3 ηνπ δείθηε HOMA (4.7 ± 3.8 vs ± 1.7, P < 0.01), θαη ησλ ιηπηδίσλ (εθηόο ησλ ηεο HDL ρνιεζηεξόιεο) θαη αύμεζε ζηελ 25OHD (15.4 ± 6.0 vs ± 5.1 ng/ml, P < 0.05), ζε ζρέζε κε ηελ θαηάζηαζε baseline. Τα επίπεδα PTH παξέκεηλαλ ακεηάβιεηα. Η αύμεζε ζηα επίπεδα ηεο 25OHD ζρεηίζηεθαλ κε ηελ κείσζε ζηα επίπεδα ηεο ηλζνπιίλεο θαη ηνλ δείθηε HOMA (r =-0.43, P < 0.05). σμπεράζμαηα: Τα επίπεδα 25OHD ζην αίκα ήηαλ ρακειά ζηηο παρύζαξθεο γπλαίθεο θαη ζπζρεηίζηεθαλ αληηζηξόθσο κε ηελ ζνβαξόηεηα ηεο παρπζαξθίαο. Η απώιεηα βάξνπο θαηά 10% κεηά από δίαηηα ρακειήο ζεξκηδηθήο πξόζιεςεο αύμεζε ηα επίπεδα ηεο 25OHD θαη απεηή ε αύμεζε ήηαλ θαηά θύξην ιόγν ζπλδεδεκέλε κε ηελ αλζεθηηθόηεηα ζηελ ηλζνπιίλε. Τν άξζξν δεκνζηεύηεθε ζην πεξηνδηθό Journal of Clinical Endocrinoly and Metabolism 95: , 2010 Introduction Vitamin D and PTH participate actively in bone metabolism and calcium homeostasis. In recent years it has become clear that vitamin D has pleiotropic effects with possible roles in the pathogenesis of cancer, immune system disorders, type 1 and 2 diabetes mellitus, cardiovascular disease, etc.; vitamin D deficiency has been associated with increased risks of these diseases (1). In fact, vitamin D receptors are expressed in a variety of tissues besides those involved in calcium homeostasis and bone development (2). Obesity, a state of body fat expansion and insulin resistance, has been found to be associated with low levels of serum 25-hydroxy-vitamin D(25OHD), the best clinical indicator of vitamin D status, and high levels of serum PTH (3 5). Recent studies in children and adults using anthropometric measurements and body composition analysis techniques confirmed associations between adipose tissue at various sites and these two metabolic parameters (6 9). The inverse correlation between obesity and 25OHD has been attributed mainly to sequestration of this fat soluble vitamin in adipose tissue and less probably to the limited sun exposure in obese subjects due to limited mobility; there is also some evidence that vitamin D inhibits the development of adipocytes (10). In vitro and in vivo studies suggest that PTH may promote fat accumulation and obesity through increases of calcium concentration within adipocytes; this increased intracellular concentration of calcium is also known to inhibit lipolysis (11). It has been reported that patients with primary and secondary hyperparathyroidism have excess body weight (BW) and fat mass (FM) (12, 13). Besides the effects of obesity on bone metabolic markers, insulin sensitivity has been found to correlate positively with levels of vitamin D and negatively with levels of PTH. Vitamin D may improve lean body mass, enhance insulin synthesis and release, increase insulin receptor expression, and suppress inflammation. These actions of vitamin D may be mediated by its active metabolite 1,25-dihydroxyvitamin D or via suppression of PTH (14, 15). Weight loss in obese subjects could influence vitamin D and PTH status. Most studies have tried to address this issue by investigating patients before and after bariatric surgery. Such an intervention, however, induces a malabsorptive state, resulting in profound decreases of vitamin D levels followed by compensated increases of PTH (16, 17). Studies with laparoscopic gastric banding surgery, which does not induce malabsorption but results in substantial weight loss showed either a stabilization or a decrease of vitamin D levels in some patients (18, 19). Reinehr et al. (20) examined obese children after a lifestyle weight loss program and found significant increase in 25OHD levels and decrease in PTH levels. To the best of our knowledge, only one study in obese adults, which was designed primarily to report on changes of osteoprotegerin, has examined changes of PTH and 25OHD at one-time point after diet-induced weight loss (21). The aims of the present pilot interventional study were to determine the short (4 wk) and longer-term (20 wk) effects of weight loss by a low-calorie diet on serum concentrations of 25OHD and PTH in
4 obese nondiabetic women and to examine the relationship between obesity and insulin resistance indices and lipid parameters. Patients and Methods Patients Forty-four obese women aged 40.6 ± 11.4 yr (range yr) with body mass index (BMI) of 36.7 ± 4.9 kg/m 2 and 25 age-matched healthy women aged 41.3 ± 13.3 yr (range yr) with normal BMI (controls), all in good general health, were selected to participate in the present interventional study. Exclusion criteria were primary hyperparathyroidism or other skeletal disease; malabsorptive, hepatic, renal, and other chronic diseases; familial or secondary dyslipidemia other than that due to the state of obesity; endocrine disorders including type 2 diabetes mellitus (defined as fasting blood glucose _7.0 mmol/liter or 126 mg/dl); excess alcohol (ingestion of more than 50 g/d of ethanol); smoking behavior (more than five cigarettes per day); or treatment with hypolipidemic, antiobesity, and hormonal drugs or drugs related to calcium and vitamin D metabolism. Thirty-three obese women (75%) and 19 controls (77%) were of reproductive age. None of the subjects had been on a slimming diet for at least 4 months before the initiation of the study. The ethical committee of the Medical School of Thessaloniki approved the study protocol. All women provided their written informed consent. All obese subjects were carefully monitored at baseline and 4 and 20 wk after the initiation of the weight loss program on an outpatient basis in the Department of Endocrinology, Diabetes, and Metabolism, Panagia General Hospital, Thessaloniki, Greece. Among the 44 obese women, 37 completed the 4-wk and 26 the 20-wk intervention study. Anthropometry All measurements were performed by the same investigator (T.T.) before and 4 and 20 wk after introduction of a weight reduction program. BW was determined to the nearest 0.1 kg with a calibrated beam balance and standing height to the nearest 0.5 cm. BMI was calculated as weight (kilograms) divided by height squared (square meters). Waist circumference (WC) was measured using a cloth tape midway between the lower rib and the iliac crest and hip circumference as the maximum circumference over the buttocks. Body composition was determined by impedance analysis with the use of a single-frequency bioelectrical impedance analysis (BIA), which emitted 50 KHz and 800κA (model BIA-101A; Akern STA, Florence, Italy) (22). Percentage of FM (FM%) was determined by using Bodygram software (version 1.21; Akern Srl, Florence, Italy). This BIA method allows discrimination between fat and fluid overload and the monitoring of changes of FM% in obese subjects undergoing weight reduction, even of minimal degree (22). Dietary intervention All obese women initially followed a 2-wk run-in period during which they were encouraged to follow their nutritional habits and maintain their habitual levels of physical activity. At day 0 of the weight reduction program, initial caloric levels of each subject were estimated using the Harris-Benedict formula for women [ (weight in kilograms) (height in centimeters) (age in years)] (23). Thereafter a lowcalorie diet was individually prescribed on the basis of an average calorie restriction of 1000 kcal/d. Initially the administered diets consisted of a mean of 1385 ± 312 kcal/d (5775 ± 1301 kj/d) and ranged from 1015 to 1880 kcal/d (4232 to 7840 kj/d), depending on the initial BW. The daily distribution of nutrients was 48.5 ± 4.1% (163.8 ± 21.7 g) carbohydrates, 28.5 ± 3.2% (43.9 ± 12.0 g) fat, and 23.0 ± 1.4% (77.7 _ 15.8 g) protein, and daily calculated contents of calcium and vitamin D were 791± 32 mg and 221 ± 37 IU,
5 respectively. The diets were analyzed for nutrient composition using the computerized nutritional system Science Fit Diet 200A (Science Fit, Athens, Greece). After 8 wk of the intervention, all diets were adapted with an additional energy restriction of 20% of the ingested calories and with approximately the same macronutrient composition until the end of the weight loss period (18 20 wk). Thereafter the subjects were stabilized for 2 wk at a steady weight before reassessment was performed at wk. During the period of the protocol, participants were asked not to change their habits of physical activity. All obese women were asked to attend the center weekly during the 20-wk follow-up. Laboratory Measurements Serum and plasma samples (obtained by centrifugation at 4 C) were taken after a 12-h overnight fast before and after the dietary treatment and stored frozen at -70 C until they were assayed. Season of blood draw was determined from the date of the baseline visit. Blood samples taken from December through February were coded as winter, from March through May as spring, from June through August as summer, and from September through November as fall. The electrochemiluminescence immunoassay ECLIA (Roche DiagnosticsGmbA, Mannheim, Germany) was used for25ohd and PTH assays. Measuring range for vitamin D was ng/ml, within-run precision %, and total precision %. Expected values for PTH were pg/ml, functional sensitivity 6.0 pg/ml, within-run precision %, and total precision %. Serum total cholesterol (TC) and triglyceride (TG) levels were measured using enzymatic methods (Bioanalyzer 30R; Wako Chemicals GmbH, Combe, Japan). High-density lipoprotein cholesterol (HDL-C) was measured in the serum supernatant after the precipitation of very low-density lipoproteins and low density lipoprotein cholesterol (LDL-C) with Mg2_/dextran. LDL-C concentrations were estimated using Friedewald s equation (24). Serum apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein (a) [Lp(a)] concentrations were determined by immunonephelometric assays (Boehring Diagnostics GmbH, Marburg, Germany). Glucose serum concentrations were measured using an enzymatic assay and serum insulin levels were determined using an immunoradiometric assay kit (Biosource INS-IRMA kit; Biosource Europe SA, Nivelles, Belgium). The normal range for insulin levels was 2 25 κiu/ml. Insulin sensitivity was also estimated by the homeostasis model assessment (HOMA) index (25). Statistical analyses Data are presented as mean±sd. Differences between groups were assessed with one-way ANOVA and post hoc tests were carried out with the Holm-Sidak method. Changes during the study were assessed with the paired-samples t test. Correlations between variables were assessed using Pearson s coefficient of correlation. In all cases, a two-tailed P < 0.05 was considered significant. All data were analyzed using the statistical package SPSS (version 15.0; SPSS, Chicago, IL). Results Baseline analyses At baseline, obese women demonstrated significantly lower levels of 25OHD compared with controls (patients 17.0 ± 6.0, controls 23.8 ± 8.7 ng/ml, P < 0.001), whereas PTH concentrations were no different between the two groups. Notably, 69.7% of the obese group had 25OHD levels less than 20 ng/ml (deficiency), 93.4% had 25OHD levels less than 30 ng/ml (insufficiency), whereas the corresponding figures for the control group were 56 and 72%, respectively. A seasonal variation of 25OHD levels was seen in obese women: 25OHD levels in the winter group (13.3 ± 3.4 ng/ml) were lower than in the summer (22.4 ± 4.7 ng/ml) and fall groups (24.6 ± 5.9
6 ng/ml, P < for both), and those in the spring group (14.7± 3.7 ng/ml) had lower levels than those in the summer and fall groups (P < and P < 0.001, respectively). No seasonal differences were observed in the control group probably due to the small number of subjects in each of the four categories. Neither 25OHD nor PTH levels varied significantly between pre- and postmenopausal subjects. Most anthropometric and lipid parameters with the exception of levels of HDL-C, ApoA1, Lp(a), and blood glucose were higher in obese women than in controls. All baseline measurements for both groups are presented in Table 1. Pearson correlation analyses for all women (n = 68) showed a negative correlation between 25OHD and the following obesity indices: BW (r = , P < 0.008), BMI (r = , P < 0.002), WC (r = , P< 0.030), and FM% (r = , P < 0.001). A negative correlation between levels of25ohd and PTHwas found only in obese women (r = , P < 0.024). No significant correlations were found between 25OHD and lipid parameters. PTH levels correlated negatively with LDL-C levels in all women(r = , P< 0.046).
7 Analyses during weight loss After 4 wk, the hypocaloric dietary intervention produced a small but significant decrease in BW, BMI, WC, and FM% (P<0.001). Weight loss was associated with a significant reduction in most of the lipoprotein and metabolic parameters measured; PTH and 25OHD did not change significantly during this time period (Table 2). After 20 wk, a decrease of BW, BMI, and FM% of the order of 10% and a decrease of WC at 9% were achieved, which were associated with significant reductions in insulin levels (19.0±12.4 vs. 13.1±7.1_U/ml,P<0.05),HOMA index (4.74±3.8 vs. 3.10±1.7, P<0.05) and serum lipids [except HDL-C, apoa1, and Lp(a)] and significant increases in 25OHD levels by 34% (15.4 ± 6.0 vs ± 5.1 ng/ml, P < 0.05). PTH levels appeared to be unaffected (Table 2). A significant negative correlation was found between changes in 25OHD levels and changes in insulin levels (r =-0.380, P < 0.045) and HOMA index (r=-0.433, P< 0.039) (Fig. 1). A trend for negative correlation was found between changes in 25OHD levels and changes in BW (r =-0.367, P<0.065) and BMI (r=-0.376, P<0.059) (Fig. 2) but no significant correlation between changes in 25OHD levels and changes in FM%.No significant correlations were found between 25OHD and lipid parameters. Discussion The present study examined the effects of a low-calorie diet on 25OHD and PTH levels in nondiabetic obese women at two different time points. At baseline, levels of vitamin D were lower in obese subjects than in controls, whereas levels of PTH were similar between the two groups. The introduction of a 4-wk low-calorie diet did not significantly influence these two metabolic parameters; however, after 20 wk a modest degree of weight loss of 10% was associated with a significant increase of 25OHD levels by 34%, whereas PTH levels remained unaffected. The changes in 25OHD levels at 20 wk were more closely associated with the changes (improvement) in insulin resistance indices than changes in obesity indices.
8 It is now well established that low vitamin D levels are commonly observed in obese children and adults (4 6). This finding was confirmed by the results of the present study, which showed that 25OHD levels were inversely correlated both with indices of total obesity such as BW, BMI, FM%, and indices of abdominal obesity such as WC. Studies performed using sophisticated equipment for assessing body composition also suggest that the low vitamin D levels found in obesity are associated both with total body and regional (sc and visceral) adipose tissue (5, 7, 9). Although the precise mechanism for the lower levels of vitamin D in obesity is not known, the most plausible
9 explanation is that the expanded adipose tissue traps and stores this fat-soluble vitamin (26). In our obese group, the vast majority of women (almost 93%) were identified as either vitamin D deficient (<20 ng/ml) or vitamin D insufficient (<30 ng/ml), whereas in controls the respective rates were 72%. These data in our small population groups are in line with the recent reports that vitamin D deficiency is an epidemic phenomenon showing particular high prevalence in southern European populations (27, 28). We also observed that the welldescribed seasonal variation effect on 25OHD was significant only in obese women; this negative result in controls cannot be explained and is probably attributed to the small sample of these subjects. PTH levels have been reported to be elevated in obese subjects, in keeping with a compensating mechanism to vitamin D insufficiency (5, 29, 30). It has been suggested that the increased PTH per se can promote lipogenesis and obesity via calcium stimulation, which enhances lipogenesis and inhibits lipolysis in adipocytes (11, 31). Although a significant negative correlation was found between 25OHD and PTH levels in the total population studied, PTHlevels in the obese group did not differ compared with controls. The absence of elevated PTH could be attributed to the small number of subjects but could also be due to a relative metabolic resistance to vitamin D despite low levels of 25OHD, which has been reported in some population groups (6, 32). It has been suggested that a low threshold of vitamin D has to be reached for PTH to rise leading to metabolic disturbances. This cutoff point has recently been proposed to be fixed at 15 ng/ml (33). In our study, baseline mean 25OHD concentrations were somehow higher than this threshold, perhaps explaining the nonelevated mean PTH levels. Current proposed molecular mechanisms to explain normal PTH in the face of low 25OHD
10 include nutrient receptor disturbances and intracellular magnesium deficiency (32). The introduction of a low-calorie diet in obese women resulted in changes of metabolic parameters that varied according to the time period after the diet and the amount of weight loss achieved. At 4 wk there was a small but significant reduction of all obesity indices, improvement of insulin resistance, and improvement of most lipid parameters with the exception of Lp(a). Changes in PTH and 25OHD were minimal and did not reach statistical significance. The content of the hypocaloric diet in vitamin D throughout the first phase of the study was estimated at about 200 IU/d, which is lower than recent recommendations for adequate intake for age and gender (34). Our findings showed that this level of dietary intake of vitamin D did not induce any significant effect on its serum levels, measured as 25OHD. After the 20-wk dietary treatment period, obese women achieved a moderate weight loss by 10% of the initial BW and improved significantly indices of insulin resistance and most blood lipids. These changes were accompanied by significant increases of25ohdlevels by 34%, whereas PTH levels remained unchanged. The effects of weight reduction on vitamin D and PTH were evaluated in two recent interventional studies. In the first study, Reinehr et al. (20) examined 133 obese children, aged 12 yr, who followed a 1-yr lifestyle interventional program. A small reduction of excess BW in 35 children by -0.9 U of BMI led to a significant increase of 25OHD levels and significant decrease of PTH levels. In the second study, Holecki et al. (21) assessed the effects of a low-calorie balanced diet weight loss program on changes of PTH and 25OHD for 3 months and found similar changes of their levels as those reported in the previous study in children. The increase of vitamin D in our study did not correlate significantly with the reduction of obesity parameters although a trend for negative correlations was found between changes of 25OHD and changes of BW and BMI. Interestingly, improvement of insulin resistance as indicated by reductions of insulin levels and HOMA index correlated with increases of 25OHD levels. This novel finding suggests that after modest weight reduction, insulin resistance is a more significant determinant of 25OHD levels than body fat. However, our findings may also indicate that increasing 25OHD levels after weight loss may improve insulin resistance. Lifestyle interventions resulting in greater weight and fat loss are necessary to clarify this important issue. The negative association between vitamin D levels and insulin resistance has been observed in many crosssectional and prospective studies (35, 36). Two very recent studies, however, suggested that in obesity both low 25OHD levels and insulin resistance could be explained in large part by the increased adiposity (37, 38). Ηn young women with polycystic ovary syndrome, which often represents a state of insulin resistance, low serum of 25OHD concentrations were also found and were associated with the presence of both obesity and insulin resistance (39, 40). Experimental studies have shown that vitamin D enhances insulin synthesis and release, increases insulin receptor expression, and suppresses inflammation (15). At present, low vitamin D levels are a risk factor for metabolic syndrome and type 2 diabetes mellitus and supplementation studies for preventing or improving these conditions are currently ongoing (41). The importance of the rise in 25OHD levels during weight loss is also highlighted by the recent reports, which have suggested a threshold for the effect of vitamin D deficiency on insulin resistance (33). Our obese subjects displayed 25OHD concentrations fairly similar to the reported threshold, and consequently, we suggest that increasing 25OHD levels through weight reduction could confer beneficial effects on insulin sensitivity. Furthermore, recent evidence suggests that chronic vitamin D deficiency may be a risk factor for atherosclerosis mediated through various mechanisms in the pathophysiology of cardiovascular disease (42). Our study illustrates that a modest amount of weight loss of about 10% of the initial body weight constitutes a relevant intervention to reduce an emerging risk factor for type 2 diabetes mellitus and cardiovascular diseases in addition to other conventional risk factors such as dyslipidemia and hypertension. Limitations of the present study, which has to be considered as a pilot study, include the relatively small number of subjects that finally completed the weight loss program and the relatively small observational period
11 of 20 wk. In conclusion, levels of 25OHD are low in obese patients and are clearly associated with the degree of obesity. Moderate weight reduction of about 10% after a low-calorie diet can increase 25OHD levels, and this increase is mainly associated with an improvement in insulin resistance. Further studies including more subjects, longer periods of weight loss and maintenance, and greater amounts of weight loss are necessary to clarify the interrelationships between adipose tissue, insulin resistance, and vitamin D levels. Acknowledgments Address all correspondence and requests for reprints to: Gerasimos E. Krassas, M.D., Ph.D., F.R.C.P. (Lond), Chairman, Department of Endocrinology, Diabetes, and Metabolism, Panagia General Hospital, Nikolaou Plastira, 22, Nea Krini, Thessaloniki, Greece. References 1. Holick MF 2004 Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80(Suppl 6):1678S 1688S 2. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M 2008 Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 29: Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S 1985 Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest 76: Parikh SJ, EdelmanM,Uwaifo GI, Freedman RJ, Semega-JannehM, Reynolds J, Yanovski JA 2004 The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab 89: Snijder MB, van Dam RM, Visser M, Deeg DJ, Dekker JM, Bouter LM, Seidell JC, Lips P 2005 Adiposity in relation to vitamindstatus and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab 90: Alemzadeh R, Kichler J, Babar G, Calhoun M 2008 HypovitaminosisDin obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism 57: Young KA, Engelman CD, Langefeld CD, Hairston KG, Haffner SM, Bryer-Ash M, Norris JM 2009 Association of plasma vitamin D levels with adiposity in Hispanic and African Americans. J Clin Endocrinol Metab 94: Kremer R, Campbell PP, Reinhardt T, Gilsanz V 2009 Vitamin D status and its relationship to body fat, final height, and peak bone mass in young women. J Clin Endocrinol Metab 94: Moschonis G, Tanagra S, Koutsikas K, Nikolaidou A, Androutsos O, Manios Y 2009 Association between serum 25-hydroxyvitamin Dlevels and body composition in postmenopausal women: the postmenopausal Health Study. Menopause 16: Reid IR 2008 Relationships between fat and bone. Osteoporos Int 19: Xue B, Greenberg AG, Kraemer FB, ZemelMB2001 Mechanism of intracellular calcium ([Ca2_]i) inhibition of lipolysis in human adipocytes. FASEB J 15: Bolland MJ, Grey AB, Gamble GD, Reid IR 2005 Association between primary hyperparathyroidism and increased body weight: a meta-analysis. J Clin Endocrinol Metab 90: Rejnmark L, Vestergaard P, Brot C, Mosekilde L 2008 Parathyroid response to vitamin D insufficiency: relations to bone, body composition and to lifestyle characteristics. Clin Endocrinol (Oxf) 69: Tai K, Need AG, Horowitz M, Chapman IM 2008 Vitamin D, glucose, insulin, and insulin sensitivity. Nutrition 24: Teegarden D, Donkin SS 2009 Vitamin D: emerging new roles in insulin sensitivity. Nutr Res Rev 22: Moreiro J, Ruiz O, Perez G, Salinas R, Urgeles JR, RiescoM,García-Sanz M 2007 Parathyroid hormone and bone marker levels in patients with morbid obesity before and after biliopancreatic diversion. Obes Surg 17: Aasheim ET, Bjo rkman S, Søvik TT, Engstro m M, Hanvold SE, Mala T, Olbers T, Bøhmer T 2009 Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. Am J Clin Nutr 90: Pugnale N, Giusti V, Suter M, Zysset E, He raïef E, Gaillard RC, Burckhardt P 2003 Bone metabolism and risk of secondary hyperparathyroidism 12 months after gastric banding in obese pre-menopausal women. Int J Obes Relat Metab Disord 27: Nadler EP, Youn HA, Ren CJ, Fielding GA 2008 An update on 73 U.S. obese pediatric patients treated with laparoscopic adjustable gastric banding: comorbidity resolution and compliance data. J Pediatr Surg 43: Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W 2007 Vitamin D status and parathyroid hormone in obese children before and after weight loss. Eur J Endocrinol 157: Holecki M, Zahorska-Markiewicz B, Janowska J, Nieszporek T, Wojaczyn ska-stanek K, Zak- Gołab A, Wiecek A 2007 The influence of weight loss on serum osteoprotegerin concentration in obese perimenopausal women. Obesity (Silver Spring) 15:
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Network of Cohorts in Europe and the United States HEALTHY AGEING: DEFINITION, RISK FACTORS AND IMPLICATIONS FOR PUBLIC HEALTH Friday, 23 rd January 2015 MEGARON - The Athens Concert Hall Athens, GREECE
NEWSLETTER Έκδοση Απριλίου Μαΐου 2010 ΤΕΥΧΟΣ 42 Αγαπητές-οι φίλες-οι, Στις σελίδες του 42 ου ηλεκτρονικού µας περιοδικού µπορείτε να περιηγηθείτε και να διαβάσετε τα ακόλουθα: ΠΕΕΡΙΙΕΕΧΟΜΕΕΝΑ ΑΑππόό ττοονν
ehealth Consumer Trends Survey in Greece: Results of the 1 st phase FORTH-ICS TR-365, December 2005 (Updated July 2006) C. E. Chronaki MSc 1, A. Kouroubali PhD 1, L. Esterle MD, PhD 1,3, E. Orphanoudaki