Marina Toutouza

National and Kapodistrian University of Athens, Athens, Attiki, Greece

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Publications (89)529.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is essential for maintenance of enzymatic function. We hypothesized that induction of BH4 synthesis might be an endothelial defense mechanism against inflammation in vascular disease states. In Study 1, 20 healthy individuals were randomized to receive Salmonella typhi vaccine (a model of acute inflammation) or placebo in a double-blind study. Vaccination increased circulating BH4 and interleukin 6 and induced endothelial dysfunction (as evaluated by brachial artery flow-mediated dilation) after 8 hours. In Study 2, a functional haplotype (X haplotype) in the GCH1 gene, encoding GTP-cyclohydrolase I, the rate-limiting enzyme in biopterin biosynthesis, was associated with endothelial dysfunction in the presence of high-sensitivity C-reactive protein in 440 coronary artery disease patients. In Study 3, 10 patients with coronary artery disease homozygotes for the GCH1 X haplotype (XX) and 40 without the haplotype (OO) underwent S Typhi vaccination. XX patients were unable to increase plasma BH4 and had a greater reduction of flow-mediated dilation than OO patients. In Study 4, vessel segments from 19 patients undergoing coronary bypass surgery were incubated with or without cytokines (interleukin-6/tumor necrosis factor-α/lipopolysaccharide) for 24 hours. Cytokine stimulation upregulated GCH1 expression, increased vascular BH4, and improved vasorelaxation in response to acetylcholine, which was inhibited by the GTP-cyclohydrolase inhibitor 2,4-diamino-6-hydroxypyrimidine. The ability to increase vascular GCH1 expression and BH4 synthesis in response to inflammation preserves endothelial function in inflammatory states. These novel findings identify BH4 as a vascular defense mechanism against inflammation-induced endothelial dysfunction.
    Circulation 10/2011; 124(17):1860-70. · 14.95 Impact Factor
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    ABSTRACT: We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.
    Hypertension 07/2011; 58(1):93-8. · 7.63 Impact Factor
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    ABSTRACT: Obesity is associated with impaired postprandial triacylglycerolemia, an independent risk factor for cardiovascular disease. Given that obesity is hard to treat, efforts should focus on treating its comorbidities. We aimed to investigate whether moderate weight loss normalizes postprandial triacylglycerol (TAG) concentrations, in the absence of the acute effects of negative energy balance. For this purpose, postprandial lipemia was investigated in eight obese but otherwise healthy, sedentary men (age: 41.3 ± 4.1 years, BMI: 36.5 ± 1.6 kg·m(-2)), once before and again after a 10% weight loss followed by ≥4 weeks of weight maintenance, and was compared with that of eight age-matched healthy lean men (BMI: 24.7 ± 0.6 kg·m(-2)). Dietary intervention consisted of reduced carbohydrate and saturated fat intake and increased monounsaturated fat intake. Obese volunteers were advised to increase physical activity using pedometers to record daily activity. Postprandial triacylglycerolemia after weight loss was reduced by 27-46% (P < 0.05), and became similar to that of lean men despite persisting obesity (BMI after weight loss: 32.9 ± 1.5 kg·m(-2)). Reduction in postprandial TAG responses was inversely correlated with the decrease in postprandial insulin sensitivity index (ISI) after weight loss (r = -0.714, P = 0.047). We conclude that moderate weight loss induced by a low-carbohydrate and saturated fat diet and a slight increase in daily physical activity normalizes postprandial triacylglycerolemia in obese men, independently of acute diet-induced negative energy balance, and possibly through enhancement of insulin action.
    Obesity 09/2010; 19(5):968-76. · 4.39 Impact Factor
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    ABSTRACT: Blood lipids and inflammatory markers levels have been associated with the development and progression of atherosclerosis. As the association of inflammatory markers with plasma fatty acids has not been extensively evaluated and understood, we sought to investigate the associations between dietary and plasma fatty acids with various inflammation and coagulation markers. High sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), fibrinogen, and homocysteine were measured in serum of 374 free-living, healthy men and women, randomly selected from the ATTICA's study database. Total plasma fatty acids were determined by gas chromatography. Dietary fatty acids were assessed through a semi-quantitative FFQ. Multi-adjusted regression analyses revealed that plasma n-3 fatty acids were inversely associated with CRP, IL-6 and TNF-alpha; plasma n-6 fatty acids were inversely associated with CRP, IL-6 and fibrinogen; monounsaturated fatty acids were inversely associated with CRP and IL-6 (all p-values<0.05). Interestingly, the n-6/n-3 ratios exhibited the strongest positive correlations with all the markers studied. No associations were observed between dietary fatty acids and the investigated markers. Measurements of total plasma fatty acids could provide insights into the relationships between diet and atherosclerotic disease. Moreover, the n-6/n-3 ratio may constitute a predictor of low-grade inflammation and coagulation.
    Clinica chimica acta; international journal of clinical chemistry 04/2010; 411(7-8):584-91. · 2.54 Impact Factor
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    ABSTRACT: We aimed to evaluate the association between renal function and various cardiovascular disease (CVD) risk factors, as well as 5-year incidence of CVD, in a sample of CVD free adults. (i) Cross-sectional information from n = 1975. Greek men and women (>18 years) without CVD and hypertension at baseline examination and (ii) 5-year (2001-06) survival data from n = 2101 individuals without CVD at baseline, all participants in the ATTICA study, were analysed in this work. Kidney function was quantified by the baseline estimated creatinine clearance rate (C(cr)), using the Cockcroft-Gault formula and the National Kidney Foundation recommendations. Outcome of interest was the development of CVD that was defined according to WHO-ICD-10 criteria. At baseline, the prevalence of moderate-to-severe renal dysfunction (i.e. C(cr) < 60) was 2.8% in males and 7.7% in females. Physical activity status, cigarette smoking, hypercholesterolemia and homocysteine levels and greater adherence to the Mediterranean diet were inversely associated with C(cr) rate (P < 0.05), while no association was found with history of diabetes. During the 5-year follow-up, people with moderate-to-severe renal dysfunction as compared with normal, had 3.21 times higher CVD risk [95% confidence interval (CI) 1.98-5.19], after adjusting for history of hypertension (hazard ratio = 2.15, 95% CI 1.48-3.11), hypercholesterolemia (1.37, 0.98-1.98), diabetes (3.28, 2.15-5.00), smoking habits (0.89, 0.60-1.32) and physical activity status (0.86, 0.56-1.21). Renal function seems to be associated with the levels of lifestyle and bio-clinical CVD risk factors and contribute to the long-term incidence of cardiac events. Public health care practitioners should take into account renal function in better preventing the burden of CVD at individual, and population level, as well.
    QJM: monthly journal of the Association of Physicians 04/2010; 103(6):413-22. · 2.46 Impact Factor
  • Journal of the American College of Cardiology 03/2010; 55(10). · 15.34 Impact Factor
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    Clinical Nutrition Supplements 01/2009; 4(2):172-172.
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    ABSTRACT: Human adult cardiomyocytes (CM) have been used in short-term cultures for in vitro studies of the adult myocardium. However, little information is available regarding human adult CMs cultured for long term (>2 weeks). Human adult CMs were isolated from atrial specimens of 43 patients undergoing cardiopulmonary bypass surgery. Cell viability, cytoskeletal properties, intercellular junctional mediators and responsiveness to extracellular stimuli were monitored in CM cultures for 8 weeks. Absolute numbers of CMs decreased through the first 2 weeks, with substantially lower rates of cell loss thereafter. Apoptosis predominated over necrosis as the principal mode of cell death, affecting 4.1+/-1.6% of freshly dissociated cells, that declined in culture (3.6+/-1.0% week 1, 1.3+/-0.5% week 2). CMs maintained rod-shaped morphology and cross-striated expression pattern of sarcomeric proteins desmin and beta-myosin heavy chain for the first 4 weeks. Levels of desmin remained stable on first 3 weeks, but declined thereafter. CMs expressed cardiac-specific adherence molecule N-cadherin throughout the culture duration, indicating conserved contractile potential. CMs remained functional early in culture, as indicated by BNP secretion, with maximal levels on 1st week that declined gradually by week 4. Cell responsiveness to metabolic stresses (serum deprivation) was detected, inducing an early (6 h) 1.8-fold increase in levels of BNP. Long-term cultured human adult CMs maintain morphological integrity, adult-type cytoskeletal protein expression, cell-cell communication potential and functionality for 3-4 weeks in vitro.
    International journal of cardiology 03/2008; 131(1):113-22. · 6.18 Impact Factor
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    ABSTRACT: We evaluated the efficacy and the safety of combining high doses of statins and ezetimibe in heterozygous familial hypercholesterolemia (hFH) patients. Seventy patients with hFH, received 10 mg of ezetimibe, in addition to their current statin therapy and were followed up for twelve months. The co-administration of statins and ezetimibe improved total cholesterol (p<0.05), LDL-c(p<0.05), triglycerides (p<0.05) and apolipoprotein-B (p<0.05) in comparison to statin monotherapy. There were no changes in high density lipoprotein cholesterol (HDL-c), apolipoprotein-A, lipoprotein (a), fibrinogen and C-reactive protein (CPR). In conclusion the combination of 10 mg of ezetimibe with high dose statin therapy is effective in hFH, offering a further reduction of LDL-c throughout the 12 months of follow up.
    International journal of cardiology 03/2008; 134(2):280-1. · 6.18 Impact Factor
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    ABSTRACT: The cardioprotective role of hormonal replacement therapy remains in doubt, but interest is increasing in the vascular effects of estrogens especially in coronary circulation. Coronary blood flow (CBF) was measured in 24 postmenopausal women (age 55+/-3 years), whose coronary arteries appeared angiographically normal, during incremental atrial pacing (AP) before and 20 minutes after intracoronary administration of either 75 ng/mL 17-beta estradiol (treated group, n=18) or 0.9% saline (controls, n=6). Before estrogen, no differences in the coronary vasomotor responses at AP between the two groups (p=NS) could be detected. After estrogen, in the treated group, at the peak of the second AP, the coronary artery diameter decreased by 0.17 mm (p<0.005) while the CBF increased by 61 mL/min (p<0.05). These changes differed significantly from those observed at the peak of first AP (p<0.001 for both cases). In contrast, in the control group no such changes were observed. The endothelin-1 (ET-1) levels in the coronary sinus were significantly reduced after estrogen infusion, which was negatively correlated with the degree of coronary artery constriction (r= -0.40, p=0.03) and positively correlated with the increase in CBF (r=0.54, p=0.01). In postmenopausal women without coronary artery disease, the intracoronary estrogen infusion mediates a greater increase in CBF and is positively correlated with the reduction of the coronary sinus ET-1 levels at the peak of AP.
    Vascular Health and Risk Management 02/2008; 4(3):705-14.
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    ABSTRACT: Familial combined hyperlipidaemia (FCH) is an inherited dyslipidaemia that is related to a high risk of coronary artery disease (CAD). We evaluated the prevalence of CAD in a large FCH population and the association of risk factors with CAD according to gender. In this single-center, observational study, lipid and lipoprotein variables were measured in untreated patients with FCH (565 males and 302 females). CAD was defined as a documented history of myocardial infarction or coronary revascularization, or an abnormal coronary angiogram (stenosis of >50% in an epicardial coronary artery), or angina plus abnormal imaging stress test. Males had higher triglyceride level (P<0.001) but lower total cholesterol (P<0.001) and HDL-cholesterol level (P<0.001) compared to women. The prevalence of CAD was 22.2% in men and 4.6% in women (P<0.001). In logistic regression analysis, male gender was associated with a higher risk of CAD independent of lipid parameters and other risk factors (adjusted ORs for CAD 9.4, P<0.001). In gender-specific analysis, age (OR=1.06 per 1-year increase, P<0.001), diabetes (OR=2.42, P<0.01) and Lp(a) (OR=1.09 per 1-mg/dL increase, P<0.01) were independent predictors of CAD in men. In women, age (OR=1.24, P<0.01), total cholesterol (OR=1.022 per 1-mg/dL increase, P<0.05) and fasting glucose (OR=1.031 per 1-mg/dL increase, P<0.05) were independently associated with CAD. In FCH patients, the prevalence of CAD is higher in males than in females, independent of lipidaemic profile and other risk factors. Among lipid variables, Lp(a) and cholesterol level are predictors of CAD in males and females respectively.
    Atherosclerosis 12/2007; 199(2):402-7. · 3.71 Impact Factor
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    ABSTRACT: Heterozygous familial hypercholesterolemia (hFH) and familial combined hyperlipidemia (FCH) have been associated with increased risk for coronary artery disease (CAD), but the impact of traditional risk factors to the incidence of CAD in these patients remains unknown. The present study evaluates the contribution of such risk factors to the development of CAD in these two dyslipidemic populations. This cross-sectional study enrolled a total 1306 subjects; 600 individuals with hFH (mean age 41+/-13 years, 261 males and 339 females), and 706 individuals with FCH (mean age 49+/-11 years, 463 males and 243 females). Blood samples were collected after 12 hours fasting period, and serum lipids were determined. Multivariate logistic regression models were used to estimate the odds ratios of CAD based on the type of hyperlipidemia, after adjustment for demographic characteristics and risk factors. Subjects with FCH were older (P<0.001), and they had a significantly increased prevalence of hypertension, diabetes and metabolic syndrome (40 vs. 10%, 13 vs. 2% and 41 vs. 6% respectively, all P<0.001) compared to the hFH group. Total cholesterol, LDL-cholesterol, and apolipoprotein B levels were higher (all P<0.001) in hFH subjects. Although in multivariate analysis lipid abnormalities found in hFH were associated with increased risk of CAD (P<0.001) compared with lipid abnormalities of FCH, the overall prevalence of CAD was similar between the two groups (16.7 vs. 15.3%, P=NS). Despite the high atherogenic potential of altered lipid metabolism found in hFH, the prevalence of CAD is similarly increased in patients with hFH or FCH. This may be related to the clustering of non-lipid cardiovascular risk factors, such as diabetes mellitus, observed in patients with FCH.
    International journal of cardiology 10/2007; 121(2):178-83. · 6.18 Impact Factor
  • Atherosclerosis Supplements 06/2007; 8(1):183-183. · 9.67 Impact Factor
  • Atherosclerosis Supplements 06/2007; 8(1):132-132. · 9.67 Impact Factor
  • Atherosclerosis Supplements 06/2007; 8(1):33-33. · 9.67 Impact Factor
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    ABSTRACT: Familial combined hyperlipidemia (FCH) is closely related with metabolic syndrome (MetSyn), and coronary artery disease (CAD) is positively associated to MetSyn and FCH. In this study, we evaluated the prevalence of MetSyn and its components between patients with FCH and a control group. We also investigated the role of MetSyn and diabetes mellitus (DM) on the incidence of CAD within the FCH group. Our study population consisted of 463 male and 243 female patients with FCH who were not receiving any hypolipidemic treatment, and 1128 men and 1154 women who came from the same geographical region. The prevalence of MetSyn was 42% and 19.8% among FCH subjects and controls, respectively, whereas MetSyn increased with age in both groups. The prevalence of CAD was 15.3% in the FCH group. Moreover, after dividing FCH patients into 3 subgroups, with and without MetSyn and with DM, CAD prevailed at a percentage of 15.2%, 11.1%, and 26.5%, respectively. However, statistically significant differences in the prevalence of CAD were observed only between FCH subjects with DM compared with the other 2 subgroups, even when an adjustment for age, sex, and smoking was conducted. People with FCH and MetSyn differed in several anthropometric, biochemical, and clinical characteristics, compared with the non-MetSyn subgroup of FCH. MetSyn is more prevalent in the FCH than in the control group. Among subjects with FCH, only DM was significantly associated with an increase in the prevalence of CAD in this subgroup compared with FCH individuals with or without MetSyn.
    Metabolism 02/2007; 56(1):135-41. · 3.61 Impact Factor
  • European Urology Supplements 04/2006; 5(2):25-25. · 3.37 Impact Factor
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    ABSTRACT: Genetic polymorphism G894T on endothelial nitric oxide synthase (eNOS) gene has been associated with endothelial dysfunction in young smokers, but its role in the pathogenesis of MI is obscure. We examined the effect of G894T polymorphism on endothelial function, on markers of endothelial cells injury and activation such as von Willebrand factor (vWF) and on serum levels of proinflammatory cytokines such as interleukins 6 (IL-6) and 1b (IL-1b), in young myocardial infarction (MI) survivors. The study population consisted of 56 patients with a history of premature MI. The forearm blood flow (FBF) was measured by using strain-gauge plethysmography during reactive hyperemia and after sublingual administration of nitroglycerin. G894T polymorphism was determined by polymerase chain reaction (PCR), while plasma vWF and serum IL1b and IL-6 levels were determined with ELISA. There was no significant difference in resting FBF and in the responses to nitroglycerin between the genotypes. However, the presence of T allele (GT+TT, n=35) was associated with decreased FBF during reactive hyperemia (10.23+/-0.70 ml/100ml tissue/min) and decreased forearm vasodilatory response to reactive hyperemia (54.28+/-4.81%) compared to GG (13.82+/-0.92 ml/100 ml tissue/min and 83.92+/-9.89% respectively, p<0.01 for both). Carriers of the T allele had also higher levels of vWF (79.66+/-5.56%) compared to GG (60.94+/-5.27% p<0.05). However, no significant difference was observed in IL-1b and IL-6 serum levels between the genotypes (p=ns for both). The presence of 894T allele on eNOS gene is associated with impaired endothelial function and higher levels of von Willebrand factor in relatively young patients with myocardial infarction. This finding implies that genetic polymorphism G894T on eNOS may affect endothelial function in patients with a history of premature myocardial infarction.
    International Journal of Cardiology 03/2006; 107(1):95-100. · 6.18 Impact Factor
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    ABSTRACT: Heart failure has been associated with impaired endothelial function, increased inflammatory process and elevated oxidative stress status. Both statins and vitamin E separately improve endothelial function in patients with hypercholesterolemia and/or advanced atherosclerosis. To evaluate the effect of atorvastatin alone or in combination with vitamin E on endothelial function and serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and vascular cells adhesion molecule (sVCAM-1) in patients with ischemic heart failure. Thirty-eight male patients with ischemic cardiomyopathy were randomly divided into three groups and received either atorvastatin 10 mg/day (n = 14), a combination of atorvastatin 10 mg/day plus vitamin E 400 IU/day (n = 12), or no statin or antioxidant treatment (n=12, controls) for 4 weeks. Forearm blood flow (FBF) was measured using venous occlusion strain-gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to nitrate (NTG%) was defined as the percent change of FBF from rest to the maximum flow during reactive hyperemia or after nitrate administration, respectively. RH% was significantly improved in both the atorvastatin-treated (p < 0.01) and atorvastatin plus vitamin E groups (p < 0.05), but the increase was significantly higher in the atorvastatin-treated group (p < 0.05). Serum levels of IL-6, TNF-alpha and sVCAM-1 were decreased in the atorvastatin-treated group (p < 0.05 for all), but remained unaffected in the other two groups (p = NS for all). Low dose atorvastatin treatment improves endothelial function and reduces the expression of proinflammatory cytokines and adhesion molecules in patients with ischemic heart failure, an effect partly depressed by vitamin E.
    European Journal of Heart Failure 01/2006; 7(7):1126-32. · 6.58 Impact Factor
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    ABSTRACT: Aortic stiffness is a marker of cardiovascular disease and an independent predictor of cardiovascular risk. Although an association between inflammatory markers and increased arterial stiffness has been suggested, the causative relationship between inflammation and arterial stiffness has not been investigated. One hundred healthy individuals were studied according to a randomized, double-blind, sham procedure-controlled design. Each substudy consisted of 2 treatment arms, 1 with Salmonella typhi vaccination and 1 with sham vaccination. Vaccination produced a significant (P<0.01) increase in pulse wave velocity (at 8 hours by 0.43 m/s), denoting an increase in aortic stiffness. Wave reflections were reduced significantly (P<0.01) by vaccination (decrease in augmentation index of 5.0% at 8 hours and 2.5% at 32 hours) as a result of peripheral vasodilatation. These effects were associated with significant increases in inflammatory markers such as high-sensitivity C-reactive protein (P<0.001), high-sensitivity interleukin-6 (P<0.001), and matrix metalloproteinase-9 (P<0.01). With aspirin pretreatment (1200 mg PO), neither pulse wave velocity nor augmentation index changed significantly after vaccination (increase of 0.11 m/s and 0.4%, respectively; P=NS for both). This is the first study to show through a cause-and-effect relationship that acute systemic inflammation leads to deterioration of large-artery stiffness and to a decrease in wave reflections. These findings have important implications, given the importance of aortic stiffness for cardiovascular function and risk and the potential of therapeutic interventions with antiinflammatory properties.
    Circulation 10/2005; 112(14):2193-200. · 14.95 Impact Factor

Publication Stats

955 Citations
529.96 Total Impact Points


  • 2000–2011
    • National and Kapodistrian University of Athens
      • Division of Cardiology III
      Athens, Attiki, Greece
    • Alexandra Regional General Hospital
      Athínai, Attica, Greece
  • 2004–2010
    • Athens State University
      Athens, Alabama, United States
    • Harokopion University of Athens
      • Department of Nutrition and Dietetics
      Athens, Attiki, Greece
  • 1993–2010
    • Hippokration General Hospital, Athens
      Athínai, Attica, Greece