P Czernichow

Hôpital Universitaire Robert Debré, Lutetia Parisorum, Île-de-France, France

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Publications (421)1722.98 Total impact

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    ABSTRACT: Background/objective: Normally sited glands account for increasing congenital hypothyroidism (CH). Mechanisms often remain unknown. To report the incidence of CH with in situ thyroid gland (ISTG) and describe the natural history of the disease without known etiology. Method: Clinical, biochemical and imaging data at diagnosis were retrospectively analyzed in 285 children positively screened for CH in Ile-de-France between 2005 and 2008. If treatment was discontinued, management of hormonal substitution and follow-up of biochemical thyroid function was performed. Results: 93 full-term CH neonates displayed ISTG (40.6%), including 50 with unexplained mechanism. Follow-up data were available in 32 of them. Therapy was withdrawn from 20 children at a median age of 23.5 months (6-66), among whom 18 remained still untreated over a median duration of 15.3 months (4.4-29.6). In 11 children, levothyroxine (L-T4) dosage was increased over time to maintain biochemical euthyroidism. No statistical differences in initial TSH or FT4 levels, iodine status or birth weight were found between children with transient and permanent hypothyroidism. Conclusion: Withdrawal of L-T4 substitution was feasible in 56.2% of full-term children with CH with ISTG but unexplained mechanism, emphasizing the need for systematic therapy withdrawal. However, further studies are warranted to standardize withdrawal protocol.
    Hormone Research in Paediatrics 01/2015; 83(2). DOI:10.1159/000362234 · 1.57 Impact Factor
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    ABSTRACT: Diabetic patients exhibit a reduction in β cells, which secrete insulin to help regulate glucose homeostasis; however, little is known about the factors that regulate proliferation of these cells in human pancreas. Access to primary human β cells is limited and a challenge for both functional studies and drug discovery progress. We previously reported the generation of a human β cell line (EndoC-βH1) that was generated from human fetal pancreas by targeted oncogenesis followed by in vivo cell differentiation in mice. EndoC-βH1 cells display many functional properties of adult β cells, including expression of β cell markers and insulin secretion following glucose stimulation; however, unlike primary β cells, EndoC-βH1 cells continuously proliferate. Here, we devised a strategy to generate conditionally immortalized human β cell lines based on Cre-mediated excision of the immortalizing transgenes. The resulting cell line (EndoC-βH2) could be massively amplified in vitro. After expansion, transgenes were efficiently excised upon Cre expression, leading to an arrest of cell proliferation and pronounced enhancement of β cell-specific features such as insulin expression, content, and secretion. Our data indicate that excised EndoC-βH2 cells are highly representative of human β cells and should be a valuable tool for further analysis of human β cells.
    The Journal of clinical investigation 03/2014; 124(5). DOI:10.1172/JCI72674 · 13.22 Impact Factor
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    ABSTRACT: Neonatal diabetes mellitus is a rare genetic form of pancreatic β-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without β-cell autoimmunity and with normal pancreas morphology. We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for β-cell autoimmunity. We assessed changes in the 6q24 locus, KATP-channel subunit genes (ABCC8 and KCNJ11), and preproinsulin gene (INS) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities. We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11, 31 (24%) had mutations in ABCC8, and 13 (10%) had mutations in INS. We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in KATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP channel subunit genes (82% vs 86%; p=0·36). Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus. Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie.
    11/2013; 1(3):199-207. DOI:10.1016/S2213-8587(13)70059-7
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    ABSTRACT: Context: Recombinant growth hormone (rhGH) improves growth and body composition in glucocorticoid-treated children. Its effects on muscle strength are poorly evaluated.Objectives: To evaluate rhGH effects on muscle strength in children receiving long-term glucocorticoid therapy; effects on height SDS and body composition were assessed also.Design and setting:Randomized, controlled, delayed-start study of rhGH for 12 months, started after randomization (M0) or 6 months later (M6).Patients:30 children with various diagnoses.Intervention:rhGH, 0.065 mg/Kg/day for 6 months then in the dosage maintaining serum IGF-1 levels <+2SDS for chronological age.Main outcome measures.The primary criterion was the between-group difference in composite index of muscle strength (CIMS) change at M6. Secondary criteria included between-group differences in CIMS SDS/height, lean mass (LM), thigh muscle area (MA), and height SDS changes at M6; these parameters were also assessed in the overall population after 1 year of rhGH therapy.Results:At M6, rhGH therapy did not significantly affect changes in CIMS or CIMS SDS/height (+17.6% vs. +7.5% and +0.14 ±0.38 vs. +0.11±0.62, respectively); the rhGH-treated group had significantly larger changes in height SDS (+0.2 [0.3] vs. -0.2 [0.3]; P=0.003), LM (+7.3% [+3.7;+21.6] vs. 0% [-4.7;+3.2]; P=0.002), and MA (+8.8% [+5;+15.6] vs. -0.6% [-6.3;+7.7]; P=0.01) compared to the untreated group. After 1 year of rhGH, height SDS, LM, and MA increased significantly, CIMS increased by 24.7% (+5.8; +34.2), and CIMS SDS/height remained within the normal range.Conclusions:rhGH increased height, LM, and MA. However, muscle strength did not improve significantly.
    The Journal of Clinical Endocrinology and Metabolism 04/2013; 98(7). DOI:10.1210/jc.2012-4201 · 6.21 Impact Factor
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    ABSTRACT: Normal growth is a sign of good health. Monitoring for growth disturbances is fundamental to children's health care. Early detection and diagnosis of the causes of short stature allows management of underlying medical conditions, optimizing attainment of good health and normal adult height.Conclusion This review summarizes currently available information on monitoring for short stature in children and conditions usually associated with short stature and summarizes the authors’ conclusions on the early recognition of growth disorders.
    Acta Paediatrica 04/2013; 102(8). DOI:10.1111/apa.12266 · 1.67 Impact Factor
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    Diabetologia 07/2012; 55(10):2845-7. DOI:10.1007/s00125-012-2645-7 · 6.67 Impact Factor
  • Philippe Ravassard · Paul Czernichow · Raphaël Scharfmann
    Medecine sciences: M/S 02/2012; 28(2):149-51. DOI:10.1051/medsci/2012282011 · 0.67 Impact Factor
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    ABSTRACT: Despite intense efforts over the past 30 years, human pancreatic β cell lines have not been available. Here, we describe a robust technology for producing a functional human β cell line using targeted oncogenesis in human fetal tissue. Human fetal pancreatic buds were transduced with a lentiviral vector that expressed SV40LT under the control of the insulin promoter. The transduced buds were then grafted into SCID mice so that they could develop into mature pancreatic tissue. Upon differentiation, the newly formed SV40LT-expressing β cells proliferated and formed insulinomas. The resulting β cells were then transduced with human telomerase reverse transcriptase (hTERT), grafted into other SCID mice, and finally expanded in vitro to generate cell lines. One of these cell lines, EndoC-βH1, expressed many β cell-specific markers without any substantial expression of markers of other pancreatic cell types. The cells secreted insulin when stimulated by glucose or other insulin secretagogues, and cell transplantation reversed chemically induced diabetes in mice. These cells represent a unique tool for large-scale drug discovery and provide a preclinical model for cell replacement therapy in diabetes. This technology could be generalized to generate other human cell lines when the cell type-specific promoter is available.
    The Journal of clinical investigation 08/2011; 121(9):3589-97. DOI:10.1172/JCI58447 · 13.22 Impact Factor
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    ABSTRACT: Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France. To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir. Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine. Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency. Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (>23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P < .001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P < .001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P < .001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment. Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.
    JAMA The Journal of the American Medical Association 07/2011; 306(1):70-8. DOI:10.1001/jama.2011.915 · 35.29 Impact Factor
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    ABSTRACT: Screening programs resulting in the early treatment of patients with congenital hypothyroidism (CH) have successfully improved neurodevelopmental outcome, but little is known about long-term health. The aim of the study was to assess health status, and socioeconomic attainment, for a population-based registry of young adult patients. All 1748 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France were invited to participate in this study at a median age of 23.4 yr. Completed questionnaires were obtained from 1202 of the selected patients. The comparison group included 5817 subjects from the last French Decennial Health Survey. Health indicators including medical conditions, hearing and visual status, sociodemographic characteristics, and quality of life were measured. Patients with CH were significantly more likely than their peers to report associated chronic diseases (5.7 vs. 2.9%), hearing impairment (9.5 vs. 2.5%), visual problems (55.4 vs. 47.9%), and being overweight with a body mass index of at least 25 kg/m(2) (22.8 vs. 15.7%) (P < 0.0001). Furthermore, fewer patients attained the highest socioeconomic category (14.6 vs. 23.1%) and were in full-time employment (39.9 vs. 44.8%) (P < 0.0001). They were more likely to still be living with their parents and had a lower health-related quality of life than their healthy peers, particularly for mental dimensions, with a mean difference for the mental summary component of 0.35 SD score (P < 0.0001). CH severity at diagnosis, treatment adequacy, and the presence of other chronic health conditions were the main determinants of educational achievement and health-related quality of life scores. These findings highlight the need for careful monitoring of neurosensory functioning, weight, and long-term treatment adequacy throughout childhood and adulthood.
    The Journal of Clinical Endocrinology and Metabolism 03/2011; 96(6):1771-82. DOI:10.1210/jc.2010-2315 · 6.21 Impact Factor
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    ABSTRACT: This study was designed to estimate the percentage of growth hormone (GH)-treated children born small for gestational age (SGA), with serum IGF-1 >2 SDS before and after GH dose adaptation. SGA boys aged 4-9 and girls aged 4-7 with a height <-2 SDS and an annual growth rate below the mean received a subcutaneous GH dose of 57 μg/kg/day for 2 years. The GH dose was to be decreased by 30% in children with serum IGF-1 >2 SDS at 12 months and on the previous sample. The GH dose could be reduced a second time to 35 μg/kg·day. IGF-1 and IGFBP-3 dosages were centralized. Among the 49 (21 boys) children included in the study, 8 (16.3%) had an IGF-1 >2 SDS consecutively at 9 and 12 months (95% CI 7.3, 29.7). The GH dose was decreased in 6/8 children. However, IGF-1 levels were elevated at several nonconsecutive determinations in 45% (95% CI 28.4, 56.6) of the patients. A high IGF-1 level is observed in 45% of the GH SGA-treated children with a relatively high dose of GH. A 30% reduction in the GH dose causes a decrease in IGF-1 below 2 SDS in most children.
    Hormone Research in Paediatrics 01/2011; 76(6):419-27. DOI:10.1159/000334651 · 1.57 Impact Factor
  • Paul Czernichow · Michel Polak
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    ABSTRACT: L’hypothyroïdie congénitale (HC) (1/3500) est due dans la majorité des cas à une dysgénésie thyroïdienne (athyréose ou ectopie). Lorsque la thyroïde est en place (GP), les dyshormonogenèses n’expliquent que 1/3 des cas. L’objectif de l’étude a été d’analyser l’étiologie et l’évolution des HC avec GP. Sujets : 131 enfants dépistés en Ile de France entre 2005 et 2008 ont été étudiés. Résultats : Une scintigraphie a été effectuée chez 84 enfants (64 %) et une dyshormonogenèse a été diagnostiqué dans 48 cas (37 %). 4 cas de faux positifs et 20 cas d’HC transitoire d’étiologie « classique » (prématurité, trouble iodé, anticorps antithyroïdiens et/ou PTU chez la mère) ont été observés. Lorsque l’étiologie était indéterminée et un traitement substitutif instauré (n = 44), un arrêt de traitement a été tenté chez 15 enfants (âge moyen 17 mois [2-46]) sans récidive de l’hypothyroïdie chez 13 d’entre eux (86 %). De même, 3 enfants avec dyshormonogenèse ont arrêté la L-Thyroxine avec succès. Au total, dans les cas d’HC avec GP d’étiologie indéterminée, un arrêt de traitement substitutif a été possible dans 86 % des cas testés et devrait donc être proposé plus systématiquement. Reste à définir les critères cliniques, biologiques et/ou radiologiques pour permettre des recommandations consensuelles.
    Archives de Pédiatrie 06/2010; 17(6):5-5. DOI:10.1016/S0929-693X(10)70233-5 · 0.41 Impact Factor
  • Elise Bismuth · Didier Chevenne · Paul Czernichow · Dominique Simon
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    ABSTRACT: To describe glucose metabolism changes during growth hormone (GH) treatment in juvenile idiopathic arthritis (JIA). Observational study in 58 children on glucocorticoid therapy (GC) for JIA, of whom 28 received late GH therapy (7.3 +/- 3.4 years into GC), 15 early GH therapy (1.2 +/- 0.1 years into GC), and 15 no GH therapy. The GH dose was 0.46 mg/kg/week. Oral glucose tolerance testing with insulin and glycosylated hemoglobin assays were performed yearly. Nonparametric tests were used to compare groups after 3 years and regression analyses to estimate factors predicting glucose AUC and HOMA-IR at baseline and after 3 years. GH combined with GC was associated with an increase in mean fasting insulinemia. Late GH therapy patients exhibited significant increases over time in mean fasting glycemia (p = 0.01), mean 2-hour postglucose load glycemia (p < 0.05), mean AUC for glucose (p < 0.05), and mean HOMA-IR (p < 0.05). Impaired glucose tolerance was found in 16/43 GH-treated patients (37%) and transient diabetes in 2 (5%) patients. GH treatment in JIA children decreased insulin sensitivity but had only modest effects on glucose tolerance. Close monitoring by oral glucose tolerance testing is crucial before and during GH treatment, particularly during puberty and relapses.
    Hormone Research in Paediatrics 04/2010; 73(6):465-72. DOI:10.1159/000313589 · 1.57 Impact Factor
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    ABSTRACT: The therapeutic benefit of growth hormone (GH) therapy in improving height in short children is widely recognized; however, GH therapy is associated with other metabolic actions that may be of benefit in these children. Beneficial effects of GH on body composition have been documented in several different patient populations as well as improvements in lipid profile. Marked augmentation of bone mineral density also seems evident in many pediatric populations. Some of these benefits may require continued therapy past the acquisition of adult height. With long-term therapy of any kind, the adverse consequences of treatment should also be considered. Fortunately, long-term GH treatment seems to be safe and well-tolerated. This review describes the long-term metabolic effects of GH treatment in the pediatric population and considers how these may benefit children who are treated with GH.
    PEDIATRICS 03/2010; 125(4):e906-18. DOI:10.1542/peds.2009-1783 · 5.47 Impact Factor
  • Article: Hypophyse
    J Léger · P Czernichow
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    ABSTRACT: Ante- and post-hypophysis are the two constituents of the hypophysis. The ante-hypophysis synthesizes and secretes mainly the growth hormone, thyrotropin, prolactin, adrenocorticotropic hormones and the gonadotrophins. The vasopressin and oxytocin hormones are secreted by the post-hypophysis. The hypophysis development and differentiation are controlled by a chain of different factors that involve numerous signalisation genes from adjacent structures, in addition to specific transcription factors, to date insufficiently known. The regulation and mode of action of the various hormones are now well identified. Activating and inhibiting hormones synthesized in the hypothalamus regulate the functioning of ante-hypophysis cells. They act through specific cellular receptors. In children, hypothalamus-hypophysis hypofunction is far more frequently observed than hyperfunction. Hypopituitarisms are serious diseases which, if untreated, may have irreversible consequences such as severe nanism in case of somatotropic insufficiency, mental retardation in case of thyrotropic insufficiency, lack of puberty development and sterility in case of gonadotropic insufficiency, and even death in case of corticotropic insufficiency. The diagnosis of hypophysis insufficiency is based on clinical data, and results of functional investigations, and brain magnetic resonance imaging. Treatments are substitutive, given for life, and concerned patients necessitate lifelong medical management. Hypophysis insufficiency may be either isolated or multiple, either acquired (mainly in relation with a tumoral or infiltrative process in the hypothalamus-hypophysis area), or congenital. Various types of human congenital insufficiency (isolated or combined) due to a genetic cause have been described these last years. However, the molecular mechanisms that produce the major part of genetic hypopituitarisms remain to be elucidated.
    01/2010; 5(2). DOI:10.1016/j.emcped.2004.02.007
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    ABSTRACT: Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with steroid-dependent nephrotic syndrome (SDNS), some CsA-treated patients require long-term steroid therapy. Data on growth in these patients are scarce. Sixty-four boys with SDNS receiving long-term CsA and steroid therapy were retrospectively analyzed. During the 10-year follow-up period, height standard deviation score (HSDS) remained in the normal range in 47 patients but was below -2 SD in 17 patients. The occurrence of growth retardation was influenced by height at diagnosis and the number of relapses. Thirty patients were followed for at least 3 years before and after age 12. The decrease in HSDS per year of disease in patients older than 12 years was twice that observed in children younger than 12. However, adult height was < or = -2 SD in only two of the 14 patients reaching adult height, reflecting potential catch-up growth during late puberty. Careful monitoring of growth is recommended, given than up to 25% of patients experienced severe growth retardation during the course of their disease.
    Pediatric Nephrology 09/2009; 24(12):2393-400. DOI:10.1007/s00467-009-1266-y · 2.86 Impact Factor
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    ABSTRACT: Obesity and type 2 diabetes (T2DM) in children and adolescents are increasing in developed and developing countries. We have every reason to fear, already, a parallel epidemic in France. We discussed the phenotypic characterization of diabetes in children and adolescent (type 1 diabetes, MODY mainly MODY3, and true T2DM), which have clinical and therapeutic implications, a distinction not always easy. Familial history of T2DM, initial BMI, body weight loss, severity of hyperglycemia and a ketonuria are often not sufficient to determine the etiologic diagnosis. The search for specific islet-cell autoantibodies and for MODY3, are often necessary for classification, and to guide therapeutic strategies. This review presents preliminary French data, based on the comparison of the annual frequency of T2DM between two periods (2001-2003 vs. 1993-1998), in our pediatric diabetes department. A significant increase of T2DM has been found: 14/271 new cases of diabetes (age <16 yrs) in 2001-2003 were T2DM vs. 8/370 in 1993-98 (i.e. 5.2% vs. 2.2%). By contrast with other countries, most of these young T2DM patients are Caucasians. The treatment allows a good glycemic control when diet and physical advices are well followed, and supported by the pediatric team. A monotherapy with metformin is usually sufficient for treating these patients after a short and transient insulin therapy.
    Médecine des Maladies Métaboliques 03/2009; 3(2). DOI:10.1016/S1957-2557(09)71644-X
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    ABSTRACT: There is increasing interest in developing human cell lines to be used to better understand cell biology, but also for drug screening, toxicology analysis and future cell therapy. In the endocrine pancreatic field, functional human beta cell lines are extremely scarce. On the other hand, rodent insulin producing beta cells have been generated during the past years with great success. Many of such cell lines were produced by using transgenic mice expressing SV40T antigen under the control of the insulin promoter, an approach clearly inadequate in human. Our objective was to develop and validate in rodent an alternative transgenic-like approach, applicable to human tissue, by performing somatic gene transfer into pancreatic progenitors that will develop into beta cells. In this study, rat embryonic pancreases were transduced with recombinant lentiviral vector expressing the SV40T antigen under the control of the insulin promoter. Transduced tissues were next transplanted under the kidney capsule of immuno-incompetent mice allowing insulinoma development from which beta cell lines were established. Gene expression profile, insulin content and glucose dependent secretion, normalization of glycemia upon transplantation into diabetic mice validated the approach to generate beta cell lines. Somatic gene transfer into pancreatic progenitors represents an alternative strategy to generate functional beta cell lines in rodent. Moreover, this approach can be generalized to derive cells lines from various tissues and most importantly from tissues of human origin.
    PLoS ONE 02/2009; 4(3):e4731. DOI:10.1371/journal.pone.0004731 · 3.23 Impact Factor
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    ABSTRACT: There is debate about how Graves' disease (GD) should be treated in children. The aim of this study was to identify predictors of relapse after antithyroid drug (ATD) treatment in children with GD. We conducted a prospective, multicenter cohort study of children (n = 154) with GD treated with carbimazole for an intended duration of 24 +/- 3 months. After the end of treatment, patients were followed up for at least 2 yr. The primary outcome was hyperthyroidism relapse. Cox's regression analysis was used and a prognostic score was constructed. The overall estimated relapse rate for hyperthyroidism was 59% (95% confidence interval 52-67%) at 1 yr and 68% (95% confidence interval 60-76%) at 2 yr after the end of treatment. Multivariate survival analysis showed that the risk of relapse was higher for patients of non-Caucasian origin [hazard ratio (HR) = 2.54, P < 0.001], with high serum thyroid-stimulating hormone receptor antibodies (HR = 1.21 by 10 U, P = 0.03) and free T(4) (HR = 1.18 by 10 pmol/liter, P = 0.001) levels at diagnosis. Conversely, relapse risk decreased with increasing age at onset (HR = 0.74 per 5 yr, P = 0.03) and duration of first course of ATD (HR = 0.57 per 12 months, P = 0.005). A prognostic score was constructed, allowing the identification of three different risk groups, with 2-yr relapse rates of 46, 77, and 98%. A longer initial duration of euthyroid state with ATD seems to be the only variable related to the risk of hyperthyroidism relapse in children that can be manipulated. Ethnic origin, age, and severity of the disease at diagnosis may guide long-term disease management decisions.
    Journal of Clinical Endocrinology &amp Metabolism 10/2008; 93(10):3817-26. DOI:10.1210/jc.2008-0842 · 6.21 Impact Factor

Publication Stats

12k Citations
1,722.98 Total Impact Points


  • 1989–2013
    • Hôpital Universitaire Robert Debré
      • Service d’Endocrinologie et de Diabétologie Pédiatriques
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 1998–2009
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Hospital Haguenau
      Hagenau, Alsace, France
  • 2008
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 1989–2007
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2006
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2004
    • Albert Einstein College of Medicine
      New York, New York, United States
  • 1984–2002
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1997
    • Hôpital Saint-Vincent-de-Paul – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
    • Centre Hospitalier Universitaire Rouen
      • Department of Epidemiology and Public Health
      Rouen, Upper Normandy, France
  • 1986
    • University of Liège
      Luik, Walloon, Belgium
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1985
    • Université Paris 13 Nord
      Île-de-France, France