An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress.

This open-label trial assessed the clinical efficacy of L-5-hydroxytryptophan (5-HTP), a natural serotonin precursor, in nondepressed young subjects with high levels of romantic stress. Since both neurotrophins and serotonin have been linked to human romantic attachment, we sought to investigate the changes in serum brain-derived neurotrophic factor (BDNF) levels and platelet serotonin content in relation to the changes in romantic stress throughout the study. A total of 15 healthy subjects (11 females and 4 males, mean age: 23.3 ± 2.1 years) who experienced a recent romantic break-up or reported recent romantic problems took part in the study. The participants were treated openly for 6 weeks with L-5-hydroxytryptophan (60 mg Griffonia simplicifolia extract containing 12.8 mg 5-HTP b.i.d., Amorex, Coropharm, Villach, Austria). The subjects were evaluated at baseline, at 3 weeks and at the end of the 6-week trial using an adapted version of the Seiffge-Krenke's Problem Questionnaire. BDNF and platelet serotonin content were determined at baseline, at 3 weeks, and after the completion of the 6-week trial. We observed significant improvements in romantic stress scores from weeks 0 through 3 (p=0.007) but no further significant improvement was evident from weeks 3 through 6 (p=0.19). At 6 weeks, subjects had a significant increase from baseline in both BDNF and platelet serotonin values. Our data suggest that direct modulation of the serotonergic system may have use for the treatment of psychological suffering associated with unreciprocated romantic love.

Serum omega-3 fatty acids are associated with ultimatum bargaining behavior.

In the ultimatum game (UG), two players are involved to bargain over a division of a given sum of money. The proposer makes an ultimatum offer of a fraction of money, while the responder can either accept or reject the proposer's decision. In case of rejection of the proposed splitting by the responder, neither player gets anything. Adverse psychological reactions are deemed to play a role in the rejection of unfair offers. Low serum levels of omega-3 polyunsaturated fatty acids have been linked to impulse control and hostility. This study examined the serum omega-3 and omega-6 fractions in relation to the ultimatum bargaining behavior. Participants were sixty economy students (31 males and 29 females, mean age: 24.4+/-2.3 years) who played a euro 10 ultimatum game. Ultimatum offers were constrained to be euro 5 (proposer keeps euro 5) or euro 1 (proposer keeps euro 9) to generate a roughly even split between fair (5:5) and unfair (1:9) offers. Fasting serum alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic acid (DHA), linoleic acid (LA) and arachidonic acid (AA) were assayed with gas chromatography. In participants who rejected unfair offers there was a significant depletion of ALA, EPA and DHA. Moreover, the ratio of serum omega-3/omega-6 fatty acids was significantly lower in patients who rejected unfair offers as compared to those who did not. The results of this study suggest that a depletion of the serum omega-3 fatty acids is associated with rejections of unfair ultimatum offers in an experimental neuroeconomic setting.

Relationship between platelet serotonin content and rejections of unfair offers in the ultimatum game.

The ultimatum game (UG), a well-studied decision task used in experimental neuroeconomics, represents a simple two-person bargaining between a proposer and a responder. The proposer offers the responder how to split a sum of money. The responder decides whether to accept or reject the offer. When the responder accepts it, each player earns money according to the proposer's offer. If the offer is rejected, neither player gets anything. Rejections of "free" money in the UG represent a deviation from the standard economic model of rationality. This behaviour could be linked to adverse psychological reactions to unfair offers, including anger, hostility and impulsiveness. Currently, it is believed that the most plausible biological system related to anger and impulsivity is the serotonergic system. We hypothesize that serotonergic activity, as measured by platelet serotonin levels, will differentiate subjects who either reject or accept low UG offers. A sample of 60 economy students (31 males and 29 females, mean age: 24.4+/-2.3 years) was investigated. As predicted, the mean platelet serotonin level was significantly lower in participants who reject unfair offers (euro 1 out of euro 10) than in those who accept (2.86+/-0.13 versus 3.48+/-0.11 nmol/10(9) platelets, respectively, p<0.001). We conclude that low platelet serotonin may serve as a reliable biomarker to identify people who are more likely to reject unfair ultimatum offers in an experimental neuroeconomic setting. Our pilot data seem to indicate that the serotonergic system may play an important role in the UG rejection behaviour.

The -374T/A RAGE polymorphism protects against future cardiac events in nondiabetic patients with coronary artery disease.

BACKGROUND: The -374T/A polymorphism of the Receptor for Advanced Glycation End products (RAGE) may exert a protective effect toward the development of atherosclerosis. No data are currently available on the potential prognostic role of this polymorphism in patients with angiographically proven coronary artery disease (CAD). Hereto we sought to address this issue in a large consecutive cohort of patients undergoing coronary revascularization. METHODS: A total of 643 CAD patients who underwent myocardial revascularization were followed for 4.2 years (interquartile range: 2.2-8.1 years). The rates of major cardiac adverse events (death, nonfatal myocardial infarction, and unstable angina) were compared according to the -374T/A RAGE polymorphism. RESULTS: During a median follow-up period of 4.2 years, the study endpoint was reached by 126/643 patients (19.6%). We observed adverse cardiac events in 13.4% of patients with AA, 17.5% of those with AT, and 24.2% of those with TT genotype (p <0.05). In univariate Cox proportional hazard analysis, the AA genotype was significantly related to a better outcome in nondiabetic patients (hazard ratio: 0.47, 95% CI: 0.20-0.96; p <0.05). No association was found with adverse events in diabetic subjects. After allowance for potential confounders, the AA genotype remained a significant prognostic factor in the nondiabetic group (adjusted HR: 0.41, 95% CI: 0.17-0.94, p <0.05). CONCLUSIONS: The -374T/A RAGE polymorphism is an independent protective factor for cardiac events in nondiabetic patients with CAD. The effect of this genetic variant seems to be attenuated in diabetics, who have chronic RAGE upregulation.

Decreased NT-3 plasma levels and platelet serotonin content in patients with hypochondriasis.

OBJECTIVE: Neurotrophins (NT) are a family of closely related proteins, including brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). NTs are deemed to regulate several aspects of neuronal survival, development, and function. Although NTs have been associated to a variety of mental disorders, the potential role of NT alterations in hypochondriasis (HC) has never been investigated. METHODS: In the present study, plasma concentrations of NTs were evaluated in 23 adult patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for HC and 22 healthy controls. Platelet serotonin (5-HT) content was chosen as a measure of serotonergic function. Hypochondriacal symptoms were assessed using the Whiteley Index of Hypochondriasis (WIH). RESULTS: Plasma NT-3 level (P=.004) and platelet 5-HT (P=.008) were significantly lower in patients with HC compared with controls. Correlation analyses showed that the WIH score was significantly and inversely associated with both NT-3 values (r=-.60, P=.002) and platelet serotonin content (r=-.53, P=.009). We used a multivariate regression model to determine independent predictors of the WIH score. After allowance for potential confounders, plasma NT-3 levels remained the unique independent predictor of the WIH (beta=.003, t=-3.5, P=.003). CONCLUSIONS: Decreased NT-3 concentration, alongside with serotonin dysfunction, may represent a biological correlate of HC.

Metalloproteinase-2 and -9 in diabetic and nondiabetic subjects during acute coronary syndromes.

The authors hypothesized that matrix metalloproteinase (MMP)-2, -9, and tissue inhibitor metalloproteinase (TIMP)-1, -2 would be abnormal in acute coronary syndromes (ACSs). MMP-2, -9, and TIMP-1, -2 plasma levels were measured in diabetic patients with ACSs compared to nondiabetic patients with ACSs. A total of 46 diabetic and 78 nondiabetic patients with ACSs were enrolled. The following parameters were measured: body mass index (BMI), glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment index (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), lipoprotein(a) [Lp(a)], plasminogen activator inhibitor-1 (PAI-1), homocysteine (Hct), fibrinogen (Fg), high-sensitivity C-reactive protein (hs-CRP), and plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2. Significant HbA1c, FPG, FPI, HOMA index, DBP, Tg, Hct, and Fg increases were present in the diabetic group with ACSs, whereas hs-CRP was lower in these patients compared to nondiabetic patients with ACSs. MMP-9, TIMP-1, and TIMP-2 plasma levels were higher in diabetic patients with ACSs compared to nondiabetic patients with ACSs. MMP-9, TIMP-1, and TIMP-2 plasma levels were increased in diabetic patients with ACSs, which may reflect abnormal extracellular matrix metabolism in diabetes during acute event.

Genetic loading on human loving styles.

OBJECTIVES: It has been hypothesized that cerebral neurotransmitters such as dopamine and serotonin could play a role in human romantic bonding. However, no data on the genetic basis of human romantic love are currently available. To address this issue, we looked for associations between markers in neurotransmitter genes (the serotonin transporter gene, 5-HTT; the serotonin receptor 2A, 5HT2A; the dopamine D2 receptor gene, DRD2; and the dopamine D4 receptor gene, DRD4) and the six styles of love as conceptualized by Lee (Eros, Ludus, Storge, Pragma, Mania and Agape). DESIGN: A total of 350 healthy young adults (165 males and 185 females, mean age: 24.1+/-3.9 years, range 18-32 years) filled the 24-item Love Attitudes Scale (LAS) and were genotyped for the following six polymorphic markers: the serotonin transporter-linked polymorphic region (5-HTTLPR), the 5HT2A T102C and C516T polymorphisms, the DRD2 TaqI A and TaqI B variants, and the DRD4 exon 3 VNTR polymorphism. RESULTS: Statistical analysis revealed a significant association between the DRD2 TaqI A genotypes and "Eros" (a loving style characterized by a tendency to develop intense emotional experiences based on the physical attraction to the partner), as well as between the C516T 5HT2A polymorphism and "Mania" (a possessive and dependent romantic attachment, characterized by self-defeating emotions). These associations were present in both sexes and remained significant even after adjustment for potential confounders. CONCLUSIONS: Our data provide the first evidence of a possible genetic loading on human loving styles.

The apolipoprotein(a) component of lipoprotein(a) mediates binding to laminin: contribution to selective retention of lipoprotein(a) in atherosclerotic lesions.

Lipoprotein(a) [Lp(a)] entrapment by vascular extracellular matrix may be important in atherogenesis. We sought to determine whether laminin, a major component of the basal membrane, may contribute to Lp(a) retention in the arterial wall. First, immunohistochemistry experiments were performed to examine the relative distribution of Lp(a) and laminin in human carotid artery specimens. There was a high degree of co-localization of Lp(a) and laminin in atherosclerotic specimens, but not in non-atherosclerotic sections. We then studied the binding interaction between Lp(a) and laminin in vitro. ELISA experiments showed that native Lp(a) particles and 17K and 12K recombinant apolipoprotein(a) [r-apo(a)] variants interacted strongly with laminin whereas LDL, apoB-100, and the truncated KIV(6-P), KIV(8-P), and KIV(9-P) r-apo(a) variants did not. Overall, the ELISA data demonstrated that Lp(a) binding to laminin is mediated by apo(a) and a combination of the lysine analogue epsilon-aminocaproic acid and salt effectively decreases apo(a) binding to laminin. Secondary binding analyses with 125I-labeled r-apo(a) revealed equilibrium dissociation constants (K(d)) of 180 and 360 nM for the 17K and 12K variants binding to laminin, respectively. Such similar K(d) values between these two r-apo(a) variants suggest that isoform size does not appear to influence apo(a) binding to laminin. In summary, our data suggest that laminin may bind to apo(a) in the atherosclerotic intima, thus contributing to the selective retention of Lp(a) in this milieu.

Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target.

The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimer's disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimer's disease.

Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease.

Eotaxin (CCL11) is an eosinophil-specific chemoattractant which has been found to be highly expressed at sites of vascular pathology. In the present study, we aimed to evaluate the association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease (CAD). Three hundred and fifty six consecutive patients attending for elective coronary angiography were investigated. Compared with 111 patients without CAD, 245 with CAD showed higher eotaxin concentrations [median (interquartile range): 76.0 (56.3-103.0)pg/ml versus 116.0 (80.5-162.0)pg/ml, respectively; P<0.001]. Importantly, a significant Spearman correlation was found between eotaxin levels and the extent score of coronary artery stenosis (r=0.449, P<0.001). A stepwise increase in plasma levels of eotaxin was also found depending on the number of >50% coronary stenosis: median value 76.0 pg/ml in CAD(-) subjects, 96.0 pg/ml in 1-vessel disease, 128.0 pg/ml in 2-vessel disease, and 129.0 pg/ml in 3-vessel disease (P<0.001 for trend). After confounding variables were controlled for, multiple stepwise regression analysis demonstrated that plasma eotaxin was an independent predictor of angiographic extent of CAD (beta=0.426, P<0.001). Our data suggest that increased eotaxin levels are associated with the presence of CAD and that circulating levels of this chemokine may reflect the extent of coronary atherosclerosis.

Raised plasma nerve growth factor levels associated with early-stage romantic love.

Our current knowledge of the neurobiology of romantic love remains scanty. In view of the complexity of a sentiment like love, it would not be surprising that a diversity of biochemical mechanisms could be involved in the mood changes of the initial stage of a romance. In the present study, we have examined whether the early romantic phase of a loving relationship could be associated with alterations in circulating levels of neurotrophins (NTs). Plasma levels of NGF, BDNF, NT-3 and NT-4 were measured in a total of 58 subjects who had recently fallen in love and compared with those of two control groups, consisting of subjects who were either single or were already engaged in a long-lasting relationship. NGF level was significantly higher (p < 0.001) in the subjects in love [mean (SEM): 227 (14) pg/ml] than in either the subjects with a long-lasting relationship [123 (10) pg/ml] or the subjects with no relationship [149 (12) pg/ml]. Notably, there was also a significant positive correlation between levels of NGF and the intensity of romantic love as assessed with the passionate love scale (r = 0.34; p = 0.007). No differences in the concentrations of other NTs were detected. In 39 subjects in love who-after 12-24 months-maintained the same relationship but were no longer in the same mental state to which they had referred during the initial evaluation, plasma NGF levels decreased and became indistinguishable from those of the control groups. Taken together, these findings suggest that some behavioural and/or psychological features associated with falling in love could be related to raised NGF levels in the bloodstream.

Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease.

Experimental data have shown an upregulated expression of toll-like receptors, particularly toll-like receptor 4 (TLR4), in neurodegeneration. The Asp299Gly polymorphism of the TLR4 gene has been associated with an attenuated receptor signalling and a blunted inflammatory response. In the present study, we sought to determine whether this common genetic variant could influence susceptibility to late-onset Alzheimer's disease (LOAD) in an Italian population sample. A cohort of 277 LOAD patients and 300 cognitively healthy controls were genotyped for the TLR4 Asp299Gly polymorphism using restriction isotyping. The frequency of the minor 299Gly allele was significantly higher in the controls than in the LOAD cases (7.2% versus 3.1%, respectively, P=0.003). Additionally, the frequency of the variant genotypes (Asp/Gly and Gly/Gly) was 13.0% in the controls and 5.4% in LOAD patients (P=0.002). After adjustment for age, gender, and the APOE varepsilon4 carrier status, the odds ratio for the development of LOAD associated with the Asp/Gly and Gly/Gly versus Asp/Asp genotype was 0.37 (95% CI: 0.20-0.69, P=0.002). Our data further support a role for innate immunity in neurodegeneration and give the first evidence that the TLR4 Asp299Gly variant may be protective toward the development of LOAD.

A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction.

BACKGROUND: Alterations in coronary vasomotor tone are deemed to play an important role in myocardial infarction (MI), and the ATP-binding cassette transporter C9-ABCC9-may be involved in the regulation of coronary artery vasomotility. We sought to determine whether genetic variations in the coding sequence of ABCC9 gene could be associated with precocious MI (myocardial infarction before the age of 60 years) in humans. METHODS: In this study, we screened using PCR-SSCP analysis the entire coding region of the ABCC9 gene in 45 patients with precocious MI and 45 age- and gender-matched controls. RESULTS: A novel missense mutation, Val734Ile in exon 17, was detected in one MI patient. We therefore analyzed by PCR-RFLPs the frequency of this nonsynonymous change in a large Italian cohort of precocious MI patients (n=584) and healthy comparison subjects (n=873). After allowance for the potential confounding effects of age, gender, and established cardiovascular risk factors, multivariate logistic regression analysis revealed that carriers of the rare 734Ile allele would have a 6.40-fold risk of suffering MI before the age of 60 years as compared to controls (95% CI=1.58-25.90, P=0.009). CONCLUSIONS: Taken together, our results provide the first important evidence that the newly discovered 734Ile allele in ABCC9 might influence susceptibility to precocious MI in our population.

Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men.

OBJECTIVE: The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose signaling pathway has been implicated in atherogenesis. RAGE has an endogenous secretory receptor form, called soluble RAGE (sRAGE), that could exert antiatherogenic effects by acting as a decoy. We sought to determine whether a decreased plasma level of sRAGE could be independently associated with the prevalence of coronary artery disease (CAD) in nondiabetic men. METHODS AND RESULTS: Plasma levels of sRAGE were determined in 328 nondiabetic male patients with angiographically proved CAD and in 328 age-matched healthy controls. The concentration of sRAGE in plasma was significantly lower (P<0.0001) in CAD cases [median (interquartile range): 966 (658-1372) pg/mL] than in control subjects [1335 (936-1954) pg/mL]. In logistic regression analysis, the multivariate-adjusted odds ratio for the presence of CAD was 6.719 (95% confidence interval, 3.773 to 11.964; P<0.0001) when the lowest quartile of the sRAGE level was compared with the highest quartile. CONCLUSIONS: Our findings indicate that low levels of sRAGE in plasma are independently associated with the presence of CAD in nondiabetic men and suggest that sRAGE is one of the clinically important molecules associated with atherosclerosis.

QT interval duration in apparently healthy men is associated with depression-related personality trait neuroticism.

OBJECTIVE: High levels of neuroticism and low self-esteem are markers for vulnerability to depression, a condition associated with a higher risk of arrhythmias. The question as to whether these depression-related personality domains are related to cardiac repolarization (duration of QT interval) in apparently healthy men has been addressed in this study. METHODS: Participants were 658 clinically healthy males who underwent a health screening programme. QT interval duration was determined in the resting 12-lead electrocardiogram using an automated analysis program. Neuroticism was assessed by the short-scale Eysenck Personality Questionnaire and self-esteem by the Rosenberg self-esteem scale. RESULTS: Heart-rate corrected QT interval {QTc, formula of Bazett [Bazett HC. An analysis of time relations of electrocardiograms. Heart 1920;7:353-370]} progressively increased across quartiles of neuroticism ratings. By contrast, no differences in QTc were observed across different degrees of self-esteem. A multivariate regression analysis showed that neuroticism was a statistically significant, independent predictor of QTc duration. CONCLUSION: After adjustment for potential confounders, neuroticism scores independently predicted QT interval duration in apparently healthy men. These findings highlight the possibility that higher arrhythmic risk could be present not only in patients with clinical depression but also in depression-prone, otherwise healthy individuals.

Elevated plasma levels of lipoprotein(a) in psychiatric patients: a possible contribution to increased vascular risk.

An increased incidence of adverse cardiovascular events has been reported in psychiatric patients, but the exact mechanisms underlying this association are still uncertain. Elevated plasma level of lipoprotein(a) [Lp(a)] is an independent risk factor for atherothrombotic disease in the general population. To study the implications of Lp(a) in psychiatric patients, we measured the plasma levels of Lp(a) in 74 patients with psychiatric disorders (39 schizophrenia, 10 major depression, 13 bipolar disorder and 12 personality disorder) and 74 healthy controls. The Lp(a) levels of the patient groups with schizophrenia, major depression and bipolar disorder were significantly higher than that of the control group. The median Lp(a) value of these diagnostic groups was comparable with those reported in patients with prior atherothrombotic events. On the other hand, no differences were found among personality disorder and controls. Our findings suggest that the elevation of plasma Lp(a) may contribute to increased cardiovascular risk in several patients with psychiatric disorders.

Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients.

BACKGROUND: Erectile dysfunction (ED) is associated with coronary artery disease (CAD). In diabetic patients, CAD is often silent. Among diabetic patients with silent CAD, the prevalence of ED has never been evaluated. We investigated whether ED is associated with asymptomatic CAD in type 2 diabetic patients. METHODS AND RESULTS: We evaluated the prevalence of ED in 133 uncomplicated diabetic men with angiographically verified silent CAD and in 127 diabetic men without myocardial ischemia at exercise ECG, 48-hour ambulatory ECG, and stress echocardiography. The groups were comparable for age and diabetes duration. Patients were screened for ED using the validated International Index of Erectile Function (IIEF-5) questionnaire. The prevalence of ED was significantly higher in patients with than in those without silent CAD (33.8% versus 4.7%; P=0.000). Multiple logistic regression analysis showed that ED, apolipoprotein(a) polymorphism, smoking, microalbuminuria, HDL, and LDL were significantly associated with silent CAD; among these risk factors, ED appeared to be the most efficient predictor of silent CAD (OR, 14.8; 95% CI, 3.8 to 56.9). CONCLUSIONS: Our study first shows a strong and independent association between ED and silent CAD in apparently uncomplicated type 2 diabetic patients. If our findings are confirmed, ED may become a potential marker to identify diabetic patients to screen for silent CAD. Moreover, the high prevalence of ED among diabetics with silent CAD suggests the need to perform an exercise ECG before starting a treatment for ED, especially in patients with additional cardiovascular risk factors.

Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia.

BACKGROUND: The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model. OBJECTIVE: To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. DESIGN: Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. MAIN OUTCOME MEASURE: Plasma levels of sRAGE. RESULTS: Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001). CONCLUSIONS: Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.

Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension.

OBJECTIVES: Advanced glycation end-products (AGE) may cause vascular stiffening by forming crosslinks through the collagen molecule or by interaction with their cellular transductional receptor (RAGE). A secreted isoform of RAGE, termed soluble RAGE (sRAGE), may contribute to the removal/detoxification of AGE by acting as a decoy. Here we studied the plasma sRAGE levels in hypertensive and normotensive human subjects. We also investigated the relationship between blood pressure parameters and plasma sRAGE concentrations. DESIGN: A cross-sectional case-control study. SETTING AND PARTICIPANTS: The outpatient clinic of a university teaching hospital. Participants were 147 never-treated patients with essential hypertension (87 men and 60 women, aged 50 +/- 10 years) and 177 normotensive controls (118 men and 59 women, aged 49 +/- 10 years). MAIN OUTCOME MEASURES: Plasma sRAGE levels determined by enzyme-linked immunosorbent assay, systolic blood pressure (SBP), diastolic blood pressure, pulse pressure (PP) and mean arterial pressure. RESULTS: The plasma concentration of sRAGE [median (interquartile range)] was 1206 (879-1658) pg/ml in hypertensive subjects and 1359 (999-2198) pg/ml in normotensive controls (P = 0.002). Simple correlation analysis revealed that log-transformed sRAGE levels were inversely correlated with SBP (r = -0.11; P < 0.001) and PP (r = -0.23; P < 0.001). Forward-selection multiple regression analysis revealed that log-transformed sRAGE levels were determined more strongly by PP (F = 3.127, P < 0.001). CONCLUSIONS: Plasma sRAGE levels are decreased in patients with essential hypertension and are inversely related to PP. Our results raise the possibility that sRAGE may play a role in arterial stiffening and its complications.