The role of nutrition in non-alcoholic fatty liver disease treatment in obese children.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs mostly in the context of insulin resistance and obesity. It has rapidly evolved into the most common cause of liver disease among children. The incidence is high in obese children and a greater risk of disease progression is associated with severe obesity, highlighting the role of nutrition. To date, there is no consensus on NAFLD management. This is a narrative review of clinical studies on the potential benefit of nutritional interventions, including lifestyle modifications, vitamins, docosahexaenoic acid, and probiotics in children with NAFLD. The Comité de nutrition de la Société Française de Pédiatrie (CN-SFP) emphasizes the effect of limiting added sugar intake, i.e., fructose or sucrose-containing beverages, and promoting physical activity in the care of NAFLD.

Transient postnatal over nutrition induces long-term alterations in cardiac NLRP3-inflammasome pathway.

BACKGROUND AND AIMS: The prevalence of obesity is increasing worldwide at an alarming rate. Altered early nutrition, in particular postnatal overfeeding (PNOF), is a risk factor for impaired cardiac function in adulthood. In the understanding of the initiation or progression of heart diseases, NLRP3 inflammasome and non-coding RNAs have been proposed as key players. In this context, the aim of this study was to decipher the role of NLRP3 inflammasome and its post transcriptional control by micro-RNAs in the regulation of cardiac metabolic function induced by PNOF in mice. METHODS AND RESULTS: Based on a model of mice exposed to PNOF through litter size reduction, we observed increased cardiac protein expression levels of NLRP3 and ETS-1 associated with alterations in insulin signaling. Additionally, miR-193b levels were down-regulated in the adult hearts of overfed animals. In a cardiomyocyte cell line, transfection with miR-193b induced down-regulation of ETS-1 and NLRP3 and improved insulin signaling. CONCLUSIONS: These findings suggest that the miR-193b could be involved in cardiac phenotypic changes observed in adulthood induced by PNOF likely through the regulation of ETS-1 and NLRP3 expression, and through this of insulin signaling.

Parenteral nutrition for preterm infants: Issues and strategy.

Due to transient gut immaturity, most very preterm infants receive parenteral nutrition (PN) in the first few weeks of life. Yet providing enough protein and energy to sustain optimal growth in such infants remains a challenge. Extrauterine growth restriction is frequently observed in very preterm infants at the time of discharge from hospital, and has been found to be associated with later impaired neurodevelopment. A few recent randomized trials suggest that intensified PN can improve early growth; whether or not such early PN improves long-term neurological outcome is still unclear. Several other questions regarding what is optimal PN for very preterm infants remain unanswered. Amino acid mixtures designed for infants contain large amounts of branched-chain amino acids and taurine, but there is no consensus on the need for some nonessential amino acids such as glutamine, arginine, and cysteine. Whether excess growth in the first few weeks of life, at a time when very preterm infants receive PN, has an imprinting effect, increasing the risk of metabolic or vascular disease at adulthood continues to be debated. Even though uncertainty remains regarding the long-term effect of early PN, it appears reasonable to propose intensified initial PN. The aim of the current position paper is to review the evidence supporting such a strategy with regards to the early phase of nutrition, which is mainly covered by parenteral nutrition. More randomized trials are, however, needed to further support this type of approach and to demonstrate that this strategy improves short- and long-term outcome.

Vitamin A in pediatrics: An update from the Nutrition Committee of the French Society of Pediatrics.

Vitamin A (retinol) fulfills multiple functions in vision, cell growth and differentiation, embryogenesis, the maintenance of epithelial barriers and immunity. A large number of enzymes, binding proteins and receptors facilitate its intestinal absorption, hepatic storage, secretion, and distribution to target cells. In addition to the preformed retinol of animal origin, some fruits and vegetables are rich in carotenoids with provitamin A precursors such as ß-carotene: 6µg of ß-carotene corresponds to 1µg retinol equivalent (RE). Carotenoids never cause hypervitaminosis A. Determination of liver retinol concentration, the most reliable marker of vitamin A status, cannot be used in practice. Despite its lack of sensitivity and specificity, the concentration of retinol in blood is used to assess vitamin A status. A blood vitamin A concentration below 0.70µmol/L (200µg/L) indicates insufficient intake. Levels above 1.05µmol/L (300µg/L) indicate an adequate vitamin A status. The recommended dietary intake increases from 250µg RE/day between 7 and 36 months of age to 750µg RE/day between 15 and 17 years of age, which is usually adequate in industrialized countries. However, intakes often exceed the recommended intake, or even the upper limit (600µg/day), in some non-breastfed infants. The new European regulation on infant and follow-on formulas (2015) will likely limit this excessive intake. In some developing countries, vitamin A deficiency is one of the main causes of blindness and remains a major public health problem. The impact of vitamin A deficiency on mortality was not confirmed by the most recent studies. Periodic supplementation with high doses of vitamin A is currently questioned and food diversification, fortification or low-dose regular supplementation seem preferable.

[Oxidative stress after preterm birth: origins, biomarkers, and possible therapeutic approaches]. / Stress oxydant chez l'enfant prématuré : causes, biomarqueurs et possibilités thérapeutiques.

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview.

Premature births are increasing worldwide (about 15 millions per year) due to several reasons (an advanced maternal age, fertility treatments, stress, smoking, nutritional deficiencies) and lead to a high societal overall cost. Among neonatal care procedures, the clinical nutrition practices are essential to promote the development and to minimize the sequelae. Premature newborns are at major risk of death by infections due to the immaturity of their intestine. Human milk provides not only nutrients but also a plethora of biologically active components that are tailored to contribute to the development of the intestinal tract early in postnatal life. Among them, some bioactive molecules exhibit trophic effects (LC­PUFA, sphingomyelin, IGF­I and IGF­II, EGF, insulin, leptin, adiponectin, lactoferrin, lactadherin, probiotics, prebiotics, miRNA) or are part of the intestinal cell membranes (PUFA, LC­PUFA, phospholipids, sphingolipids, cholesterol), others educate the intestine for innate microbial recognition (sCD14, sTLR­2, miRNA), many of them display direct fighting against pathogens (some fatty acids and monoglycerides, some phospholipids and sphingolipids, BSSL, insulin, lactoferrin, sIgAs, MUC­1, lactadherin, probiotics, prebiotics), or contribute to establish the gut microbiota (LC­PUFA, lactoferrin, probiotics, prebiotics). A synergetic action exists between several bioactive molecules. All together these precious agents regulate the maturation of the intestinal mucosal barrier, and might program early in postnatal life the future adult intestinal health. This review lists the main bioactive compounds and addresses their plausible roles and mechanisms of action.

[Breastfeeding: health benefits for child and mother]. / Allaitement maternel: les bénéfices pour la santé de l'enfant et de sa mère.

The prevalence of breastfeeding in France is one of the lowest in Europe: 65% of infants born in France in 2010 were breastfed when leaving the maternity ward. Exclusive breastfeeding allows normal growth until at least 6 months of age, and can be prolonged until the age of 2 years or more, provided that complementary feeding is started after 6 months. Breast milk contains hormones, growth factors, cytokines, immunocompetent cells, etc., and has many biological properties. The composition of breast milk is influenced by gestational and postnatal age, as well as by the moment of the feed. Breastfeeding is associated with slightly enhanced performance on tests of cognitive development. Exclusive breastfeeding for at least 3 months is associated with a lower incidence and severity of diarrhoea, otitis media and respiratory infection. Exclusive breastfeeding for at least 4 months is associated with a lower incidence of allergic disease (asthma, atopic dermatitis) during the first 2 to 3 years of life in at-risk infants (infants with at least one first-degree relative presenting with allergy). Breastfeeding is also associated with a lower incidence of obesity during childhood and adolescence, as well as with a lower blood pressure and cholesterolemia in adulthood. However, no beneficial effect of breastfeeding on cardiovascular morbidity and mortality has been shown. Maternal infection with hepatitis B and C virus is not a contraindication to breastfeeding, as opposed to HIV infection and galactosemia. A supplementation with vitamin D and K is necessary in the breastfed infant. Very few medications contraindicate breastfeeding. Premature babies can be breastfed and/or receive mother's milk and/or bank milk, provided they receive energy, protein and mineral supplements. Return to prepregnancy weight is earlier in breastfeeding mothers during the 6 months following delivery. Breastfeeding is also associated with a decreased risk of breast and ovarian cancer in the premenopausal period, and of osteoporosis in the postmenopausal period.

[Malnutrition screening in clinical practice]. / Dépister la dénutrition de l'enfant en pratique courante.

Protein energy malnutrition (PEM) occurs when energy and protein intake do not meet requirements. It has a functional and structural impact and increases both morbidity and mortality of a given disease. The Nutrition Committee of the French Pediatric Society recommends weighing and measuring any child when hospitalized or seen in consultation. The body mass index (BMI) must be calculated and analyzed according to references any time growth kinetics cannot be analyzed. Any child with a BMI below the third centile or -2 standard deviations for age and sex needs to be examined looking for clinical signs of malnutrition and signs orienting toward an etiology and requires having his BMI and height dynamics plotted on a chart. PEM warrants drawing up a nutritional strategy along with the overall care plan. A target weight needs to be determined as well as the quantitative and qualitative nutritional care including its implementation. This plan must be evaluated afterwards in order to adapt the nutritional therapy.

Vitamin D: still a topical matter in children and adolescents. A position paper by the Committee on Nutrition of the French Society of Paediatrics.

The aims of the present position paper by the Committee on Nutrition of the French Society of Paediatrics were to summarize the recently published data on vitamin D in infants, children and adolescents, i.e., on metabolism, physiological effects, and requirements and to make recommendations on supplementation after careful review of the evidence. Scientific evidence indicates that calcium and vitamin D play key roles in bone health. The current evidence, limited to observational studies, however, does not support other benefits for vitamin D. More targeted research should continue, especially interventional studies. In the absence of any underlying risk of vitamin D deficiency, the recommendations are as follows: pregnant women: a single dose of 80,000 to 100,000 IU at the beginning of the 7th month of pregnancy; breastfed infants: 1000 to 1200 IU/day; children less than 18 months of age, receiving milk supplemented with vitamin D: an additional daily dose of 600 to 800 IU; children less than 18 months of age receiving milk not supplemented with vitamin D: daily dose of 1000 to 1200 IU; children from 18 months to 5 years of age: 2 doses of 80,000 to 100,000 IU every winter (November and February). In the presence of an underlying risk of vitamin D deficiency (dark skin; lack of exposure of the skin to ultraviolet B [UVB] radiation from sunshine in summer; skin disease responsible for decreased exposure of the skin to UVB radiation from sunshine in summer; wearing skin-covering clothes in summer; intestinal malabsorption or maldigestion; cholestasis; renal insufficiency; nephrotic syndrome; drugs [rifampicin; antiepileptic treatment: phenobarbital, phenytoin]; obesity; vegan diet), it may be justified to start vitamin D supplementation in winter in children 5 to 10 years of age as well as to maintain supplementation of vitamin D every 3 months all year long in children 1 to 10 years of age and in adolescents. In some pathological conditions, doses of vitamin D can be increased. If necessary, the determination of 25(OH) vitamin D serum concentration will help determine the level of vitamin D supplementation.

The French Society of Neonatology's proposals for neonatal end-of-life decision-making.

BACKGROUND: Opinions and practice regarding end-of-life decisions in neonatal medicine show considerable variations between countries. A recent change of the legal framework, together with an ongoing debate among French neonatologists, led the French Society of Neonatology to reconsider and update its previous recommendations. OBJECTIVES: To propose a set of recommendations on the ethical principles to be respected in the making and application of end-of-life decisions. METHODS: A multidisciplinary working group on ethical issues in perinatal medicine composed of neonatologists, obstetricians and ethicists. RESULTS: Withholding or withdrawing life-sustaining treatment may be acceptable, and unreasonable therapeutic obstinacy is condemned. This implies that the child's best interests must always be the central consideration. Although the parents must be involved in the decision process so that they form an alliance with the healthcare team, and a collegial approach is of utmost importance, any crucial decision affecting the patient's life calls for individual medical responsibility. Because every newborn is rightfully an integral member of a human family, his or her dignity must be preserved. The goal of palliative care is to preserve the quality of a life, also at its end. The intention underlying an act has to be analyzed perceptively. Euthanasia, i.e. to perform an act with the deliberate intention to cause or hasten a patient's death, is legally and morally forbidden. Conversely, to withhold or withdraw a life-sustaining treatment can be justified when the intention is to cease opposing, in an unreasonable manner, the natural course of a disease. CONCLUSIONS: This statement provides the principles identified by French neonatologists on which to base their decisions concerning the ending of life. Arguments are set forth, discussed and compared with international statements and previously published considerations.

[Very premature births: Dilemmas and management. Part 1. Outcome of infants born before 28 weeks of postmenstrual age, and definition of a gray zone]. / Naissances très prématurées : dilemmes et propositions de prise en charge. Première partie : pronostic des naissances avant 28 semaines, identification d'une zone grise.

With very preterm deliveries, the decision to institute intensive care, or, alternatively, to start palliative care and let the baby die, is extremely difficult, and involves complex ethical issues. The introduction of intensive care may result in long-term survival of many infants without severe disabilities, but it may also result in the survival of severely disabled infants. Conversely, the decision to withhold resuscitation and/or intensive care at birth, which is an option at the margin of viability, implies allowing babies to die, although some of them would have developed normally if they had received resuscitation and/or intensive care. Withholding intensive care at birth does not mean withholding care but rather providing palliative care to prevent pain and suffering during the time period preceding death. The likelihood of survival without significant disabilities decreases as gestational age at birth decreases. In addition to gestational age, other factors greatly influence the prognosis. Indeed, for a given gestational age, higher birth weight, singleton birth, female sex, exposure to prenatal corticosteroids, and birth in a tertiary center are favorable factors. Considering gestational age, there is a gray zone that corresponds to major prognostic uncertainty and therefore to a major problem in making a "good" decision. In France today, the gray zone corresponds to deliveries at 24 and 25 weeks of postmenstrual age. In general, babies born above the gray zone (26 weeks of postmenstrual age and later) should receive resuscitation and/or full intensive care. Below 24 weeks, palliative care is the only option offered in France at the present time. Decisions within the gray zone will be addressed in the 2nd part of this work.

[Very premature births: Dilemmas and management. Second part: Ethical aspects and recommendations]. / Naissances très prématurées : dilemmes et propositions de prise en charge. Seconde partie : enjeux éthiques, principes de prise en charge et recommandations.

In the first part of this work, the outcome following very premature birth was assessed. This enabled a gray zone to be defined, with inherent major prognostic uncertainty. In France today, the gray zone corresponds to deliveries occurring at 24 and 25 weeks of postmenstrual age. The management of births occurring below and above the gray zone was described. Withholding intensive care at birth for babies born below or within the gray zone does not mean withholding care but rather providing palliative care to prevent pain and suffering during the time period preceding death. Given the high level of uncertainty, making good decisions within the gray zone is problematic. Decisions should be based on the infant's best interests. Decisions should be reached with the parents, who are entitled to receive clear and comprehensive information. Possible decisions to withhold intensive care should be made following the procedures described in the French law of April 2005. Guidelines, based on gestational age and the other prognostic elements, are proposed to the parents before birth. They are applied in an individualized fashion, in order to take into account the individual features of each case. At 25 weeks, resuscitation and/or full intensive care are usually proposed, unless unfavorable factors, such as severe growth restriction, are associated. A senior neonatologist will attend the delivery and will make decisions based on both the baby's condition at birth and the parents' wishes. At 24 weeks, in the absence of unfavorable associated factors, the parents' wishes should be followed in deciding between initiating full intensive care or palliative care. Below 24 weeks, palliative care is the only option to be offered in France at the present time.

[Implementing palliative care for newborns in various care settings. Part 3 of "Palliative care in the neonatal period"]. / La mise en oeuvre pratique des soins palliatifs dans les différents lieux de soins : 3(e) partie des réflexions et propositions autour des soins palliatifs en période néonatale.

Palliative care in newborns may take place in the delivery room and then continued either in maternity wards or in the neonatal unit. For babies developing a chronic condition, going home may be advantageous. The population concerned includes babies born with a severe intractable congenital malformation and certain extremely preterm newborn babies at the limits of viability. Care procedures as well as withholding and withdrawing treatments are reviewed.

Cullins in human intra-uterine growth restriction: expressional and epigenetic alterations.

Intra-uterine growth restriction (IUGR) is defined by a restriction of fetal growth during gestation. It is a prevalent significant public health problem that jeopardizes neonatal health but also that can have deleterious consequences later in adult life. Cullins constitute a family of seven proteins involved in cell scaffold and in selective proteolysis via the ubiquitin-proteasome system. Most Cullins are critical for early embryonic development and mutations in some Cullin genes have been identified in human syndromes including growth retardation. Our work hypothesis is that Cullins, particularly CUL4B and CUL7, are involved in placental diseases and especially in IUGR. Thus, expression of Cullins and their cofactors was analyzed in normal and pathological placentas. We show that they present a constant significant over-expression in IUGR placentas, whose extent is dependent on the position of the interrogated fragment along the cDNAs, suggesting the existence of different isoforms of the genes. Particularly, the CUL7 gene is up-regulated up to 10 times in IUGR and 15 times in preeclampsia associated with IUGR. The expression of cofactors of Cullins participating to functional complexes has also been evaluated and showed a similar significant increase in IUGR. Promoters of Cullin genes appeared to be under the control of the SP1 transcription factor. Finally, methylation levels of the CUL7 promoter in placental tissues are modulated according to the pathological conditions, with a significant hypomethylation in IUGR. These results concur to pinpoint the Cullin family as a new set of markers of IUGR.

Antioxidant status of neonates exposed in utero to tobacco smoke.

To investigate the influence of maternal smoke exposure on neonatal and maternal antioxidant status, 39 mothers who were active smokers, 14 mothers exposed to environmental tobacco smoke (ETS), 17 controls, and their newborns were included in a prospective, controlled study. Plasma total antioxidant capacity, measured as total radical-trapping antioxidant parameter (TRAP) and ferric reducing antioxidant power (FRAP), and concentrations of specific antioxidants were measured in cord and in maternal blood. A similar, significant increase in ceruloplasmin concentration was observed in neonates born to actively smoking mothers and in those born to ETS exposed mothers. Uric acid and TRAP concentrations were significantly increased in ETS-exposed newborns and their mothers, compared to newborns and mothers from the active smoking and no-exposure groups with a trend towards increased uric acid, TRAP and FRAP concentrations being observed in the active smokers group. Neonatal and maternal antioxidant concentrations correlated significantly, except for ceruloplasmin. Cord blood vitamin A, E and C concentrations were unaffected by smoke exposure. These results show that maternal active smoking as well as ETS exposure significantly affect neonatal and maternal antioxidant status.

[Efficacy of early cerebral MR in the detection of brain lesions in high risk preterm infants compared with conventional US]. / Apporti della Risonanza Magnetica cerebrale precoce rispetto all'ecografia nella sorveglianza neurologica del grande prematuro.

To identify the efficacy of early cerebral MR, performed in the first month of birth, in the detection of brain lesions in high risk preterm infants, compared with conventional US, we recruited into the study a group of 30 preterm infants born at or below a gestational age of 30 weeks, who had a pathologic scan. The findings on US were compared with those of the early MR scan, performed in the same days, the results of which were considered as the final diagnosis. The value of cranial US as a predictor of MR signal intensity was assessed by calculating sensitivity, specificity, positive and negative predictive values. Agreement between two investigations was evaluated by calculating the K coefficient. US showed 33 haemorrhagic lesions in 25 preterms; MR showed 27 haemorrhagic lesions in 22 infants: in 16 cases MR gave the same results of US. Cranial US was reliable in detecting lesions such as GLH and IVH, but less sensitive in the definition of their size and distribution. Sensitivity of US for haemorrhagic lesions was 96.3%, PPV 78.8%, K coefficient 0.55 (p < 0.001). About the White Matter, cranial US demonstrated 20 lesions in 20 preterms; MR showed 16 lesions in 16 infants: in 3 cases MR was agree to US. US showed high reliability in the detection of cystic lesions, but significant limitations in the demonstration of non-cystic injury. We founded that normal WM echogenicity on US is not a good predictor of normal WM signal intensity on MR (30%). Sensitivity of US for WM lesions was 81.3%, PPV 65%, K coefficient 0.23 (p = 0.04). Finally US showed 4 lesions in other brain locations, MR confirmed 3 of them and discovered other 10. Sensitivity of US for these lesions was 23.1%, PPV 75%, K coefficient 0.21 (p = 0.11). We founded that cranial US is a good method for detecting GLH, IVH, HPI and severe WM lesions (cystic PVL), but it can miss non-cystic PVL, punctate haemorrhages, WMD and lesions in other brain locations, that, on the other hand, MR detects clearly.

Renal effects of antenatally or postnatally administered steroids.

Steroids administrated antenatally to the mothers improve postnatal outcomes of the newborns with pleiotropic effects. Furthermore steroids have been used in preterm infants to prevent or treat chronic lung disease. Synthetical glucocorticoids readily cross placental barrier and reach significant pharmacologic levels in the fetus: besides their well known pulmonary effects they have a concomitant maturational effect of postnatal renal function in preterm infants both with a direct and indirect effect. Endogenous and exogenous glucocorticoids play a role in the maintenance of glomerular filtration (GFR). The antenatal administration of steroids increases the GFR, in association to the maturation of the tubular function. According to different studies the improvement of renal function, expressed by the increase of GFR, is only partially referable to the increase of MAP and the improvement of the cardiovascular status, while it was imputable to a direct renal effect of the steroids, especially on the renal blood flow, on functional glomerular surface area available for filtration and on the glomerular filtrate of the single cortical nephron. However debate remains about the mechanism through which steroids would act on the renal vascular smooth muscolature. The increase the GFR observed after the antenatal administration of glucocorticoids in premature fetuses is also accompanied by an increase of urinary flow and of fractional excretion of sodium. Glucocorticoids would increase the proximal reabsorption of sodium increasing directly the function and the expression of the sodium transporters and both indirectly and directly increasing the activity of Na-K-ATPase. In extremely low weight antenatal administration of betamethasone or dexamethasone was associated with lower estimated insensible water loss, secondary to a direct maturational effect in the skin epithelial barrier, as well as an increased reabsorption of the fetal lung fluid. Moreover antenatal glucocorticoid administration was associated, at birth, to a significant suppression of plasma renin activity and angiotensin II in comparison to the controls. Despite the wide use of the steroidal therapy in the prevention of the bronchopulmonary dysplasia, only few articles, in literature, analyse the effects of glucocorticoids on postnatal renal function, such as the increase in urinary flow. The authors think that steroids contribute in a meaningful way to the clinical improvement observed in children with BPD through the maturative action on the premature kidney with effect both at glomerular and tubular level.