Influence of a lifestyle intervention in preschool children on physiological and psychological parameters (Ballabeina): study design of a cluster randomized controlled trial.

Childhood obesity and physical inactivity are increasing dramatically worldwide. Children of low socioeconomic status and/or children of migrant background are especially at risk. In general, the overall effectiveness of school-based programs on health-related outcomes has been disappointing. A special gap exists for younger children and in high risk groups. This paper describes the rationale, design, curriculum, and evaluation of a multicenter preschool randomized intervention study conducted in areas with a high migrant population in two out of 26 Swiss cantons. Twenty preschool classes in the German (canton St. Gallen) and another 20 in the French (canton Vaud) part of Switzerland were separately selected and randomized to an intervention and a control arm by the use of opaque envelopes. The multidisciplinary lifestyle intervention aimed to increase physical activity and sleep duration, to reinforce healthy nutrition and eating behaviour, and to reduce media use. According to the ecological model, it included children, their parents and the teachers. The regular teachers performed the majority of the intervention and were supported by a local health promoter. The intervention included physical activity lessons, adaptation of the built infrastructure; promotion of regional extracurricular physical activity; playful lessons about nutrition, media use and sleep, funny homework cards and information materials for teachers and parents. It lasted one school year. Baseline and post-intervention evaluations were performed in both arms. Primary outcome measures included BMI and aerobic fitness (20 m shuttle run test). Secondary outcomes included total (skinfolds, bioelectrical impedance) and central (waist circumference) body fat, motor abilities (obstacle course, static and dynamic balance), physical activity and sleep duration (accelerometry and questionnaires), nutritional behaviour and food intake, media use, quality of life and signs of hyperactivity (questionnaires), attention and spatial working memory ability (two validated tests). Researchers were blinded to group allocation. The purpose of this paper is to outline the design of a school-based multicenter cluster randomized, controlled trial aiming to reduce body mass index and to increase aerobic fitness in preschool children in culturally different parts of Switzerland with a high migrant population. Trial Registration: (clinicaltrials.gov) NCT00674544.

Activity and exploratory behavior after lesions of the medial entorhinal cortex in the woodmouse (Apodemus sylvaticus).

The effects of bilateral electrolytic lesions of the entorhinal cortex were studied in male adult woodmice. Experiments were designed to allow separate analysis of the basal activity level and exploratory behavior. Activity recording was conducted in three situations: (a) 24-hr wheel running in the home cage pre- and postoperatively; (b) 24-hr activity composition in a large enclosure over 4 days, 5 to 9 days postoperatively; and (c) sequence and duration of visits in a residential plus maze 11 to 14 days postoperatively. Medial entorhinal cortex lesion involving the para- and presubiculum increased the 24-hr amount of movements in the enclosure (b) without increasing wheel running in any situation (a or b). This lesion also enhanced the locomotor reactivity to being introduced into the plus maze and impaired exploratory behavior. This last effect was equally apparent when the whole situation was new or when part of the familiar maze was modified. Lesioned woodmice did notice the new element but did not show active focalization of their behavior on that element. Data showed that lesion induced hyperactivity and changes of exploratory behavior were not necessarily associated. Novelty detection was performed but it is not clear now on what information this discrimination was based.

The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation.

The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.

The concept of instability: a French perspective on the concept of ADHD.

Historical references to the emergence of the current concept of ADHD typically cite descriptions from medical textbooks by Weikard (1775) and Crichton (An inquiry into the nature and origin of mental derangement: Comprehending a concise system of the physiology and pathology of the human mind and a history of the passion and their affects. Cardell Jr and Davies, Londres, 1798) on attention disorders, poems of Hoffman on hyperactive and impulsive behaviors (Der Struwwelpeter. Frankfurt am Main, Literarische Anstalt, 1843), as well as the work of Still (Lancet 1:1008-1012, 1077-1082, 1163-1168, 1902a, Lancet 159(4102):1008-1013, 1902b, Lancet 159(4103):1077-1082, 1902c, Lancet 159(4104):1163-1168, 1902d) on impulsive behaviors and defective moral regulation of behavior. The notion of "instability" developed by French physicians between 1887 and 1910 is rarely mentioned and often ignored. Writings from this period show that in France, the emergence of the concept of ADHD according to modern terminology comes from the notion of "mental instability" introduced in the 1890s under the leadership of Désiré-Magloire Bourneville at the Hospital Bicêtre in Paris, based on his observations of children and adolescents who had been labeled "abnormal" and placed in medical and educational institutions. In the early twentieth century, elaborating on the observations of Bourneville, Jean Phillipe and Georges Paul-Boncour showed the presence of a subgroup of "unstable" children who suffered from a disease entity in its own right within the population of "abnormal" schoolchildren (the terminology of the time). This new pathological entity included symptoms of hyperactivity, impulsivity and inattention, corresponding to today's classic triad of ADHD symptoms. While noting the lack of behavioral inhibition, clinical descriptions of Bourneville, Philip and Paul-Boncour also considered the notion of "moral disorder" which at that time played an important role in psychopathology. This resulted in some degree of confusion between impulsive symptoms and major behavioral disturbances often associated with ADHD.

Investigating mineralocorticoid hypertension.

About 3% of our hypertensive patients have high blood pressure induced by corticosteroids. Muscle weakness, tiredness, polyuria and polydipsia may indicate hypokalaemia. Hypokalaemic hypertension in the presence of a low plasma renin activity is the typical finding of corticosteroid hypertension. The most frequent cause of corticosteroid hypertension is primary aldosteronism (Conn's syndrome) due to an adrenal adenoma or bilateral hyperplasia of the adrenal glands. The plasma concentration of aldosterone and the ratio between plasma aldosterone and renin concentrations are high, and the kaliuresis exceeds 30 mmol/24 h in the presence of hypokalaemia. Adrenal carcinomas are rare and very malignant. The localization of an adrenal tumour is made by computer tomography (CT-scan) or nuclear magnetic resonance imaging and by measurement of the aldosterone/cortisol concentrations in the adrenal venous blood. Adenomas are removed under laparoscopy, and adrenal hyperplasias are treated with spironolactone (50-400 mg daily) or amiloride (5-30 mg daily). In rare cases (<1%), excessive stimulation of the mineralocorticoid receptor is due to cortisol (apparent mineralocorticoid excess, Cushing's disease, liquorice, or hereditary deficiency of 11beta-hydroxysteroid dehydrogenase) or to a chimeric gene coding for 11beta-hydroxylase (CYP11B1/CYP11B2). In these rare cases, the synthesis of aldosterone is under the control of the adrenocorticotrophic hormone, so treatment with glucocorticoids (dexamethasone 0.25-1.0 mg daily) is therefore possible (glucocorticoid-remediable aldosteronism). Excessive deoxycorticosterone (DOC) causes the same symptoms and signs as hyperaldosteronism. Excessive DOC is found in patients with adrenal tumours that secrete DOC, in those with hereditary or acquired disorders with dysfunctioning glucocorticoid receptors, or in those with congenital hyperplasia of the adrenal glands (deficiency of 17alpha-hydroxylase or 11beta-hydroxylase). Liddle's syndrome is a constitutive hyperactivity of the transepithelial transport of sodium, which under normal conditions is controlled by the mineralocorticoid receptor. Plasma renin and aldosterone concentrations are suppressed and the plasma potassium concentration may be normal. In contrast, plasma aldosterone and renin concentrations are increased in patients with hypokalaemic hypertension which represents secondary aldosteronism. The increased aldosterone is the consequence of stimulated renin activity due to renal or renovascular or other disorders, antihypertensive drugs or other medications. In conclusion, a work-up for corticosteroid-induced hypertension is indicated in patients with hypokalaemic hypertension and in those with severe hypertension even in the absence of hypokalaemia, and in hypertensive patients with a family history of cardiovascular diseases.

Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.

Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat(Y136F) mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies. We analyzed whether the Lat(Y136F) pathology constitutes a bona fide autoimmune disorder dependent on TCR specificity. Using adoptive transfer experiments, we demonstrated that the expansion and uncontrolled Th2-effector function of Lat(Y136F) CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3(+) regulatory T cells are present in Lat(Y136F) mice and that pathogenic Lat(Y136F) CD4 T cells were capable of escaping the control of infused wild-type Foxp3(+) regulatory T cells. These results argue against a scenario where the Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat(Y136F) CD4 T cells with the ability to trigger the production of Abs and of autoantibodies in a TCR-independent, quasi-mitogenic fashion. Therefore, despite the presence of autoantibodies causative of severe systemic disease, the pathological conditions observed in Lat(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.

Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence.

CgPdr1p is a Candida glabrata Zn(2)-Cys(6) transcription factor involved in the regulation of the ABC-transporter genes CgCDR1, CgCDR2, and CgSNQ2, which are mediators of azole resistance. Single-point mutations in CgPDR1 are known to increase the expression of at least CgCDR1 and CgCDR2 and thus to contribute to azole resistance of clinical isolates. In this study, we investigated the incidence of CgPDR1 mutations in a large collection of clinical isolates and tested their relevance, not only to azole resistance in vitro and in vivo, but also to virulence. The comparison of CgPDR1 alleles from azole-susceptible and azole-resistant matched isolates enabled the identification of 57 amino acid substitutions, each positioned in distinct CgPDR1 alleles. These substitutions, which could be grouped into three different "hot spots," were gain of function (GOF) mutations since they conferred hyperactivity to CgPdr1p revealed by constitutive high expression of ABC-transporter genes. Interestingly, the major transporters involved in azole resistance (CgCDR1, CgCDR2, and CgSNQ2) were not always coordinately expressed in presence of specific CgPDR1 GOF mutations, thus suggesting that these are rather trans-acting elements (GOF in CgPDR1) than cis-acting elements (promoters) that lead to azole resistance by upregulating specific combinations of ABC-transporter genes. Moreover, C. glabrata isolates complemented with CgPDR1 hyperactive alleles were not only more virulent in mice than those with wild type alleles, but they also gained fitness in the same animal model. The presence of CgPDR1 hyperactive alleles also contributed to fluconazole treatment failure in the mouse model. In conclusion, this study shows for the first time that CgPDR1 mutations are not only responsible for in vitro/in vivo azole resistance but that they can also confer a selective advantage under host conditions.

Analyse de la prescription de méthylphénidate dans le canton de Vaud en 2005 et comparaison 2002/2005

L'objectif de cette recherche est d'évaluer les prescriptions de méthylphénidate faites en 2005 aux enfants domiciliés dans le canton de Vaud et de commenter l'évolution depuis 2002. L'analyse comporte 3 volets. Un premier volet cherche à établir si les prescriptions semblent adaptées aux normes et aux recommandations émises quant à l'âge du patient et au traitement à suivre. Il porte sur les doses, la posologie, la durée de traitement et ses formes. Un deuxième volet s'intéresse aux tranches d'âge concernées par les traitements au méthylphénidate et observe s'il existe des variations selon le sexe des patients. Une répartition géographique des cas traités en comparant la répartition des prescripteurs et des patients traités a été faite à l'échelle des districts du canton. Le troisième volet s'intéresse aux médecins prescripteurs de méthylphénidate : est-ce que des différences existent selon la spécialisation médicale ? Est-ce que les médecins, qui, du fait de leur spécialisation (psychiatres ou pédiatres) sembleraient à première vue plus en mesure de décider de la nécessité d'un tel traitement pour un patient, sont plus nombreux à prescrire du méthylphénidate ? Pour chacun de ces volets, une analyse de l'évolution entre 2002 et 2005 des résultats a été faite. [Extrait, p. 4]

Unusual fatal petrositis presenting as myofascial pain and dysfunction of the temporal muscle.

Petrositis is a rare and severe complication of acute otitis media and mastoiditis. Although the extension of the inflammatory process from the petrous apex to the adjacent Meckel cave can lead to trigeminal pain, an irritation of the trigeminal nerve roots resulting in acute or chronic hyperactivity of masticatory muscles has never been reported. We report here the unusual case of an 86-year-old man who presented with a handicapping myofascial pain and dysfunction syndrome of the right temporal muscle as a heralding manifestation of an unusual form of petrositis. The patient progressively developed a retropharyngeal abscess, a right sphenoid sinusitis, and fatal meningitis. This case demonstrated that (1) myofascial pain and dysfunction syndrome that does not respond to conventional treatments may suggest an unusual etiology and warrant further medical investigations and a detailed medical history and that (2) petrositis can manifest itself with atypical clinical symptoms and radiologic signs. (Quintessence Int 2011;42:419-422).

Risk of mental disorders in children of parents with alcohol or heroin dependence: a controlled high-risk study.

Aim: To assess the specific effect of alcohol dependence (AD) or heroin dependence (HD) in patients and their spouses on the risk of psychopathology in their 276 6.0- to 17.9- year-old children (mean 11.3 years). Methods: The sample included 101 offspring of patients with AD, 23 of patients with HD, and 152 of medical controls, as well as their 2 parents. Participants were assessed using semistructured diagnostic interviews and family history reports by psychologists blind to patient diagnoses. Results: Children of HD and AD patients had largely elevated rates of recurrent major depressive disorder. Children of HD patients were also at an increased risk for attention deficit hyperactivity disorder and substance use disorders (SUD). There were interactions between SUD in the 2 parents to increase the risk of SUD in offspring. Conclusions: These results emphasize the need for prompt identification and treatment of these children and highlight the need to pay clinical attention not only to the patient, but also to the co-parent in order to optimize prevention in offspring.

Early tailored assertive community case management for hard-to-engage adolescents suffering from psychiatric disorders: an exploratory pilot study.

AIM: The study aims to evaluate the effects of assertive community treatment (ACT) on the mental health and overall functioning of adolescents suffering from severe psychiatric disorders and who refuse any traditional child psychiatric care. There are a few studies evaluating the effects of ACT on a population of adolescents with psychiatric disorders. This short report highlights the impact of an ACT programme tailored to the needs of these patients, not only as an alternative to hospitalization, but also as a new form of intervention for patients that are difficult to engage. METHODS: The effect of ACT on 35 adolescents using the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) as a measuring tool in pre- and post-intervention was evaluated. RESULTS: The results show that the intervention was associated with a significant improvement on the HoNOSCA overall score, with the following items showing significant amelioration: hyperactivity/focus problems, non-organic somatic symptoms, emotional symptoms, scholastic/language skills, peer relationships, family relationships and school attendance. CONCLUSION: ACT appears as a feasible intervention for hard-to-engage adolescents suffering from psychiatric disorders. The intervention seems to improve their mental health and functioning. This pilot study may serve as a basis to prepare a controlled study that will also take the costs of the intervention into account.

Importance of ENaC-mediated sodium transport in alveolar fluid clearance using genetically-engineered mice.

The lung possesses specific transport systems that intra- and extracellularly maintain salt and fluid balance necessary for its function. At birth, the lungs rapidly transform into a fluid (Na(+))-absorbing organ to enable efficient gas exchange. Alveolar fluid clearance, which mainly depends on sodium transport in alveolar epithelial cells, is an important mechanism by which excess water in the alveoli is reabsorbed during the resolution of pulmonary edema. In this review, we will focus and summarize on the role of ENaC in alveolar lung liquid clearance and discuss recent data from mouse models with altered activity of epithelial sodium channel function in the lung, and more specifically in alveolar fluid clearance. Recent data studying mice with hyperactivity of ENaC or mice with reduced ENaC activity clearly illustrate the impaired lung fluid clearance in these adult mice. Further understanding of the physiological role of ENaC and its regulatory proteins implicated in salt and water balance in the alveolar cells may therefore help to develop new therapeutic strategies to improve gas exchange in pulmonary edema.

Extreme prematurity and intra uterine growth restriction effects in brain network topology at school age

Higher risk for long-term behavioral and emotional sequelae, with attentional problems (with or without hyperactivity) is now becoming one of the hallmarks of extreme premature (EP) birth and birth after pregancy conditions leading to poor intra uterine growth restriction (IUGR) [1,2]. However, little is know so far about the neurostructural basis of these complexe brain functional abnormalities that seem to have their origins in early critical periods of brain development. The development of cortical axonal pathways happens in a series of sequential events. The preterm phase (24-36 post conecptional weeks PCW) is known for being crucial for growth of the thalamocortical fiber bundles as well as for the development of long projectional, commisural and projectional fibers [3]. Is it logical to expect, thus, that being exposed to altered intrauterine environment (altered nutrition) or to extrauterine environment earlier that expected, lead to alterations in the structural organization and, consequently, alter the underlying white matter (WM) structure. Understanding rate and variability of normal brain development, and detect differences from typical development may offer insight into the neurodevelopmental anomalies that can be imaged at later stages. Due to its unique ability to non-invasively visualize and quantify in vivo white matter tracts in the brain, in this study we used diffusion MRI (dMRI) tractography to derive brain graphs [4,5,6]. This relatively simple way of modeling the brain enable us to use graph theory to study topological properties of brain graphs in order to study the effects of EP and IUGR on childrens brain connectivity at age 6 years old.

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1, MRR1, and UPC2 in Virulence.

Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, only UPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.