[Puff alert: addiction to nicotine products among young people]. / Alerte aux puffs : addiction aux produits nicotiniques chez les jeunes.

Consumption of e-cigarettes (particularly the famous "puffs") and other nicotine products has risen sharply among Swiss teenagers, and now exceeds consumption of traditional cigarettes. Yet these products are harmful to health. Nicotine is highly addictive for young people, and e-cigarette use causes significant respiratory morbidity for both active and passive users. We are just measuring the extent of the toxic effects of these products, given their recent appearance on the market, but the initial scientific evidence is extremely worrisome and calls for a rapid response. Prevention among young people is crucial, and better legislation is urgently needed.

La consommation d'e-cigarettes (notamment des fameuses « puffs ¼) et d'autres produits nicotiniques a fortement augmenté chez les adolescents suisses, dépassant désormais la consommation de cigarettes traditionnelles. Ces produits sont pourtant nocifs pour la santé. La nicotine a un très fort pouvoir addictif chez les jeunes et la consommation d'e-cigarette induit une importante morbidité respiratoire pour les consommateurs actifs mais aussi passifs. Nous mesurons à peine l'étendue des effets toxiques de ces produits vue leur apparition récente sur le marché, mais les premiers éléments scientifiques sont extrêmement préoccupants et appellent à une réaction rapide. La prévention auprès des jeunes est capitale et un meilleur encadrement législatif nécessaire.

[Respiratory issues in children with severe neurological impairment]. / Atteinte respiratoire chez l'enfant en situation de polyhandicap sévère.

Respiratory problems have a significant impact on morbidity and mortality in children with severe neurological impairment. In particular, impaired airway clearance, recurrent respiratory infections, bronchial hyper reactivity can lead to acute decompensation and, with time, to chronic respiratory failure. Multiple coexisting and interacting factors that influence the respiratory status of these children should be recognized and effectively addressed to reduce respiratory morbidity and mortality. An accurate assessment involving a multidisciplinary approach and relatively simple interventions can lead to significant improvements in the quality of life of children as well as their parents and carers.

Les complications respiratoires ont un impact significatif sur la morbidité et la mortalité chez les enfants en situation de polyhandicap sévère. En particulier l'encombrement bronchique, les infections respiratoires récurrentes et l'hyperréactivité bronchique peuvent conduire à des décompensations aiguës et, avec le temps, à une insuffisance respiratoire chronique. De multiples facteurs coexistant et interagissant qui influencent l'état respiratoire de ces enfants doivent être reconnus et traités efficacement afin de réduire la morbidité et la mortalité respiratoires. Une évaluation précise impliquant une approche multidisciplinaire et des interventions relativement simples peuvent conduire à une amélioration significative de la qualité de vie de ces enfants ainsi que de leurs parents et tuteurs.

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism.

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian transcriptome, which in turn alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induce Klf10, which helps mitigate glucose intolerance and hepatic steatosis in mice challenged with a sugar beverage. Functional genomics further reveal that KLF10 target genes are primarily involved in central carbon metabolism. Together, these findings show that in the liver KLF10 integrates circadian timing and sugar metabolism-related signaling, and serves as a transcriptional brake that protects against the deleterious effects of increased sugar consumption.

MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice.

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor.

Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia.

SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.

Immunoadsorption in Anti-GBM Glomerulonephritis: Case Report in a Child and Literature Review.

Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a rare autoimmune disease that is characterized by rapidly progressive glomerulonephritis that may be associated with pulmonary hemorrhage. Anti-GBM GN is caused by autoantibodies (classically type G immunoglobulin) directed against the α3 subunit of type IV collagen. Without any appropriate treatment, the disease is generally fulminant, and patient and kidney survival is poor. The current guidelines recommend the use of plasma exchanges and immunosuppressive drugs. Immunoadsorption (IA) can remove pathogenic IgGs from the circulation and do not require plasma infusions, contrary to plasma exchanges. IA has seldom been used in adult patients with good tolerance and efficiency. We report herein the first pediatric case successfully treated with IA combined with immunosuppressive drugs in a 7-year-old girl who presented acute kidney injury (estimated glomerular filtration rate 38 mL/minute/1.73 m2). A kidney biopsy revealed numerous >80% glomerular crescents and linear IgG deposits along the glomerular basement membrane. Ten IA sessions led to rapid and sustained clearance of autoantibodies and improvement of kidney function until 21 months after onset (glomerular filtration rate 87 mL/minute/1.73 m2). No adverse effect was noted. This report adds to the growing body of evidence suggesting IA as a therapeutic alternative to plasma exchanges in anti-GBM GN. The other 27 published pediatric cases of anti-GBM GN are reviewed.

Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice.

The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression. Here we show that the non-circadian nuclear receptor and metabolic sensor Liver X Receptor alpha (LXRα) which is known to regulate glucocorticoid production in mice modulates the sex specific circadian pattern of plasma corticosterone. Lxrα(-/-) males display a blunted corticosterone profile while females show higher amplitude as compared to wild type animals. Wild type males are significantly slower than females to resynchronize their locomotor activity rhythm after an 8 h phase advance but this difference is abrogated in Lxrα(-/-) males which display a female-like phenotype. We also show that circadian expression patterns of liver 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and Phosphoenolpyruvate carboxykinase (Pepck) differ between sexes and are differentially altered in Lxrα(-/-) animals. These changes are associated with a damped profile of plasma glucose oscillation in males but not in females. Sex specific alteration of the insulin and leptin circadian profiles were observed in Lxα(-/-) females and could be explained by the change in corticosterone profile. Together this data indicates that LXRα is a determinant of sexually dimorphic circadian patterns of key physiological parameters. The discovery of this unanticipated role for LXRα in circadian physiology underscores the importance of addressing sex differences in chronobiology studies and future LXRα targeted therapies.

The hepatic circadian clock regulates the choline kinase α gene through the BMAL1-REV-ERBα axis.

The circadian timing system adapts most of the mammalian physiology and behaviour to the 24 h light/dark cycle. This temporal coordination relies on endogenous circadian clocks present in virtually all tissues and organs and implicated in the regulation of key cellular processes including metabolism, transport and secretion. Environmental or genetic disruption of the circadian coordination causes metabolic imbalance leading for instance to fatty liver, dyslipidaemia and obesity, thereby contributing to the development of a metabolic syndrome state. In the liver, a key metabolic organ, the rhythmic regulation of lipid biosynthesis is known, yet the molecular mechanisms through which the circadian clock controls lipogenesis, in particular, that of phospholipids, is poorly characterised. In this study, we show that the wild-type mice display a rhythmic accumulation of hepatic phosphatidylcholine with a peak at ZT 22-0 while clock-deficient Bmal1(-/-) mice show elevated phosphatidylcholine levels in the liver associated with an atherogenic lipoprotein profile. Profiling of the mRNA expression of enzymes from the Kennedy and phosphatidylethanolamine N-methyltransferase pathways which control the production of hepatic phosphatidylcholine revealed a robust circadian pattern for Chkα while other mRNA showed low amplitude (Chkß and Pemt) or no rhythm (Cctα and Chpt1). Chkα mRNA expression was increased and no longer rhythmic in the liver from clock-deficient Bmal1(-/-) mice. This change resulted in the upregulation of the CHKα protein in these animals. We further show that the robust circadian expression of Chkα is restricted to the liver and adrenal glands. Analysis of the Chkα gene promoter revealed the presence of a conserved response element for the core clock transcription factors REV-ERB and ROR. Consistent with the antiphasic phase relationship between Chkα and Rev-erbα expression, in cotransfection experiments using HepG2 cells we show that RORα4-dependent transactivation of this element is repressed by REV-ERBα· Correspondingly, Rev-erbα(-/-)mice displayed higher Chkα mRNA levels in liver at ZT 12. Collectively, these data establish that hepatic phosphatidylcholine is regulated by the circadian clock through a Bmal1-Rev-erbα-Chkα axis and suggest that an intact circadian timing system is important for the temporal coordination of phospholipid metabolism.

Can we simplify the hospital accreditation process? Predicting accreditation decisions from a reduced dataset of focus priority standards and quality indicators: results of predictive modelling.

OBJECTIVES: Accreditation in France relies on a mandatory 4-year cycle of self-assessment and a peer review of 82 standards, among which 14 focus priority standards (FPS). Hospitals are also required to measure yearly quality indicators (QIs-5 in 2010). On advice given by the accreditation committee of HAS (Haute Autorité en Santé), based on surveyors proposals and relying mostly on compliance to standards, accreditation decisions are taken by the board of HAS. Accreditation is still perceived by hospitals as a burdensome process and a simplification would be welcomed. The hypothesis was that a more limited number of criteria might give sufficient amount of information on hospitals overall quality level, appraised today by accreditation decisions. DESIGN: The accuracy of predictions of accreditation decisions given by a model, Partial Least Square-2 Discriminant Analysis (PLS2-DA), using only the results of FPS and QIs was measured. Accreditation decisions (full accreditation (A), recommendations or reservation (B), remit decision or non-accreditation (C)), results of FPS and QIs were considered qualitative variables. Stability was assessed by leave one out cross validation (LOOCV). SETTING AND PARTICIPANTS: All French 489 acute care organisations (ACO) accredited between June 2010 and January 2012 were considered, 304 of them having a rehabilitation care sector (RCS). RESULTS: Accuracy of prediction of accreditation decisions was good (89% of ACOs and 91% of ACO-RCS well classified). Stability of results appeared satisfactory when using LOOCV (87% of ACOs and 89% of ACO-RCS well classified). Identification of worse hospitals was correct (90% of ACOs and 97% of ACO-RCS predicted C were actually C). CONCLUSIONS: Using PLS2-DA with a limited number of criteria (QIs and FPS) provides an accurate prediction of accreditation decisions, especially for underperforming hospitals. This could support accreditation committees which give advices on accreditation decisions, and allow fast-track handling of 'safe' reports.

Constructing a composite quality score for the care of acute myocardial infarction patients at discharge: impact on hospital ranking.

OBJECTIVE: To determine the impact on hospital ranking of different aggregation methods when creating a composite score from a set of quality indicators relating to a single clinical condition. DESIGN: The analysis was based on 14966 medical records taken from all French hospitals that treated over 30 patients with acute myocardial infarction in 2008 (n=275). Five quality indicators measuring the quality of care delivered to patients with acute myocardial infarction at hospital discharge were aggregated by 5 methods issued from a variety of activity sectors (indicator average, all-or-none, budget allocation process, benefit of the doubt, and unobserved component model). MAIN OUTCOME MEASURES: Each aggregation method was used to rank hospitals into 3 categories depending on the position of the 95% confidence interval of the composite score relative to the overall mean. Variations in rank according to method were estimated using weighted κ coefficients. RESULTS: Agreement between methods ranged from poor (κ=0.20) to almost perfect (κ=0.84). A change of method led to a change in rank for 71% (196 of 275) of hospitals. Only 14 of 121 hospitals which were ranked top and 20 of 118 which were ranked bottom, by at least 1 of the 5 methods, held their rank on a switch to the 4 other methods. CONCLUSION: Hospital ranking varied widely according to 5 aggregation methods. If one method has to be chosen, for instance for reporting to governments, regulatory agencies, payers, health care professionals, and the public, it is necessary to provide its rationale and characteristics, and information on score uncertainty.