section II-A. Algorithm 1 shows the pseudo-code of the Social Query Optimization (SQO) algorithm. Given the graph G(V, E) and two nodes v i and v j (source and destination), SQO returns a set of potential paths that connect the two nodes (i.e. people). The SocialDimension variable (line 2) holds the different solutions. Our algorithm retrieves paths with a maximum length of 2. We believe that beyond this length, paths are meaningless for viewers (line 6). Thus, if an actor is not a direct acquaintance of a direct acquaintance of the viewer, the SocialDimension becomes too long and difficult to follow. This principle is followed by many social network sites such as Facebook which stops at this level also for friends recommendations. We agree that in this case some actors may remain with empty SocialDimension, but this heuristic keeps the algorithm fast. If we try to retrieve longer paths the complexity of the algorithm will increase and it may become useless for a realtime adaptation scenario.

We enqueue the first and second level descendants of the state whose category belongs to the category set returned by the heuristic function GetConcernedCategory (line 8). This function returns the potentially concerned relationship categories according to time, space or situation constraints. For exemple, if the situation is "working", the concerned Algorithm 1 Social Query Optimization (SQO) design 1: Input: G(V, E), source node v i , destination node v D 2: Output: SocialDimension List of List 3: N odesCovered List, P arentState List, q queue, ConcernedCategory List 4: q ← , state ← v i , j ← 0, P arentsState ← , N odesCovered ← 5: repeat 6:

if

(v i ∈ N(state) OR state = v i ) then 7:
ConcernedCategory ← GetConcernedCategory(state) 8:

for all Cat ∈ ConcernedCategory do 9:

Enqueue v in q such that v / ∈ q and ∃ C(v, state) = Cat 10:

end for 11:

end if 12:

Add state to N odesCovered 13:

state ← q.front() 14:

q.dequeue() until state= v i 32:

Increment j 33: state = v j 34: end for 35: return SocialDimension category is "Professional relationship". Considering only paths of length ≤ 2 and filtering the social categories enables us to reduce the complexity of the BFS algorithm. The complexity is detailed with the experimental results in a further section. If the viewer doesn't know any actor, the algorithm will only return the destination node v j (line 17). After retriving the path between v i and v j , the SQO algorithm constructs the SocialDimension of v j for v i . This SocialDimension can contain several paths. For example, Steven may be the brotherin-law of my colleague David, as he can be the mentor of my friend Peter. An example of the different levels in the social graph are represented in Figure 2.

IV. IMPLEMENTATION AND EXPERIMENTAL RESULTS

In this section we will discuss two main aspects: (i) the system architecture which supports our proposal, and (ii) an experimental study which describes results of the evaluation of the optimized search. It is important to stress here that since the annotation task is directly related to the user appreciation, it is actually very hard to provide concrete results about it at this stage. In fact, we are confronted to the common difficulties in the evaluation of such processes: users' subjectivity, statistical significance of the obtained results (since the participant set is very small), etc. This part is under consideration and Fig. 2. Different levels in the social graph. V i represents Jennifer in the graph. N (V i ) represents the set of direct neighbors of V i . N\V i represents the set of vertices that are neighbors of N (V i ). Finally, V is the set of vertives in the social graph.

will not be described in this paper. Instead, we discuss more concrete and quantifiable results, related to execution times.

A. System Architecture

Figure 3 shows the general architecture of the system. The system assumes three main layers: (i) back-end social layer, (ii) advanced social annotation engine, and (iii) front-end interactions layer. The first layer (from the bottom to the top in Figure 3) is responsible of managing the interactions between our annotation system and the existing social network sites. This layer is important in the overall architecture of our system since this system is expected to complement the existing social network sites and not to replace them. The front-end layer as for it is dedicated to manage the interactions of the user with the system. This includes the introduction of queries by the user (in the form of a selection of a photo), and the results showing (in the form of extended and adapted annotations to the specific user). This layer is composed of three main components: Fig. 3. Overview of the system architecture 1) Basic Profile Manager: This component is responsible for maintaining and managing the profiles as they are defined in the different social network sites. This component is composed of different gateways that enable our system to communicate with the different social network sites.

2) Extended FOAF and Social inference engine: Relations between basic profiles are extended as we have discussed it before. This engine helps to maintain a meaningful link between the basic profiles by capturing the semantic relations that can exist between people. The extension of FOAF, as described in the previous sections, is applied at this stage. The correspondences between the basic profiles and the FOAF extended definitions are operated off-line. This component is also responsible of extracting (i.e. inferring) a meaningful semantic description according to the viewer's profile and role. It exploits both the basic profiles as well as the extended FOAF definitions of the relationships. This task operates on-line.

3) Optimized search engine: This engine implements the described algorithm in Section III to improve the search.

4) Data Storage Engine: This engine supports a relational database that stores the captured context of a photo. The context data associated to a photo, containing Location, Time, as well as the identifiers of Actors and Witnesses is captured by a client application and uploaded to the database 8 .

5) Relevance Feedback Engine: This engine supports the tag suggestion improvement, using widgets that appear next to each Social Dimension tag. These widgets are: Accept (when the suggestion is meaningful), Reject (when the suggestion in not meaningful and the viewer wants a re-computation) or Edit (when no suggestion has been found and thus the user can manually describe the social dimension). The use of the system is not conditioned by the use of these widgets. In fact, the user may not give her feedback. In this case, the system doesn't integrate this information in the next queries.

B. Preliminary Results

The objective of our experiments is to compare the proposed algorithm (SQO) with the classical Breadth First Search (BFS) algorithm [START_REF] Knuth | The art of computer programming[END_REF]. The two algorithms are implemented using Java on a machine with 2.10 GHz CPU and 2 GB RAM. We have measured the response time with respect to the data size (i.e., the number of RDF triples). We evaluate the performance of the proposed algorithm with respect to the size of the data (i.e. the number of RDF triples). We considered a dataset with ≈ 1 million of RDF triples. To compare the performances of our algorithm, we considered the classical Breadth First Search (BFS) as a reference. The experimental protocol is as follows: we vary the size of the FOAF graph from 153 to 1,060683 million triples and we recover the execution times of the two algorithms (BFS and SQO). The obtained results are reported on Figure 4 where the execution time is expressed in milliseconds.

Figure 4 clearly shows: (i) the important gain that can be obtained using the proposed optimization compared to the classical algorithm and (ii) the difference in the behavior between the two approaches. More specifically, execution times of the BFS algorithm increased from 1594 s with 154 triples to 16429 minutes with 1 millions triples. More importantly, the curve in the Figure 4 shows an exponential behavior of the Breadth First Search algorithm.

The time and space complexity of the BFS is O(b m ) (where b stands to the branching factor and m to the maximum path The curve in Figure 4 shows that the behavior of the SQO algorithm does not vary much, meaning that our algorithm isez faster. This is very encouraging since we can tackle a very large datasets. As an example, if we consider a dataset with n = 10 6 nodes, the algorithm can theoretically process it in about 4 seconds.

V. RELATED WORK

Tagging has emerged as a popular means to annotate online objects such as bookmarks, photos, and videos. Tags vary in semantic meaning and can describe different aspects of a media object. Tags describe the content of a media as well as locations, dates, peoples and other associated meta-data. Tagging content is now a natural capability of social media services, like Flickr, Youtube, Del.icio.us or social networking sites (SNS), like Facebook. Tagging can take different forms: automatic, when the system automatically assigns keywords to the image; semi-automatic, when the system assigns tags in the form of suggestions and the user accepts/rejects the result (relevance feedback) or manual, when the user enters a freely selected keyword. There are a number of research prototypes that address tagging in photos in automatic or semiautomatic manner. To achieve this perspective, they use data in the captured context of the user (location, environment, time, users around). CONFOTO [START_REF] Nowack | Confoto: A semantic browsing and annotation service for conference photos[END_REF] is a system with the capability of semantic tagging and navigation in photos that are related to conferences. PhotoCompas [START_REF] Sigurbjörnsson | Flickr tag recommendation based on collective knowledge[END_REF] uses the moment of the photo shot and location for the high-level interpretation of the context. The system suggests the identity of persons by comparing the context of the photo with the previously taken in a similar context. Zonetag [START_REF] Monaghan | Automating photo annotation using services and ontologies[END_REF] , a prototype system for Motorola and Nokia smart phones, allows uploading photos to Flickr with semantic tags. The system uses contextual information such as the location and the time of the shot to suggest tags. The suggestion is based on the principle that in a similar context there is a higher chance to be with the same people and to make the same activity. This work captures the social context of a photo with Bluetooth (actors and witnesses) and annotates the photo with this information.

The difference between our approach and these approaches is that we enrich the identity tags of photos using social relationships which are derived from the profiles of persons. In addition, the derived annotations are adapted to the current user profile making the annotation more dynamic and autoadaptable. To the best of our knowledge, this is the first work that considers the dynamic and auto-adaptability of the tags.

Image tagging is known in other research areas as image annotation. Image annotation is investigated in different fields like data mining, databases, and statistics. Several approaches have been proposed to tackle this problem. Most of the work is based on a coupling of image processing techniques, e.g. color and texture, and data analysis techniques to provide the most suitable annotation to an image [START_REF] Hacid | Neighborhood graphs for semi-automatic annotation of large image databases[END_REF]. Clustering is heavily used to attach a text to images [START_REF] Naaman | Automatic organization for digital photographs with geographic coordinates[END_REF]. With these methods, it is possible to predict the label of a new image by calculating some probabilities. Minka and Picard [START_REF] Picard | Vision texture for annotation[END_REF] proposed a semi-automatic image annotation system which allows users to choose the area to be annotated in the image. On the other hand, probabilistic models such as Cross Media Relevance model [START_REF] Jeon | Automatic image annotation and retrieval using cross-media relevance models[END_REF] and Latent Semantic Analysis [START_REF] Monay | On image auto-annotation with latent space models[END_REF] were also proposed. Jia and Wang [START_REF] Li | Automatic linguistic indexing of pictures by a statistical modeling approach[END_REF] use a two-dimensional hidden markov chains to annotate images. All these approaches rely on some intelligent way to associate a tag to an image after a heavy processing. The result of the process is a static list of keywords that are associated to each image. Our work doesn't focus on low-level image processing for annotation. Instead, it relies mainly on the users, i.e. manual annotation (also called tagging), as it's the case currently on the web.

VI. CONCLUSION AND FUTURE WORK

Image annotation is currently performed in a static way, i.e. we associate static tags to objects or people on the photo. These tags are thus presented in the same form to any person regardless if they can be meaningful for her or not. We have then tackled in this paper the problem of using social relations to provide a user with more meaningful annotations that help her to situate unknown persons according to potentially known ones in a photo, i.e. directly connected in the social network. First we have proposed a new annotation model that considers the social interactions in a social network. This helps in modeling additional information to characterize the relation that can exist between people. Then, the FOAF vocabulary has been extended to consider more relationships. This was necessary in order to offer the user with more meaningful annotation. The last contribution is an optimized search algorithm that improves the search performances in a semantic, i.e. FOAF, database. Furthermore, we have described a system architecture that supports the proposals of this paper. Finally, preliminary results have been discussed showing the interest of the proposed search algorithm and the important gains compared to the classical one.

As a future work, we first plan to perform an intensive evaluation of the proposed approach to consider possible problems or improvements. The idea is to invite real users to test our application and perform a qualitative evaluation. A second important future work is to extend the proposed approach in the context of mobility. The idea is to capture the current user context (i.e. location and time) according to his communication means, and use this information to better exploit the annotations. We are currently investigating a data mining approach to handle this part and a preliminary discussion has been already started in this paper. Another possible research direction is to improve the optimization algorithm by considering the social proximity. At the present, we don't define any metric to measure the proximity between people considering the number of times that a person appears as actor in social media. Finally, in this paper we have considered only the case of a viewer. It would be interesting to investigate how to consider the different people that are included in the whole photo sharing process (e.g. Actor, Witness, etc.).

  Tags = [David; Steven; Edward; Joe; Andrew; Alex], [Vancouver],[SocialCom Conference], [Jade; Stanley Park], [29 august 2009].

  Tags' = [Steven, brother-in-law of my colleague David; David, My colleague; Edward, apprenticeTo my colleague, David; Joe, colleague of my colleague David; Andrew, collabo-ratesWith my colleague David; Alex, colleagueOf my colleague David], [Vancouver], [SocialCom conference], [Jade; Stanley Park],[29 august 2009]

Fig. 1 .

 1 Fig. 1. Use Case Example. (a) identity suggestion for David, (b) identity suggestion for Jennifer

Fig. 4 .

 4 Fig. 4. Comparison of the two algorithms

  15: until state = v j OR q.empty() 16: if state = v j then 17: return v j 18: end if 19: P arentState ← (v, v ∈ N(state) AND v ∈ N odesCovered) 20: for all v ∈ P arentState do 21:

repeat 22: Add state to SocialDimension[j] 23: if v i ∈ N(state) then 24: Add 'My' to SocialDimension[j] 25: Add R(state, v i ) to SocialDimension[j] 26: state = v i 27: else 28: Add R(state,v) to SocialDimension[j] 29: state = v 30: end if 31:

htt://www.flickr.com/

htt://www.del.icio.us/

htt://www.facebook.com/

htt://www.youtube.com/

http://vocab.org/relationship/rel-vocab-20050810.rdf

The context capture is out of the main scope of this paper so we don't detail it.

The objective in this paper is not to detail the usage of association rules. Thus, we only discuss briefly this aspect of the solution here.

The different techniques of capturing these data with a mobile device are not detailed in this paper.