P Chatelain

Claude Bernard University Lyon 1, Villeurbanne, Rhône-Alpes, France

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Publications (28)91.08 Total impact

  • Acta Paediatrica 04/2008; 88(s428):180 - 180. · 1.97 Impact Factor
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    ABSTRACT: A mathematical model for predicting the growth response in patients with Turner syndrome who received growth hormone (GH) therapy was developed by analysing data from KIGS, the Pharmacia & Upjohn International Growth Database. A Model for year 1 of GH therapy explained 46% of the variability of the growth response, with GH dose being the most important of the predictors of height velocity. In years 2-4 of therapy, height velocity during the previous year was the most important predictor, suggesting that an individual's initial response to GH may determine the height outcome of treatment. Additional treatment with oxandrolone. The predictions in all 4 years were highly accurate, as indicated by the low error SDs. However, relatively low predictive power (R) during years 2-4 of treatment suggests the models are missing other parameters that would explain more of the variability of the growth response. These growth prediction models could help clinicians to design individualized treatment regimens, provide realistic expectations of therapy outcomes, and adjust treatment on the basis of detected differences between observed and predicted height velocities.
    Acta Paediatrica 04/2008; 88(s433):122 - 125. · 1.97 Impact Factor
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    ABSTRACT: GH treatment has demonstrated favourable effects on most features of GH deficiency in hypopituitary adults. However, most studies employed supraphysiological GH doses, resulting in deterioration in insulin sensitivity (SI). The short-term metabolic effects of physiological doses of GH therapy in GH deficient (GHD) adults are largely unknown. We therefore compared the effects of short-term administration of two 'physiological' ('lowest' dose: 0.0017 mg/kg/day; 'low' dose: 0.0033 mg/kg/day) with two 'supraphy-siological' ('high' dose: 0.010 mg/kg/day; 'highest' dose: 0.025 mg/kg/day) GH doses on SI, beta-cell function, IGF-1 and IGFBPs -1 and -3 in a group of GHD adults. Thirteen GHD adults were recruited (seven men, aged 23-63 years). For each of the four doses, six patients (three men) were allocated randomly to undergo a 7-day treatment phase. Fasting blood samples were collected daily (days 1-8), and SI and beta-cell function were calculated using the homeostasis model assessment (HOMA). All four GH doses increased IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio, and decreased IGFBP-1 from day 3 onwards (P < 0.05). The highest dose increased fasting glucose (P < 0.001), insulin (P < 0.001) and beta-cell function (P < 0.001), but decreased SI (P < 0.001). The high and low doses did not modify fasting glucose and insulin, SI or beta-cell function, whereas the lowest dose enhanced beta-cell function (P < 0.05). The overall increase in the GH dose increased IGF-1, IGFBP-3, fasting glucose and insulin (P < 0.001), demonstrated a positive correlation with the final change in fasting glucose (r = 0.5, P < 0.05) and insulin (r = 0.8, P < 0.001) and a negative correlation with final SI (r = -0.5, P < 0.05). Our results suggest that short-term administration of the highest GH dose induced insulin resistance, whereas the lowest dose (0.0017 mg/kg/day) could represent the optimal starting dose in GHD adults due to its beneficial effects on beta-cell function without compromising SI. It is, however, yet to be determined whether the positive effects of the lowest GH dose on beta-cell function can be demonstrated over a longer period of time.
    Clinical Endocrinology 09/2002; 57(3):333-41. · 3.40 Impact Factor
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    ABSTRACT: GH has both diabetogenic and insulin-like actions. Supraphysiological GH doses are known to reduce insulin sensitivity (S(I)), but lower doses are less well studied. We therefore compared the effects of two physiological GH doses (intermediate, 0.0033 mg/kg x d; low, 0.0017 mg/kg x d) with the standard adult GH deficiency replacement dose (standard, 0.008 mg/kg x d) on S(I), beta-cell function, IGF-I, and IGF binding proteins (IGFBPs)-1 and -3 in healthy adults. Eleven healthy nonobese volunteers (4 males and 7 females, aged 21-38 yr) received 7 daily injections of the standard and intermediate GH doses, and 10 (5 males and 5 females, aged 21-38 yr) received the low dose. Fasting blood samples were collected daily (days 1-8). S(I) and beta-cell function were calculated using the Homeostasis model assessment. All GH doses increased IGF-I and IGFBP-3 levels, with the standard dose inducing the greatest rise (P < 0.001). At day 2 vs. baseline, all three doses increased the IGF-I/IGFBP-3 ratio, but only the standard dose lowered IGFBP-1 levels (P = 0.03). The standard dose reduced S(I) (P = 0.01), whereas the intermediate dose increased S(I) (P < 0.005) and lowered fasting insulin levels (P < 0.01). The low dose did not modify S(I), but reduced fasting glucose levels (P < 0.0001) and increased beta-cell function (P = 0.001). Males demonstrated higher IGF-I and IGFBP-3 responsiveness to the standard dose than females. Males also showed greater increase in S(I) and decrease in fasting glucose levels on both intermediate and low doses. In conclusion, the metabolic effects of GH are dose- and gender-dependent. The standard adult GH deficiency replacement dose induced insulin resistance, whereas lower doses improved S(I), especially in males. The low GH dose lowered fasting glucose levels and could represent the optimal dose to stimulate beta-cell function without compromising S(I) in insulin-resistant GH-deficient adults.
    Journal of Clinical Endocrinology &amp Metabolism 05/2002; 87(5):1989-95. · 6.43 Impact Factor
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    ABSTRACT: The aim of this retrospective analysis was to evaluate the effects of growth hormone (GH) treatment on testicular development in boys with idiopathic short stature (ISS) and isolated GH deficiency (IGHD) followed in the KIGS (Pharmacia International Growth Database). For inclusion in the study, the patients had to have received more than 1 year of prepubertal GH treatment, at least 4 consecutive years of GH treatment in total, and to have attained their final height, defined as a height velocity of less than 2 cm/year. Data on 107 boys in the KIGS database have been analyzed. No significant differences in duration of GH treatment and testicular volume at the start of treatment or at final height were found between the boys with ISS and those with IGHD. The progression of testicular volume in boys with ISS or IGHD during GH treatment did not differ from the reference population. This analysis shows that GH treatment does not alter testicular growth in boys with ISS or IGHD. However, prospective controlled studies are needed to rule out moderate attenuating or stimulating effects.
    Hormone Research 02/2002; 58(2):83-7. · 2.48 Impact Factor
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    ABSTRACT: Various prediction models have been developed, based on data documented within KIGS (Pharmacia International Growth Database), for use in the growth hormone (GH) treatment of children with short stature resulting from GH deficiency (GHD) or other causes. In addition to the practical value of such models as part of a 'forward strategy' guiding GH treatment, we now propose that prediction models may also be useful for the identification of individual variance in responsiveness. In a comparison involving 1,800 children with idiopathic GHD (IGHD), 151 children who acquired GHD after treatment for medulloblastoma and 192 children with GHD accompanying craniopharyngioma, it was shown that the responsiveness to GH of patients with craniopharyngioma equalled that of IGHD patients, whereas patients with medulloblastoma were less responsive. These observations and the identification of 'good' and 'poor' responders to GH have practical clinical consequences (e.g. modification of treatment), and will, in the future, lead to the identification of those factors which determine the variability of sensitivity to GH. This will improve the efficacy and safety of GH treatment as well as reducing the costs involved.
    Hormone Research 02/2001; 55 Suppl 2:44-8. · 2.48 Impact Factor
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    ABSTRACT: Various prediction models have been developed, based on data documented within KIGS (Pharmacia International Growth Database), for use in the growth hormone (GH) treatment of children with short stature resulting from GH deficiency (GHD) or other causes. In addition to the practical value of such models as part of a ‘forward strategy’ guiding GH treatment, we now propose that prediction models may also be useful for the identification of individual variance in responsiveness. In a comparison involving 1,800 children with idiopathic GHD (IGHD), 151 children who acquired GHD after treatment for medulloblastoma and 192 children with GHD accompanying craniopharyngioma, it was shown that the responsiveness to GH of patients with craniopharyngioma equalled that of IGHD patients, whereas patients with medulloblastoma were less responsive. These observations and the identification of ‘good’ and ‘poor’ responders to GH have practical clinical consequences (e.g. modification of treatment), and will, in the future, lead to the identification of those factors which determine the variability of sensitivity to GH. This will improve the efficacy and safety of GH treatment as well as reducing the costs involved.
    Hormone Research - HORM RES. 01/2001; 55:44-48.
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    ABSTRACT: It has become common practice to apply GH treatment in short Turner syndrome patients with the objective of promoting growth. The variability in response and the high costs of this treatment demand the individualization and optimization of therapy. Based on 686 prepubertal Turner patients from the Kabi International Growth Study (KIGS; Pharmacia & Upjohn, Inc. International Growth Database), we undertook a multiple regression analysis of height velocity (centimeters per yr) by using various parameters of potential relevance. Derived prediction models for the first 4 yr of GH treatment were validated with 76 additional KIGS patients and 81 patients from Tuebingen, Germany. Among the 6 predictors identified, the most influential variable for first year growth response was the natural log (ln) of the weekly GH dose. The first year growth response was also correlated with age and distance between height and target height (SD score; both negative) and body weight SD, number of GH injections per week, and oxandrolone treatment given additionally (positive). The first year model explains 46% of the variability, with 1 SD of 1.26 cm. For the second to fourth years, 5 predictors were identified: height velocity during previous years, weekly GH dose (ln), weight SD, oxandrolone therapy (all positive), and age (negative). These models explained 32%, 29%, and 30% of the variability, respectively, with SD scores of 1.1, 1.0, and 1.0 cm, respectively. When the models were applied to the other cohorts, no significant difference was noted between observed and predicted responses. Although the parameters used in our models do not entirely explain the variability in the growth response in Turner syndrome, the parameters themselves were clinically relevant to our present understanding and proved to be of high precision. Some of the tested markers, such as karyotype, do not contribute to the growth response. These variables make the models practical and suitable for planning beneficial and cost-effective therapy.
    Journal of Clinical Endocrinology &amp Metabolism 12/2000; 85(11):4212-8. · 6.43 Impact Factor
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    ABSTRACT: We report an epi-analysis of 6-yr growth responses obtained with GH treatment in short children born small for gestational age (SGA). Four randomized, multicenter studies explored the effects of continuous and discontinuous regimens of GH treatment in short, non-GH-deficient SGA children. A total of 49 untreated and 139 treated children were followed over 2 and 6 yr, respectively. At the start of the study, the age of these 188 children averaged 5.2 yr (range, 2-8 yr), height was -3.4 SD score, and height adjusted for parental height was -2.4 SD score. Onset of puberty was observed in 46% of the GH-treated cohort, on the average, at 10.7 yr in girls and 11.7 yr in boys. Two studies essentially investigated the effects of continuous GH treatment at a dose of 33 or 67 microg/kg, day, and two studies focused on the growth characteristics during an initial GH treatment for 2-3 yr (dose range, 33-100 microg/kg x day), followed by a withdrawal phase of 1-2 yr, and then by either no or 1 or more episodes of further GH treatment (33 or 67 microg/kg x day). Continuous GH treatment for 6 yr resulted in height increments of 2.0 +/- 0.2 SD (33 microg/kg x day; n = 35) and 2.7 +/- 0.2 SD (67 microg/kg x day; n = 27). Discontinuous GH treatment was given to 77 children, most of them experiencing only 1 (n = 47) or 2 (n = 26) treatment phases with an average duration of 2.0 yr. All these children received GH during the first 2 yr; the dose was only 32 microg/kg x day when averaged over 6 yr. Some individualization of treatment schedules was allowed, and the majority of investigators seemed to aim for a low normal height level, adjusted for parental height. After 2 yr, the mean adjusted height SD score had increased to -0.4 +/- 0.1 and stabilized thereafter. Bone maturation progressed similarly in all treatment subgroups, and after 6 yr of study, bone age remained slightly delayed compared to chronological age. Multivariate analysis identified the average GH dose over 6 yr, parental-adjusted height SD score, and age at start as prime predictors of the growth response. GH treatment was well tolerated. In conclusion, this epi-analysis of growth responses over 6 yr confirms the administration of GH as an effective approach to normalize the stature of short, non-GH-deficient SGA children, at least during childhood and early puberty. In addition, it is now increasingly apparent that a relatively broad spectrum of GH regimens is effective, and this experience should facilitate the design of more individualized treatment schedules in the future, in particular for young children.
    Journal of Clinical Endocrinology &amp Metabolism 09/2000; 85(8):2816-21. · 6.43 Impact Factor
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    ABSTRACT: Growth hormone (GH) contributes to insulin resistance, but whether children treated with GH are at increased risk of diabetes has not been established. We undertook a retrospective analysis of data from an international pharmacoepidemiological survey of children treated with GH to find out the incidence of impaired glucose tolerance and types 1 and 2 diabetes mellitus. Reports to the survey of abnormal glucose metabolism were investigated and classified. The incidence and age-distribution of type 1 diabetes were compared with values from a model of reference data. The incidence of type 2 diabetes was compared with data from two reports of children not treated with GH. 85 (0.36%) of 23333 children were reported with abnormal glucose metabolism. After investigation, 43 had confirmed glucose disorders (11 with type 1 diabetes, 18 with type 2 diabetes, and 14 with impaired glucose tolerance). The incidence and age at diagnosis of type 1 diabetes in children treated with GH did not differ from expected values. The incidence of type 2 diabetes was 34.4 cases per 100000 years of GH treatment which was six-fold higher than reported in children not treated with GH. Type 2 diabetes did not resolve after GH therapy was stopped. GH treatment did not affect the incidence of type 1 diabetes mellitus in any age group. We postulate that the higher than expected incidence of type 2 diabetes mellitus with GH treatment may be an acceleration of the disorder in predisposed individuals.
    The Lancet 03/2000; 355(9204):610-3. · 39.06 Impact Factor
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    ABSTRACT: The advent of unlimited supplies of recombinant human growth hormone (rhGH) since 1985 has certainly led to improvements in the treatment of short children with classical growth hormone deficiency (GHD). However, it has also enabled enrolment of many short children in numerous uncontrolled trials of GH treatment in non-GHD states (e.g. idiopathic short stature, IUGR, skeletal dysplasias, osteogenesis imperfecta, Prader-Willi syndrome, Down syndrome, Noonan syndrome, glucocorticoid-induced growth failure, and post-renal transplantation), in which sufficient data regarding effect of treatment on height or metabolic indices as well as safety aspects are still lacking. Current registered indications in most European countries include classical GHD (children and adults), chronic renal failure and Turner syndrome in children. There is concordance between FDA and European licensing authorities with respect to approved use of GH in children and adults apart from the fact that AIDS-related wasting in adults has also become a registered indication in the USA. In Japan, achondroplasia has become a registered indication of GH treatment.
    Hormone Research 01/2000; 51(6):284-99. · 2.48 Impact Factor
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    ABSTRACT: A mathematical model for predicting the growth response in patients with Turner syndrome who received growth hormone (GH) therapy was developed by analysing data from KIGS, the Pharmacia & Upjohn International Growth Database. A model for year 1 of GH therapy explained 46% of the variability of the growth response, with GH dose being the most important of the predictors of height velocity. In years 2-4 of therapy, height velocity during the previous year was the most important predictor, suggesting that an individual's initial response to GH may determine the height outcome of treatment. Additional predictors of height velocity in years 1-4 of GH therapy included age (negative), weight SDS and additional treatment with oxandrolone. The predictions in all 4 years were highly accurate, as indicated by the low error SDs. However, relatively low predictive power (R) during years 2-4 of treatment suggests the models are missing other parameters that would explain more of the variability of the growth response. These growth prediction models could help clinicians to design individualized treatment regimens, provide realistic expectations of therapy outcomes, and adjust treatment on the basis of detected differences between observed and predicted height velocities.
    Acta paediatrica (Oslo, Norway: 1992). Supplement 01/2000; 88(433):122-5.
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    ABSTRACT: Postmarketing surveillance studies of recombinant human GH therapy, such as the Kabi Pharmacia International Growth Study (KIGS; Pharmacia & Upjohn, Inc., International Growth Database), have accumulated extensive data concerning the characteristics and growth outcomes of children with various causes of short stature. These data provide an opportunity to analyze the factors that determine responsiveness to GH and allow the development of disease-specific growth prediction models. We undertook a multiple regression analysis of height velocity (centimeter per yr) with various patient parameters of potential relevance using data from a cohort of 593 prepubertal children with idiopathic GH deficiency (GHD) from the KIGS database. Our aim was to produce models that would have practical utility for predicting prepubertal growth during each of the first 4 yr of GH replacement therapy. These models were validated by a prospective comparison of predicted and observed growth outcomes in an additional 3 cohorts of prepubertal children with idiopathic GHD: 237 additional KIGS patients, 29 patients from the Australian OZGROW study, and 33 patients from Tubingen, Germany. The most influential variable for first year growth response was the natural log (ln) of the maximum GH response during provocation testing, which was inversely correlated with height velocity. The first year growth response was also inversely correlated with chronological age and height SD score minus midparental height SD score. First year growth was positively correlated with body weight SD score, weekly GH dose (ln), and birth weight SD score. Two first year models were developed using these parameters, 1 including and 1 excluding the maximum GH response to provocative testing. The former model explained 61% of the response variability, with a SD of 1.46 cm; the latter model explained 45% of the variability, with a SD of 1.72 cm. The two models gave similar predictions, although the model excluding the maximum GH response to testing tended to underpredict the growth response in patients with very low GH secretory capacity. For the second, third, and fourth year growth responses, 4 predictors were identified: height velocity during the previous year (positively correlated), body weight SD score (positively correlated), chronological age (negatively correlated), and weekly GH dose (ln; positively correlated). The models for the second, third, and fourth year responses explained 40%, 37%, and 30% of the variability, respectively, with SDs of 1.19, 1.05, and 0.95 cm, respectively. When the models were applied prospectively to the other cohorts, there were no significant differences between observed and predicted responses in any of the cohorts in any year of treatment. The fourth year response model gave accurate prospective growth predictions for the fifth to the eighth prepubertal years of GH treatment in a subset of 48 KIGS patients. Analyses of Studentized residuals provided further validation of the models. The parameters used in our models do not explain all of the variability in growth response, but they have a high degree of precision (low error SDs). Moreover, the parameters used are robust and easily accessible. These properties give the models' practical utility as growth prediction tools. The availability of longitudinal, disease-specific models will be helpful in the future for enabling growth-promoting therapy to be planned at the outset, optimized for efficacy and economy, and individualized to meet treatment goals based on realistic expectations.
    Journal of Clinical Endocrinology &amp Metabolism 04/1999; 84(4):1174-83. · 6.43 Impact Factor
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    ABSTRACT: Final height was evaluated in 369 patients with idiopathic growth hormone deficiency (IGHD) enrolled in KIGS--the Pharmacia & Upjohn International Growth Database. At the start of growth hormone (GH) therapy, the patients were 9.8 years of age, their mid-parental height SDS was -0.8, and their height SDS was -3.1. Of the 369 patients, 50% had multiple hormone deficiencies, and puberty was induced in 31%. Patients were 18 years of age at completion of GH therapy, and had received GH at a dose of 0.49 IU/kg/week (0.16 mg/kg/week), with a mean of 5.2 injections/week for 8.1 years. Final height SDS was -1.5, final minus initial height SDS was 1.7 and final minus mid-parental height SDS was -0.5. A Swedish subgroup (n = 69) received conventional GH therapy throughout at 0.65 IU/kg/week (0.22 mg/kg/week), with seven injections/week for a mean of 9.4 years. These patients achieved their genetic potential (final minus mid-parental height SDS, 0.03), with a normal final height SDS of -0.3. For the total group, the following variables were associated with final height: mid-parental height SDS (r = 0.62), injection frequency (r = 0.37), duration of GH treatment (r = 0.28), peak stimulated GH concentration (r = -0.25), age (r = -0.19) (all p < 0.001) and height velocity SDS in the first year of treatment (r = 0.20, p = 0.004). In conclusion, genetic potential, expressed as the mid-parental height, is the variable with the greatest identified influence on final height during GH treatment in IGHD. Current GH regimens will lead to a normal height and attainment of mid-parental height. However, higher dose, individualized GH regimens are likely to be necessary for patients with IGHD who are disadvantaged at the time of commencing GH therapy, such as those with short parents, those whose treatment began in late childhood or adolescence and those with less severe GHD.
    Acta paediatrica (Oslo, Norway: 1992). Supplement 03/1999; 88(428):72-5.
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    ABSTRACT: Cutfield W, Lindberg A, Albertsson Wikland K, Chatelain P, Ranke MB, Wilton P, on behalf of the KIGS International Board. Final height in idiopathic growth hormone deficiency: the KIGS experience. Acta Pædiatr 1999; Suppl 428: 72–5. Stockholm. ISSN 0803–5326Final height was evaluated in 369 patients with idiopathic growth hormone deficiency (IGHD) enrolled in KIGS - the Pharmacia & Upjohn International Growth Database. At the start of growth hormone (GH) therapy, the patients were 9.8 years of age, their mid-parental height SDS was -0.8, and their height SDS was -3.1. Of the 369 patients, 50% had multiple hormone deficiencies, and puberty was induced in 31%. Patients were 18 years of age at completion of GH therapy, and had received GH at a dose of 0.49 IU/kg/week (0.16 mg/kg/week), with a mean of 5.2 injections/week for 8.1 years. Final height SDS was -1.5, final minus initial height SDS was 1.7 and final minus mid-parental height SDS was -0.5. A Swedish subgroup (n= 69) received conventional GH therapy throughout at 0.65 IU/kg/week (0.22 mg/kg/week), with seven injections/week for a mean of 9.4 years. These patients achieved their genetic potential (final minus mid-parental height SDS, 0.03), with a normal final height SDS of -0.3. For the total group, the following variables were associated with final height: mid-parental height SDS (r= 0.62), injection frequency (r= 0.37), duration of GH treatment (r= 0.28), peak stimulated GH concentration (r= -0.25), age (r= -0.19) (all p < 0.001) and height velocity SDS in the first year of treatment (r= 0.20, p= 0.004). In conclusion, genetic potential, expressed as the mid-parental height, is the variable with the greatest identified influence on final height during GH treatment in IGHD. Current GH regimens will lead to a normal height and attainment of mid-parental height. However, higher dose, individualized GH regimens are likely to be necessary for patients with IGHD who are disadvantaged at the time of commencing GH therapy, such as those with short parents, those whose treatment began in late childhood or adolescence and those with less severe GHD. □Final height, growth hormone treatment, height, idiopathic growth hormone deficiency, KIGS
    Acta Paediatrica 01/1999; 88:72-75. · 1.97 Impact Factor
  • 01/1999: pages 245-258;
  • 01/1999: pages 147-158;
  • Paediatr Endocrinol. 01/1999; 8:(Suppl 13) 47-51.
  • 01/1999: pages 371-384;
  • 01/1999: pages 93-110;

Publication Stats

670 Citations
91.08 Total Impact Points

Institutions

  • 2000–2008
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
  • 2000–2001
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 1999–2000
    • University of Auckland
      • Department of Paediatrics: Child and Youth Health
      Auckland, Auckland, New Zealand
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 1996–1997
    • University of Lyon
      Lyons, Rhône-Alpes, France