S. Zacharieva

Medical University of Sofia, Ulpia Serdica, Sofia-Capital, Bulgaria

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Publications (131)190.6 Total impact

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    Dataset: ERC150038

    Full-text · Dataset · Dec 2015
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    ABSTRACT: Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and current/previous abnormal growth velocity for age or final height >2SD above country normal means. The median onset of rapid growth was 13.0 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs. 21.5 years, respectively). Adenomas were ≥10 mm (i.e. macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF-1 control was achieved in 39% during long-term follow-up. Final height was greater in those with younger age of onset, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 -X-linked acro-gigantism (X-LAG)- occurred in two familial isolated pituitary adenoma (FIPA) kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically-negative patient groups. AIP-mutated and X-LAG patients had significantly younger age at onset and diagnosis, but disease control was worse in genetically-negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
    Full-text · Article · Jul 2015 · Endocrine Related Cancer
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    Full-text · Dataset · May 2015

  • No preview · Conference Paper · May 2015
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    ABSTRACT: X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.
    Full-text · Article · Feb 2015 · Endocrine Related Cancer
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    ABSTRACT: We described biochemical outcome in regards to different treatment modalities in patients with acromegaly in Bulgaria. It was a retrospective analysis using data from the Bulgarian Acromegaly Database. Patients with eligible data on at least one treatment modality were included in the study. Disease control was assessed by both GH and IGF-1 values or by GH/IGF-1 alone in cases with one marker. Last follow-up was median 7.0 (range 0.5-51) years after diagnosis. We identified 534 patients with interpretable data, 65.4% of whom were females. Overall surgical cure rate was 28.8%. Adjuvant bromocriptine and cabergoline treatment was analyzed in 133 and 70 patients with disease control achieved in 18.8% and 31.4% respectively. Patients without prior radiotherapy had 16.3% and 18.2% control rates respectively. Predictors of response to dopamine agonist (DA) therapy were disease activity, radiotherapy and medication dose. Adjuvant somatostatin analog (SSA) treatment led to biochemical control in 38.6% of 70 patients. Combination of SSA and cabergoline led to remission in 25% of 20 patients. Growth hormone receptor antagonist (GHRA) alone or in combination resulted in remission in 61.5% of 13 patients. Approximately one third of the patients were cured median 10 years after irradiation. Overall disease control was observed in 51.4% of our patients increasing to 70.3% in the last 5 years of the study period. DAs are efficient in less than 20% of non-irradiated patients. They are a good cost-effective alternative for carefully selected patients. © Georg Thieme Verlag KG Stuttgart · New York.
    Full-text · Article · Jan 2015 · Experimental and Clinical Endocrinology & Diabetes
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    ABSTRACT: Various factors influence quality of life (QoL) in acromegaly. Whether disease control and treatment approach are related to QoL is still a matter of debate. The aim of the present study was to evaluate QoL in patients with acromegaly using the disease-specific Acromegaly Quality of Life Questionnaire in respect to disease activity, treatment modalities, and other factors. We studied 212 patients with acromegaly in a cross-sectional manner over a 6-year period in a single tertiary center. As a second step, seventy of the patients who were with active disease at baseline were followed up prospectively and 45 of them were in remission at re-evaluation. In regard to the cross-sectional group, active acromegaly independently predicted worse appearance scores. Prior radiotherapy and older age were independent negative predictors of all scales. Female gender negatively predicted all scales except the appearance domain. Longer duration of remission predicted worse personal relations scores in biochemically controlled patients. The use of somatostatin analog (SSA) was associated with worse personal relations scores, while higher IGF-1 index predicted worse appearance scores in patients with active acromegaly. In the prospective group, achievement of remission independently predicted improvement of the total scale. Lower corresponding baseline scores predicted improvement of the total, physical, and appearance scales, while the absence of hypopituitarism independently predicted improvement of the appearance scale. The use of SSA was associated with improvement of the total and appearance scores. In conclusion, QoL is a multifactorial issue that needs an individualized approach for detection and management.
    Full-text · Article · Jan 2015 · Endocrine
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    ABSTRACT: Objective: Growth hormone deficiency in adults (GHDA) is considered to be associated with increased cardiovascular risk, most commonly reflected by the prevalence of the metabolic syndrome (MS). However, there are still a limited number of studies comparing directly the MS prevalence in GHD patients to that in general population. The aim of this study was to investigate the individual risk factors of the MS in a cohort of GHD patients and to compare its prevalence with an age- and sex-matched control group. Design: A cross-sectional case-control study. Methods: In total, 54 adult patients with GHD (childhood onset GHD (COGHD): n=19, adult onset GHD (AOGHD): n=35) and 2 153 control subjects were studied. GHD was diagnosed according to the Endocrine Society Clinical Practice Guideline recommendations from 2011 and MS was scored by the NCEP-ATP III definition. Results: The main metabolic abnormalities in GHD group were increased waist circumference (50.0%), low HDL-cholesterol (42.6%) and hypertriglyceridemia (40.7%) and their prevalence was significantly higher (p=0.013, p=0.019 and p=0.010, respectively) than in control group, where increased blood pressure prevailed (64.2%, p<0.0001). However, the difference in the MS prevalence between the 2 groups (29.6% vs. 24.9% in controls) failed to reach statistical significance (p=0.429). Patients with MS from both groups did not differ significantly in their metabolic profile (except for increased blood pressure), mean age and gender distribution. Conclusions: Although GHDA was associated with the development of visceral obesity and dyslipidemia, these adverse cardiovascular risk factors did not determine a higher prevalence of the MS in Bulgarian GHD patients compared to control subjects. Furthermore, the individual risk factors of the MS did not significantly differ between patients with MS from both groups. © Georg Thieme Verlag KG Stuttgart · New York.
    No preview · Article · Nov 2014 · Experimental and Clinical Endocrinology & Diabetes
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    Joanna Matrozova · Silvia Vandeva · Sabina Zacharieva
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    ABSTRACT: We describe a patient with a rare combination of acromegaly and primary aldosteronism. A 37 year-old female patient was diagnosed with acromegaly on the basis of typical clinical, hormonal and image characteristics. She presented also with one of the most common co-morbidities – arterial hypertension. The patient has been regularly followed-up and after three surgical interventions, irradiation and adjuvant treatment with a dopamine agonist, acromegaly was finally controlled in 2008 (20 years after diagnosis). Arterial hypertension however, remained a therapeutic problem even after prescription of four antihypertensive drugs. She had normal biochemical parameters, except for low potassium levels 3.2 (3.5-5.6) mmol/l. This raised the suspicion of primary hyperaldosteronism, confirmed by a high aldosterone to plasma rennin activity ratio, high aldosterone level after a Captopril challenge test and visualization of a 35 mm left adrenal nodule on a CT scan. After an operation, the patient recovered from hypokalemia and antihypertensive therapy was reduced to a small dose of a Ca blocker. Co-morbid arterial hypertension is common in acromegaly, though it is rare for this to be caused by Conn’s adenoma. The association of Conn’s adenoma with acromegaly has been interpreted in two lines: as a component of multiple endocrine neoplasia type (MEN1) syndrome or as a direct mitogenic effect of hyperactivated GH-IGF1 axis.
    Preview · Article · Jun 2014 · F1000 Research
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    ABSTRACT: Background: Mortality in acromegaly strictly depends on optimal control of GH and IGF1 levels. Modern medical therapy with somatostatin analogs (SSAs) and GH receptor antagonists (GHRAs) is not available in many countries due to funding restrictions. This retrospective, comparative, cohort study investigated the impact of different treatment modalities on disease control (GH and IGF1) and mortality in acromegaly patients. Methods: Two cohorts of patients with acromegaly from Bulgaria (n=407) and Campania, Italy (n=220), were compared, and mortality rates were evaluated during a 10-year period (1999-2008). Results: The major difference in treatment approach between cohorts was the higher utilization of SSAs and GHRAs in Italy, leading to a decreased requirement for radiotherapy. Significantly more Italian than Bulgarian patients had achieved disease control (50.1 vs 39.1%, P=0.005) at the last follow-up. Compared with the general population, the Bulgarian cohort had a decreased life expectancy with a standardized mortality ratio (SMR) of 2.0 (95% CI 1.54-2.47) that was restored to normal in patients with disease control - SMR 1.25 (95% CI 0.68-1.81). Irradiated patients had a higher cerebrovascular mortality - SMR 7.15 (95% CI 2.92-11.37). Internal analysis revealed an independent role of age at diagnosis and last GH value on all-cause mortality and radiotherapy on cerebrovascular mortality. Normal survival rates were observed in the Italian cohort: SMR 0.66 (95% CI 0.27-1.36). Conclusions: Suboptimal biochemical control was associated with a higher mortality in the Bulgarian cohort. Modern treatment options that induce a strict biochemical control and reduce the necessity of radiotherapy might influence the life expectancy. Other factors, possibly management of comorbidities, could contribute to survival rates.
    Preview · Article · May 2014 · European Journal of Endocrinology

  • No preview · Article · Apr 2014
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    ABSTRACT: Aim To evaluate the clinical features, hormonal activity and natural evolution of adrenal incidentalomas (AI) in patients investigated in a single endocrinological centre and compare the prevalence of metabolic disorders and hypertension between subjects with AI and the general population. Patients and methods 515 patients with AI evaluated between 1995 and 2010 were retrospectively included in the study. Their anthropometric, clinical, metabolic and hormonal parameters were analyzed. Follow-up data was available for 142 patients. Results Mean age of all participants was 53.45 ± 13.4 years (range 13 — 84) with strong female predominance — 376 (73%) vs. 139 (27%) males. Median size of AI was 28 mm (range 10 — 190 mm). Hormonal investigations revealed that 82.9% of patients harboured non-functioning adenomas, subclinical hypercortisolism was detected in 5.94%, overt Cushing’s syndrome — in 2.7%, pheochromocytoma — in 1.9% and primary aldosteronism was diagnosed in 1% of patients. Adrenal carcinoma was identified in 1.7%. The prevalence of metabolic abnormalities and hypertension did not differ between patients with subclinical Cushing’s syndrome and non-functioning adrenal adenomas. When compared to the general population, however hypertension, type 2 diabetes and metabolic syndrome were significantly more common in patients with hormonally inactive tumours. During the course of follow-up progression to overt hormonal hypersecretion was not observed. Conclusion These results confirm other contemporary studies reporting lower rates of hormonally active and malignant lesions among AI as well as increased prevalence of hypertension and metabolic abnormalities in patients with non-functioning adrenal adenomas.
    Full-text · Article · Apr 2014 · Central European Journal of Medicine
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    V Vasilev · J Matrozova · A Elenkova · S Vandeva · G Kirilov · S Zacharieva
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    ABSTRACT: Endothelial dysfunction is a common feature of hypertension and is associated with reduced nitric oxide bioavailability. The endogenous inhibitor of nitric oxide syntase, asymmetric dimethylarginine (ADMA), and soluble adhesion molecules such as vascular cell adhesion molecule 1 (sVCAM-1) have been established as markers of endothelial dysfunction in a number of pathologic conditions including essential hypertension. There is little information, however, about these markers in endocrine hypertension.To investigate the levels of circulating ADMA and sVCAM-1 in patients with pheochromocytoma.Serum ADMA and sVCAM-1 concentrations were assayed by ELISA technique in 18 patients with pheochromocytoma, 18 patients with essential hypertension (EH) and 18 healthy subjects serving as a control group.ADMA and sVCAM-1 levels were significantly elevated in pheochromocytoma patients compared to normotensive healthy controls (0.479±0.072 vs. 0.433±0.054 µmol/l, p=0.037 and 690±181 vs. 577±108 ng/ml, p=0.03, respectively). Patients with EH also had higher ADMA concentrations than the control group, but the difference was not significant (0.476±0.075 vs. 0.433±0.054 µmol/l, p=0.06). No associations were found between the levels of ADMA, sVCAM-1 and some potential risk factors for endothelial dysfunction.Endothelial function is impaired in patients with pheochromocytoma as indicated by the elevated circulating levels of ADMA and sVCAM-1. The lack of association of these markers with cateholamines, glucose and lipid abnormalities together with their comparable levels in EH patients suggests that endothelial dysfunction is most likely related to hypertension itself.
    Full-text · Article · Sep 2013 · Experimental and Clinical Endocrinology & Diabetes

  • No preview · Article · Sep 2013
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    ABSTRACT: Data on the incidence, mortality and causes of death in patients with Cushing's syndrome (CS) are scarce, due to the rarity of CS. The aim of the study was to analyze mortality rates in CS in a large cohort of patients of all etiologies and to determine the cause of death. This was a retrospective study of patients with CS, treated over a period of 45 years in the main tertiary referral center in Bulgaria. 386 patients with CS of all etiologies were included. The main outcome measures were the standardized mortality ratio (SMR) and the cause of death. Mean (± SD) age at diagnosis was 38±13 years; 84% of patients were women; mean follow up was 85 months (range: 0-494 months). The SMR in the CS cohort was 4.05 (95% confidence interval (CI) 2.50-5.80) (p<0.0001). The following subgroups did not have a significantly increased SMR: patients with Cushing's disease SMR - 1.88 (95%CI 0.69-4.08), adrenal adenomas 1.67 (95%CI 0.20-6.02) and ACTH-independent bilateral adrenal hyperplasia 1.14 (95 %CI 0.21-6.34). Patients with adrenal carcinomas, ectopic CS and those with CS of undetermined etiology had significantly increased SMR: 48.00 (95%CI 30.75-71.42), 13.33 (95%CI 0.00-24.59) and 4.00 (95%CI 0.48-14.45), respectively (p<0.0001). The significant predictors for mortality were active disease at death, age, male sex, etiology of the disease, the overall duration of active disease. The major causes of death were vascular events (40%) -cardiovascular 29% and cerebrovascular 11%, followed by infections (12%). Patients with CS have increased mortality due to vascular events and infections.
    No preview · Article · Aug 2013 · European Journal of Endocrinology
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    ABSTRACT: Transforming growth factor-β1 (TGF-β1) signaling pathway is crucial for both human fibrogenesis and tumorigenesis. Objective: to investigate the usefulness of TGF-β1 and MMP-2 as potential circulating markers for fibrotic valvular heart disease (FVHD) and invasiveness as well as of Fetuin A as a marker of calcification in patients with prolactinomas. Design: Study population consisted of 147 subjects enrolled into 4 groups: 30 DA-treated prolactinoma patients with proven FVHD and 3 control groups with normal echocardiography: 43 DA treated pts; 26 naïve patients and 48 healthy subjects. Results: We observed significantly higher serum TGF-β1 levels in all three patients groups compared to healthy subjects (21.4 ± 8.86 vs. 19.1 ± 9.03 vs. 20.7 ± 11.5 vs. 15.8 ± 7.2 ng/ml; p=0.032). Moreover, TGF-β1 levels were significantly higher in patients with macro- and invasive prolactinomas in comparison to micro- and non invasive tumors respectively. In addition, a strong positive linear relationship between TGF-β1 levels and the score of invasiveness (ρ=0.924; p<0.001) and a moderate correlation between TGF-β1 and the tumor volume (r=0.546; p<0.002) in invasive prolactinomas were found. In contrast, PRL levels showed a better correlation with the tumor volume (r=0.721; p<0.001) then with the invasive score (ρ=0.436; p<0.020). No significant difference was observed in Fetuin A levels between patients with FVHD and healthy controls. Results concerning MMP-2 were unclear. Conclusions: TGF-β1, MMP-2 and Fetuin A are not reliable biomarkers for valvular fibrosis and calcification in DA-treated patients with prolactinomas, but TGF-β1 may represent a usefull serum marker for invasiveness. The simultaneous evaluation of TGF-β1 and PRL could improve the noninvasive assessment of prolactinoma behaviour.
    Full-text · Article · Jun 2013 · European Journal of Endocrinology
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    ABSTRACT: Background: This study aims to explore the changes in maternal serum adipocytokines during pregnancy and post partum in normal and complicated with gestational diabetes (GDM) pregnancies and to investigate the relationship between serum adipocytokines and some of major metabolic parameters. Materials and methods: 236 pregnant women (127 with GDM and 109 control group) and 50 postpartum women (30 with GDM during pregnancy and 20 controls). Using ELISA and EIA kits, serum levels of adipocytokines were tested during pregnancy and post partum. Maternal adipocytokines levels were correlated with some metabolic parameters. Results: Women with GDM had lower values of adiponectin and higher values of leptin during pregnancy (p<0.001; 0.0001) and post partum (p<0.002; 0.0001). Serum apelin was significantly lower in GDM group (p<0.009). However, we did not find significance for resistin (p<0.317) and apelin (p<0.218). Positive correlation for leptin and negative for adiponectin was found for pre-pregnancy and pregnancy body mass index, glycated hemoglobin and homeostasis model assessment of insulin resistance index. Using cut point of 8.2 μg/ml for adiponectin and 28.7 ng/ml for leptin could exclude GDM with a sensitivity of 83.6%/81.2% and specificity of 56.6%/64.2% (area under the curve 0.702 and 0.827). Conclusion: There are constant differences in adiponectin and leptin levels between GDM and control group during pregnancy and post partum. Apelin was decreased in our GDM group and no differences were found for resistin and visfatin. Further studies are required to verify the mechanism of this alteration and whether the adipocytokines can be predictors for GDM at an early stage of pregnancy.
    No preview · Article · May 2013 · Journal of endocrinological investigation
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    ABSTRACT: Data on the prevalence of macroprolactinemia in patients with prolactinomas is quite limited as the presence of high-molecular prolactin forms is suspected mainly in subjects with mild hyperprolactinemia and negative pituitary imaging.The main objective of this observational case-control study was to assess the prevalence and clinical significance of macroprolactinemia among patients with prolactinomas.The study population consisted of 239 subjects: 131 prolactinoma patients and 108 sex-, age- and ethnicity- matched healthy controls. Macroprolactinemia was defined by a PRL recovery after PEG precipitation of<40%.The prevalence of macroprolactinemia among newly diagnosed prolactinoma patients did not differ statistically from the prevalence in the control group (3.5 vs. 3.7%; p=1.000) but was lower although non-significantly than the subgroup of patients treated with dopamine agonists (DA) (3.5 vs.10.8%; p=0.072). Significant association between disruptions of ovarian function and serum levels of the monomeric as well as high-molecular prolactin isoform was found.In few cases, the presence of typical hyperprolactinemia-related clinical symptoms and their disappearance after treatment with DA suggests biological activity of macroprolactin comparable with that of monomeric prolactin isoform. Decrease of macroprolactin levels after DA treatment could suggest tumoral origin of the high-molecular isoform in these rare cases. Although macroprolactinemia is considered a benign condition, pituitary imaging, DA treatment, and prolonged follow-up may be necessary in certain cases. An individualized approach to the management of patients with macroprolactinemia should be applied.
    Full-text · Article · Apr 2013 · Experimental and Clinical Endocrinology & Diabetes

  • No preview · Article · Mar 2013
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    ABSTRACT: Background. Macroprolactin, the high-molecular prolactin isoform, is considered to be an inactive in vivo product with extrapituitary origin. Patients with macroprolactinemia are usually asymptomatic, with negative pituitary imaging. Based on these data, most authors do not recommend treatment and long-term followup in subjects with macroprolactinemia. However, there is evidence for overlapping clinical features among subjects with hyperprolactinemia due to monomeric or "big big" PRL isoform. Case Presentation. We present a 35-year-old female patient with secondary amenorrhea, mild obesity, hirsutism, headache and blurred vision. Hormonal evaluation revealed an extreme hyperprolactinemia (PRL = 10 610 mIU/L) almost exclusively due to macroprolactin isoform (MPRL = 10 107 mIU/L; recovery after PEG precipitation 4.7%) and hypogonadotropic hypogonadism. An invasive pituitary macroadenoma was visualized on MRI, and cabergoline therapy was initiated. Disappearance of clinical signs and symptoms, normalization of gonadotropin levels, and restoration of regular ovulatory menstrual cycles after 1 year of treatment are arguments in favor of preserved-macroprolactin bioactivity in this case. The significant decrease in MPRL levels and tumor volume in response to dopamine agonist therapy is suggestive for the tumoral origin of this isoform. Conclusions. Although macroprolactinemia is considered to be a benign condition, pituitary imaging, dopamine agonist treatment, and prolonged followup should be recommended in some particular cases.
    Full-text · Article · Jan 2013 · Case Reports in Endocrinology

Publication Stats

835 Citations
190.60 Total Impact Points

Institutions

  • 2003-2015
    • Medical University of Sofia
      • Clinical Center of Endocrinology and Gerontology
      Ulpia Serdica, Sofia-Capital, Bulgaria
  • 2014
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2004-2013
    • New Bulgarian University
      • Department of Informatics
      Ulpia Serdica, Sofia-Capital, Bulgaria
  • 2010
    • University of Liège
      • Department of Endocrinology
      Luik, Walloon, Belgium
  • 2008-2009
    • University Children's Hospital Sofia Bulgaria
      Ulpia Serdica, Sofia-Capital, Bulgaria