Publications by authors named "Tiphanie Ginhoux"

13 Publications

  • Page 1 of 1

Assessment of mineral and bone biomarkers highlights a high frequency of hypercalciuria in asymptomatic healthy teenagers.

Acta Paediatr 2019 12 15;108(12):2253-2260. Epub 2019 Jul 15.

Laboratoire de Biochimie et Biologie Moléculaire, Groupe Hospitalier Sud, Hospices Civils de Lyon, Lyon, France.

Aim: Assessment of mineral metabolism is complex in paediatrics.

Methods: We assessed the evolution of the main mineral and bone biomarkers (total/bone alkaline phosphatase ALP/BAP, β-crosslaps, osteocalcin, sclerostin, C-terminal and intact FGF23) in 100 healthy teenagers (10-18 years, 50 boys).

Results: At a mean age of 13.7 ± 2.2 years, phosphatemia, tubular phosphate reabsorption, ALP and BAP significantly decreased along puberty in both genders, whilst parathyroid hormone (PTH), 25-vitamin D (25D), FGF23, plasma calcium and urinary calcium were not modified. In girls, osteocalcin, β-crosslaps and sclerostin significantly decreased at the end of puberty. Calciuria above the crystallisation threshold (>3.8 mmol/L) and urinary calcium/creatinine ratio >0.7 mmol/mmol were found in 39% and 6% of subjects, respectively. Multivariable analyses showed that renal function and PTH were significant predictors of calciuria and urinary calcium/creatinine, whilst 25D remained a predictor only of urinary calcium/creatinine ratio.

Conclusion: Using the most recent assays, this study provides data for mineral/bone biomarkers across puberty and highlights the risk of hyper-calciuria in apparent asymptomatic healthy teenagers, not related to calcium intake but rather to 25D. Future studies are required to dissect the underlying mechanisms increasing calciuria and prevent nephrolithiasis as early as during childhood.
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December 2019

Nutritional Status Deterioration Occurs Frequently During Children's ICU Stay.

Pediatr Crit Care Med 2019 08;20(8):714-721

Faculty of Health & Applied Sciences, University of the West of England, Bristol BS16 1DD, United Kingdom.

Objectives: Malnutrition and faltering growth at PICU admission have been related to suboptimal outcomes. However, little is known about nutritional status deterioration during PICU stay, as critical illness is characterized by a profound and complex metabolism shift, which affects energy requirements and protein turnover. We aim to describe faltering growth occurrence during PICU stay.

Design: Single-center prospective observational study.

Setting: Twenty-three-bed general PICU, Lyon, France.

Patients: All critically ill children 0-18 years old with length of stay longer than 5 days were included (September 2013-December 2015).

Interventions: Weight and height/length were measured at admission, and weight was monitored during PICU stay, in order to calculate body mass index for age z score. Faltering growth was defined as body mass index z score decline over PICU stay. Children admitted during the first year of the study and who presented with faltering growth were followed after PICU discharge for 3 months.

Measurements And Main Results: We analyzed 579 admissions. Of them, 10.2% presented a body mass index z score decline greater than 1 SD and 27.8% greater than 0.5. Admission severity risk scores and prolonged PICU stay accounted for 4% of the variability in nutritional status deterioration. Follow-up of post-PICU discharge nutritional status showed recovery within 3 months in most patients.

Conclusions: Nutritional deterioration is frequent and often intense in critically ill children with length of stay greater than 5 days. Future research should focus on how targeted nutritional therapies can minimize PICU faltering growth and improve post-PICU rehabilitation.
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August 2019

Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial.

BMC Pediatr 2019 05 28;19(1):170. Epub 2019 May 28.

Hospices Civils de Lyon, Service de Néphrologie Pédiatrique, et centre de référence maladies rénales rares- Néphrogones, Filière ORKiD, -69500, Bron, France.

Background: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure.

Methods: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups.

Results: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008).

Conclusion: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome.

Trials Registration: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).
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May 2019

Skin microvascular dysfunction as an early cardiovascular marker in primary hyperoxaluria type I.

Pediatr Nephrol 2019 02 1;34(2):319-327. Epub 2018 Oct 1.

Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France.

Background: Primary hyperoxaluria type 1 (PH1) is an orphan inborn error of oxalate metabolism leading to hyperoxaluria, progressive renal failure, oxalate deposition, and increased cardiovascular complications. As endothelial dysfunction and arterial stiffness are early markers of cardiovascular risk, we investigated early endothelial and vascular dysfunction in young PH1 patients either under conservative treatment (PH1-Cons) or after combined kidney liver transplantation (PH1-T) in comparison to healthy controls (Cont-H) and patients with a past of renal transplantation (Cont-T).

Methods: Skin microvascular function was non-invasively assessed by laser Doppler flowmetry before and after stimulation by current, thermal, or pharmacological (nitroprussiate (SNP) or acetylcholine (Ach)) stimuli in young PH1 patients and controls.

Results: Seven PH1-Cons (6 F, median age 18.2) and 6 PH1-T (2 F, median age 13.3) were compared to 96 Cont-H (51 F, median age 14.2) and 6 Cont-T (4 F, median age 14.5). The endothelium-independent vasodilatation (SNP) was severely decreased in PH1-T compared to Cont-H. Ach, current-induced vasodilatation (CIV), and thermal response was increased in PH1-Cons and Cont-T compared to controls.

Conclusions: PH1-T patients displayed severely decreased smooth muscle capacity to vasodilate. An exacerbated endothelial-dependent vasodilation suggests a role for silent inflammation in the early dysfunction of microcirculation observed in PH1-Cons and Cont-T.
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February 2019

Multiple Micronutrient Plasma Level Changes Are Related to Oxidative Stress Intensity in Critically Ill Children.

Pediatr Crit Care Med 2018 09;19(9):e455-e463

Department of Biochemistry, Lyon Sud Hospital, Laboratoire d'Analyse de Traces et Métaux Toxiques, Hospices Civils de Lyon, Lyon, France.

Objectives: Micronutrient supplementation in critically ill adults remains controversial. In the pediatric setting, the impact of oxidative stress on the overall micronutrient status has been poorly explored, due to the limited number of studies and to confounding factors (i.e., malnutrition or extra losses). In order to better understand this phenomenon, we aim to describe micronutrient status, focusing on seven micronutrients, in well-nourished critically ill children presenting with severe oxidative stress.

Design: Prospective, transversal, observational, single-center study.

Setting: PICU, and anesthesiology department, Lyon, France.

Patients: Three groups of patients were clinically defined: severe oxidative stress PICU group (at least two organ dysfunctions), moderate oxidative stress PICU group (single organ dysfunction), and healthy control group (prior to elective surgery); oxidative stress intensity was controlled by measuring plasma levels of glutathione peroxidase and glutathione. Children presenting any former condition leading to micronutrient deficiency were excluded (malnutrition, external losses).

Interventions: Plasma levels of selenium, zinc, copper, vitamin A, vitamin E, vitamin C, and β-carotene were measured in PICU oxidative stress conditions and compared with those of healthy children.

Measurements And Main Results: Two hundred one patients were enrolled (51, 48, and 102 in severe, moderate, and healthy control groups, respectively). Median age was 7.1 years (interquartile range, 2.1-13.8 yr). There was a significant trend (p < 0.02) toward plasma level decrease of six micronutrients (selenium, zinc, copper, vitamin E, vitamin C, and β-carotene) while oxidative stress intensity increased. Biological markers of oxidative stress (glutathione peroxidase and glutathione) were in accordance with the clinical definition of the three groups.

Conclusions: A multiple micronutrient deficiency or redistribution occurs in critically ill children presenting with severe oxidative stress. These findings will help to better identify children who might benefit from micronutrient supplementation and to design adapted supplementation trials in this particular setting.
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September 2018

The interplay between bone and vessels in pediatric CKD: lessons from a single-center study.

Pediatr Nephrol 2018 09 5;33(9):1565-1575. Epub 2018 Jun 5.

Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, Hôpital Femme Mère Enfant, Boulevard Pinel, 69677, Bron, France.

Objective: Mineral and bone disorders associated to chronic kidney disease (CKD-MBD) are a daily challenge for pediatric nephrologists, with a significant risk of long-term bone and vascular comorbidities.

Methods: This single-center study is a prospective transversal evaluation of pediatric CKD patients of our center, part of the European 4C study. In addition to clinical and biochemical data, vascular and bone evaluation was performed: 24-h blood pressure assessment, carotid intima-media thickness (cIMT), pulse wave velocity (PWV), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the ultra-distal tibia. Results are presented as median (range).

Results: At a median age of 12.9 years (10.2-17.9), SDS height of - 1.0 (- 3.3-1.2) and estimated glomerular filtration rate (eGFR) of 33 mL/min/1.73m (11-72), 32 patients (8 girls) were evaluated. Median calcium, phosphate, parathyroid hormone (PTH), and 25 OHD3 levels were 2.44 mmol/L (2.24-2.78), 1.43 mmol/L (1.0-2.7), 80 pg/mL (9-359), and 70 nmol/L (32-116), respectively. Bivariate Spearman and backward multivariable analyses showed that calcium and bone trabecular thickness (Tb.Th), were positively associated with diastolic and mean arterial blood pressure (both for the 24 h, day and night assessment), whereas PTH and vitamin D did not predict blood pressure.

Conclusions: We show that the greater the serum levels of calcium, the greater the (diastolic and mean) blood pressure; moreover, the greater the Tb. Th, the greater the (diastolic and mean) blood pressure. The role of calcium supplements to explain such findings in early pediatric CKD can be discussed.
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September 2018

Faltering growth in the critically ill child: prevalence, risk factors, and impaired outcome.

Eur J Pediatr 2018 Mar 14;177(3):345-353. Epub 2017 Dec 14.

Paediatric Intensive Care Unit, Hôpital Universitaire Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Lyon-Bron, France.

Low body mass index (BMI) z score is commonly used to define undernutrition, but faltering growth allows for a complementary dynamic assessment of nutritional status. We studied the prevalence of undernutrition and faltering growth at admission in the pediatric intensive care (PICU) setting and their impacts on outcome. All (685) consecutive children (aged 0 to 18 years old) admitted in a single-center PICU over a 1-year period were prospectively enrolled. Nutritional status assessment was based on anthropometric measurements performed at admission and collected from medical files. Undernutrition was considered when z score BMI for age was < - 2SD. Faltering growth was considered when the weight for age curve presented a deceleration of > - 1 z score in the previous 3 months. Undernutrition was diagnosed in 13% of children enrolled, and faltering growth in 13.7% mostly in children with a normal BMI. Faltering growth was significantly associated with a history of underlying chronic disease, and independently with extended length of PICU stay in a multivariate analysis.

Conclusion: Assessment of nutritional status in critically ill children should include both undernutrition and faltering growth. This study highlights that faltering growth is independently associated with suboptimal outcome in PICU. What is Known: • Malnutrition, defined according to BMI-for-age z score, is correlated with poor outcome in the critically ill child. • In this setting, nutritional assessment should consist not only of a static assessment based on BMI-for-age z score but also of a dynamic assessment to identify recent faltering growth. What is New: • Critically ill children frequently present with faltering growth at admission. • Faltering growth is a newly identified independent associated factor of suboptimal outcome in this setting (extended length of stay).
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March 2018

A double-blind placebo-controlled randomised trial of omega-3 supplementation in children with moderate ADHD symptoms.

Eur Child Adolesc Psychiatry 2018 Mar 5;27(3):377-384. Epub 2017 Oct 5.

Service de Psychopathologie de l'enfant et de l'adolescent, Hôpital Pierre Wertheimer, 69500, Bron, France.

Objective: Clinical trials and inconclusive meta-analyses have investigated the effects of omega-3 supplements in children with Attention-Deficit Hyperactivity Disorder (ADHD). We performed a randomised placebo-controlled trial to evaluate the efficacy of omega-3 fatty acids.

Methods: Children aged 6-15 years with established diagnosis of ADHD were randomised 1:1 to receive either supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or a placebo for 3 months. Psychotropic or omega-3-containing treatments were not authorised during the study. The primary outcome was the change in the Attention-Deficit Hyperactivity Disorder Rating Scale version 4 (ADHD-RS-IV). Other outcomes included safety, lexical level (Alouette test), attention (Test of Attentional Performance for Children-KiTAP), anxiety (48-item Conners Parent Rating Scale-Revised-CPRS-R), and depression (Children's Depression Inventory-CDI).

Results: Between 2009 and 2011, 162 children were included in five French child psychiatry centres. The mean age was 9.90 (SD 2.62) years and 78.4% were boys. The inclusion ADHD-RS-IV at was 37.31 (SD 8.40). The total ADHD-RS-IV score reduction was greater in the placebo group than in the DHA-EPA group: -19 (-26, -12)  % and -9.7 (-16.6, -2.9) %, respectively, p = 0.039. The other components of the Conners score had a similar variation but the differences between groups were not significant. Two patients in the DHA-EPA group and none in the placebo group experienced a severe adverse event (hospitalisation for worsening ADHD symptoms).

Conclusion: This study did not show any beneficial effect of omega-3 supplement in children with mild ADHD symptoms.
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March 2018

Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF1 + ADHD) and ADHD Per Se.

J Atten Disord 2020 11 6;24(13):1807-1823. Epub 2017 Jun 6.

Laboratoire d'Étude des Mécanismes Cognitifs, EA 3082, Université de Lyon, Université Lumière-Lyon 2, Lyon, France.

To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. One group of children with NF1 + ADHD ( = 32), one group of children with ADHD ( = 31), and one group of healthy controls ( = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1.
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November 2020

Familial and syndromic lupus share the same phenotype as other early-onset forms of lupus.

Joint Bone Spine 2017 Oct 28;84(5):589-593. Epub 2016 Dec 28.

Immunologie et rhumatologie pédiatrique, Hôpital Necker, APHP, 75015 Paris, France. Electronic address:

Objective: Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE.

Methods: GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE ( #NCT01992666). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE (n=10) and familial SLE (n=12) - both presumed to have a strong genetic component - and other forms of early-onset SLE (n=42).

Results: The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE (P<0.05) and a lower frequency of joint manifestations in familial SLE.

Conclusions: In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability.
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October 2017

Management of adolescents with very poorly controlled type 1 diabetes by nurses: a parallel group randomized controlled trial.

Trials 2015 Sep 8;16:399. Epub 2015 Sep 8.

Endocrinologie, Diabétologie, Nutrition Pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, F-69677, Bron, France.

Backgrounds: Fluctuation in glycemia due to hormonal changes, growth periods, physical activity, and emotions make diabetes management difficult during adolescence. Our objective was to show that a close control of patients' self-management of diabetes by nurse-counseling could probably improve metabolic control in adolescents with type 1 diabetes.

Methods: We designed a multicenter, randomized controlled, parallel group, clinical trial. Seventy seven adolescents aged 12-17 years with A1C >8% were assigned to either an intervention group (pediatrician visit every 3 months + nurse visit and phone calls) or to the control group (pediatrician visit every 3 months). The primary outcome was the evolution of the rate of A1C during the 12 months of follow-up. Secondary outcomes include patient's acceptance of the disease (evaluated by visual analog scale), the number of hypoglycemic or ketoacidosis episodes requiring hospitalization, and evaluation of A1C rate over time in each group.

Results: Seventy-seven patients were enrolled by 10 clinical centers. Seventy (89.6%) completed the study, the evolution of A1C and participants satisfaction over the follow-up period was not significantly influenced by the nurse intervention.

Conclusion: Nurse-led intervention to improve A1C did not show a significant benefit in adolescents with type 1 diabetes because of lack of power. Only psychological management and continuous glucose monitoring have shown, so far, a slight but significant benefit on A1C. We did not show improvements in A1C control in teenagers by nurse-led intervention.

Trial Registration: Clinical registration number: NCT00308256, 28 March 2006.
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September 2015

The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial.

Orphanet J Rare Dis 2014 Sep 10;9:142. Epub 2014 Sep 10.

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of about 1/3000, independent of ethnicity, race, or gender. Attention Deficit Hyperactivity like Disorder (ADHD)-like characteristics are often reported in patients with NF1. We hypothesised that learning disabilities in NF1 children were related to ADHD symptoms. Treatment with methylphenidate (MPD) has improved learning disabilities in ADHD by acting on neurotransmitters. Our objective was to evaluate its efficacy on ADHD-like symptoms in neurofibromatosis type 1 children (7-12 years).

Methods: This was a randomised, double blind, placebo controlled, and crossover trial comparing 0.5 to 0.8 mg/kg/d of MPD as it is indicated for ADHD to placebo in NF1 children with ADHD-like symptoms. Children aged 7 to 12 years were eligible when their IQ was between 80 and 120. The total follow-up was 9 weeks including 4 weeks for each period and 1 week wash out. Fifty subjects (25 for each period) were required for testing the primary study hypothesis. The main outcome was an improvement in scores on the simplified Conners' Parent Rating Scale.

Results: Thirty-nine patients were included between April 2004 and December 2010. Twenty participants received MPD and 19 placebo during the first period. They all completed the trial. MPD decreased the simplified Conners by 3.9 points (±1.1, p = 0. 0003).

Conclusions: This is the first randomised controlled trial showing the short-term benefit of MPD on simplified Conners scores in NF1 children.

Trial Registration: NCT00169611.
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September 2014

[Public clinical trials: which kind of monitoring should be used?].

Therapie 2013 May-Jun;68(3):135-41. Epub 2013 Jul 26.

Service de Pharmacologie Clinique, Lyon, France.

Objective: Sponsors must take responsibility for the quality of trials at the best possible cost. Our objective was to describe the most frequent quality failures, how they impact trial results, and identify the most efficient monitoring strategies using published articles and reports.

Results: Errors affecting clinical trials include conception, procedures, data management, and data analysis. The consequences are usually an overestimation of the treatment effect. No study shows that monitoring reduces the risk of errors, and there is no comparison of monitoring methods. Many research organisations advocate for monitoring based on risk analysis and recommend an extensive use of centralised monitoring.

Conclusions: Trial quality depends on trial conception and design. Study conduct should guarantee a maximum level of quality level. This should be done using risk management and extensive centralised monitoring.
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September 2013