Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

International audienceLHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients' phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations

Cellular and molecular adaptations to exercise-induced inflammatory response in children with juvenile idiopathic arthritis

L'arthrite juvénile idiopathique (AJI) est une maladie rare chronique caractérisée par une inflammation persistante qui se manifeste par des douleurs articulaires, le gonflement des articulations et la limitation des mouvements articulaires. La fatigue et les douleurs entraînent une diminution de l'activité physique et une sédentarité accrue. Ce manque d'activité physique a pour conséquence une altération de la qualité de vie et une aggravation de la fatigue chronique, des troubles de l'humeur et des troubles métaboliques chez ces enfants. Les études sur les programmes d'exercices physiques montrent que l'exercice physique est bénéfique pour cette population. Mais les mécanismes d’action permettant de comprendre comment elle améliore la qualité de vie et la santé de l'enfant atteint d'arthrite juvénile idiopathique sont encore mal connus. Notre objectif était d’explorer la réponse physiologique à l’exercice des enfants et adolescents atteints d’arthrites juvéniles idiopathiques. Nous nous sommes intéressés principalement au métabolisme énergétique à l’exercice et à la fonction musculaire chez ces enfants. Nous avons étudié l’impact de la pathologie, des traitements par anti-TNF-α et de l’activité de la maladie sur ce métabolisme. Ensuite, nous avons étudié la sécrétion induite par l’exercice des myokines telles que l’IL-6 et les calgranulines en post exercice immédiat et dans les 24h suivant l’exercice.Juvenile idiopathic arthritis (JIA) is a rare chronic inflammatory disease characterized by persistent inflammation that is manifested by joint pain, swelling of the joints and limitation of range of motion. Fatigue and pain are the most frequent complaints in patients with JIA, lead to a decline in physical activity and a sedentary lifestyle of these children. This lack of physical activity results in impaired quality of life and worsening of chronic fatigue, mood disorders and metabolic disorders in these children. Studies of exercise programs show that exercise is beneficial for this population. But the mechanisms of action to understand how it improves the quality of life and health of children with juvenile idiopathic arthritis are still poorly understood. Our aim was to explore the physiological response to exercise in children and adolescents with juvenile idiopathic arthritis. We focused primarily on energy metabolism to exercise and muscle function in these children. We looked at the impact of the pathology, anti-TNF-α treatments and the activity of the disease on this metabolism. Next, we adressed the exercise-induced secretion of myokines such as IL-6 and calgranulins in immediate post exercise and within 24 hours after exercise

Acute intense exercise improves sleep and decreases next morning consumption of energy-dense food in adolescent girls with obesity and evening chronotype

Acute intense exercise improves sleep and decreases next morning consumption of energy-dense food in adolescent girls with obesity and evening chronotyp

Global and Regional Myocardial Work in Female Adolescents with Weight Disorders

Background: Anorexia nervosa (AN) and obesity (OB) lead to changes in SBP (i.e., loading conditions) that may affect left ventricular (LV) myocardial work (MW). The novel concept of LV pressure-strain loops allows non-invasive estimation of MW, this latter being correlated with cardiac energy metabolism. In addition, the study of regional MW can detect subtle alterations in cardiac function by highlighting an abnormal distribution of MW. Objective: The aim of this study was to assess the cardiac function of AN and OB patients by evaluating global and regional LV strains and MW. Methods: Eighty-seven female adolescents, comprising 26 with AN (14.6 ± 1.9 yrs. old), 28 with OB (13.2 ± 1.4 yrs. old), and 33 controls (14.0 ± 2.0 yrs. old) underwent speckle-tracking echography to assess global and regional LV strains and MW. Results: SBP was higher in adolescents with obesity than in AN patients or controls. Global MW was similar between groups. In AN patients and controls, longitudinal strains were higher at the apex than at the base of the LV, whereas they were similar in obesity patients, owing to a decrease in their apical longitudinal strain. Consequently, their MW was higher at the basal level than either of the other two groups (1854 ± 272 vs. 1501 ± 280 vs. 1575 ± 295 mmHg% in OB patients, AN patients, and controls, respectively. Conclusion: Despite altered SBP, the global MW of adolescents with weight disorders was unaffected. However, in adolescents with obesity, the distribution of their regional LV MW was altered, which might reflect specific regional remodeling

Calcium- and ADP-magnesium-induced respiratory uncoupling in isolated cardiac mitochondria : influence of cyclosporin A

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Urinary club cell protein 16 (CC16): Utility of its assay during acute bronchiolitis.

Acute bronchiolitis is responsible for high morbidity in infants. Club cell protein 16 kDa (CC16) is a major pneumoprotein secreted by club cells of the bronchial epithelium and eliminated by the renal pathway. CC16 seems to be a biomarker of epithelial damage in asthma. However, its value as a marker of acute bronchiolitis severity and later recurrent wheezing are uncertain, especially the value of its urinary assay for this purpose. A prospective, observational, analytical study was conducted at Clermont-Ferrand University Hospital to correlate serum CC16 level with clinical severity of bronchiolitis in hospitalized infants aged less than 1 year. We analyzed correlations between serum and urinary CC16, CC16 levels and Wainwright score, immediate morbidity due to bronchiolitis, causal viruses, and recurrent wheezing 1 year after inclusion. In 166 infants, serum CC16 did not correlate with acute bronchiolitis severity (P = .49), but urinary CC16 did (P < .001). In multivariate analysis, urinary CC16 correlated mainly with urinary retinol binding protein (RBP; r = 0.70; P < .001). The logCC16u/logRBPu ratio correlated significantly with severity (P = .02). CC16 levels were not correlated with recurrent wheezing at 1 year. Urinary CC16 could be a useful biomarker in acute bronchiolitis for specific indications. This noninvasive assay would be particularly useful in the young infant population. Several factors must be taken into account in its interpretation, mainly tubular function. Further studies are needed to assess these factors

Urinary club cell protein 16 (CC16): Utility of its assay during acute bronchiolitis

Acute bronchiolitis is responsible for high morbidity in infants. Club cell protein 16 kDa (CC16) is a major pneumoprotein secreted by club cells of the bronchial epithelium and eliminated by the renal pathway. CC16 seems to be a biomarker of epithelial damage in asthma. However, its value as a marker of acute bronchiolitis severity and later recurrent wheezing are uncertain, especially the value of its urinary assay for this purpose. A prospective, observational, analytical study was conducted at Clermont-Ferrand University Hospital to correlate serum CC16 level with clinical severity of bronchiolitis in hospitalized infants aged less than 1 year. We analyzed correlations between serum and urinary CC16, CC16 levels and Wainwright score, immediate morbidity due to bronchiolitis, causal viruses, and recurrent wheezing 1 year after inclusion. In 166 infants, serum CC16 did not correlate with acute bronchiolitis severity (P = .49), but urinary CC16 did (P < .001). In multivariate analysis, urinary CC16 correlated mainly with urinary retinol binding protein (RBP; r = 0.70; P < .001). The logCC16u/logRBPu ratio correlated significantly with severity (P = .02). CC16 levels were not correlated with recurrent wheezing at 1 year. Urinary CC16 could be a useful biomarker in acute bronchiolitis for specific indications. This noninvasive assay would be particularly useful in the young infant population. Several factors must be taken into account in its interpretation, mainly tubular function. Further studies are needed to assess these factors

Single Bout Exercise in Children with Juvenile Idiopathic Arthritis: Impact on Inflammatory Markers"

Objective. In a context of inflammatory disease such as juvenile idiopathic arthritis (JIA), we do not know what impact physical activity may have on a deregulated immune system. The objective is to measure the impact of a single bout of exercise on plasma inflammatory markers such as calprotectin, IL-6, sIL-6R, sgp130, and the hypothalamic-pituitary-adrenal axis in children with juvenile idiopathic arthritis. Methods. Twelve children with JIA performed a nonexercise control day and a consecutive day that included a 20 min exercise bout at 70% of max-HR at 08:30 am. Venous blood samples were taken at 08:30, 08:50, 09:30, 10:30 am, and 12:00 pm to measure plasma concentrations of calprotectin, IL-6, sIL-6R, sgp130, cortisol, and ACTH. Pain was evaluated at 08:30, 08:50 am, and 06:00 pm. Results. There was a transient twofold increase in postexercise self-evaluated pain () that disappeared in the evening. A single bout of exercise resulted in a 1.7-fold increase in plasma calprotectin () but not IL-6 and its soluble receptors. Calprotectin levels returned to baseline within 3 hours after cessation of exercise. Conclusion. Acute exercise in children with JIA induced slightly musculoskeletal leg pain and transient increased plasma calprotectin levels but not IL-6 levels

Inflammatory Response 24 h Post-Exercise in Youth with Juvenile Idiopathic Arthritis

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Sleep in children and adolescents with juvenile idiopathic arthritis: a systematic review and meta-analysis of case-control studies

International audienceAbstract Study Objectives Juvenile idiopathic arthritis (JIA) is one of the most common pediatric rheumatic disease. However, sleep alteration associated with this autoimmune disease remain unclear. We aimed in this systematic review and meta-analysis to compare sleep duration, quality, and architecture in JIA subjects with those in their healthy peers. Methods Systematic search performed in PubMed, EMBase, Cochrane, and PsycINFO databases included 19 studies in the qualitative synthesis of which 10 met the inclusion criteria for the meta-analysis. Results Pooled results from subjective methods indicated pronounced sleep disturbances and complaints in youth with JIA compared with their healthy counterparts. This was further confirmed by increased difficulty maintaining sleep (wake after sleep onset [WASO]; standardized mean differences [SMD]: −0.69; CI: −1.29 to −0.09, p = .02) and a tendency to increased difficulty initiating sleep (sleep onset latency [SOL]; SMD: −0.29; CI: −0.60 to 0.03, p = .07). There were no remarkable differences in sleep duration or sleep architecture between JIA patients and healthy controls. High heterogeneity was found for several outcomes. This could be explained by the different methods used as well as associated sleep disorders, medication, and comorbidities. Conclusions Although included studies were methodologically diverse, the summarized results of our review and meta-analysis bring evidence that children with JIA present more fragmented sleep compared to healthy peers. Thereby, the implementation of strategies to manage and improve sleep in this population are needed and might have a beneficial effect on the symptoms and functions of JIA. Statement of Significance We observed that youth with Juvenile idiopathic arthritis (JIA) present pronounced sleep disturbances compared to their healthy counterparts: Meta-analysis found more difficulty maintaining sleep and a tendency to increased sleep latency in youth with JIA. However, results show discrepancies due to the different materials and methods used. Larger sample and further disentanglement of sample composition, considering associated sleep disorders, medication and comorbidities should be addressed in future studies