Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.

BACKGROUND: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA. METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

[The Tunisian Revolution in the eyes of children]. / La revolution tunisienne dans le regard des enfants.

BACKGROUND: The child uses drawing as a language. By reflecting faithfully all that is involved in the psychic life of the child, the drawing participates in the diagnosis and plays a role in the therapeutic management of young people suffering from psychological difficulties. AIM: To analyze the drawings of children and adolescents followed at the department of Child and Adolescent Psychiatry, further to the events of the Tunisian Revolution. METHOD: it is about a cross sectional study conducted among outpatients consulting the department of Child and Adolescent Psychiatry at Razi hospital in Manouba during the period from January 25 to February 28, 2011. These patients were divided into two groups with a specific instruction for each, to represent the events experienced by the patient and his family for the first group and to do a free drawing for the second. RESULTS: both groups consisted of 16 patients each with successively average age of 10, 5 and 10.33 years and sex ratio of 2.20 and 1.25. Patients in both groups were exposed to different stressors. The first group of children used in their drawings few colors, mostly black and red. The instruments of war such as bullets, guns, tanks and military helicopters were well represented. The characters were mostly male who were angry and looking for leakage. The drawings depicted scenes of war and conflict with people in distress or dead. The drawings of the second group were essentially about nature. CONCLUSION: We find that the instruction has significantly changed the behavior of children from the sheet. The instruction in this context seems to be a necessary to help these children overcome their concerns and express their pain.

Symptomatic bradyarrhythmias in the athlete-Underlying mechanisms and treatments.

Bradyarrhythmias including sinus bradycardia and atrioventricular (AV) block are frequently encountered in endurance athletes especially at night. While these are well tolerated by the young athlete, there is evidence that generally from the fifth decade of life onward, such arrhythmias can degenerate into pathological symptomatic bradycardia requiring pacemaker therapy. For many years, athletic bradycardia and AV block have been attributed to high vagal tone, but work from our group has questioned this widely held assumption and demonstrated a role for intrinsic electrophysiological remodeling of the sinus node and the AV node. In this article, we argue that bradyarrhythmias in the veteran athlete arise from the cumulative effects of exercise training, the circadian rhythm and aging on the electrical activity of the nodes. We consider contemporary strategies for the treatment of symptomatic bradyarrhythmias in athletes and highlight potential therapies resulting from our evolving mechanistic understanding of this phenomenon.

Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction.

AIMS: In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. METHODS AND RESULTS: We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. CONCLUSION: Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

Model Predictive Control with Integrated Model Reduction for a Continuous Lactide Ring-Opening Polymerization Process.

Poly(lactic acid) production has received increasing attention, mainly due to its inherent biodegradable thermoplastic properties and to its renewable-resource-based composition. This process is affected by changes in the operating conditions and by raw material impurities which influence the reaction rate and degrade the polymer properties. As the system model is multivariable with coupled dynamics and constraints, linear model predictive control (LMPC) is employed here. A model reduction technique is proposed to obtain an approximate linear representation of the nonlinear system around the operating point to minimize the calculation cost of the controller. The proposed LMPC approach is validated by simulation and is compared to a proportional-integral controller and a nonlinear model predictive control. It is found that LMPC has a superior performance in terms of off-spec time when a disturbance occurs in the feed, and it can restore the target conditions better and faster.

[Clinical characteristics of Rett Syndrome]. / Particularités cliniques du syndrome de Rett.

BACKGROUND: Rett Syndrome is a neurodevelopmental disorder, one of the least commonly occurring autism spectrum disorders (ASD),affecting mainly females. AIM: To describe features and molecular specificities of Rett syndrome. METHODS: To identify articles for this review, a Pubmed search was conducted using the following keywords: Rett syndrome, regression,mutation, stereotypes. RESULTS: This syndrome is characterized by cognitive impairment,communication dysfunction, stereotypic movement disorder, and growth failure. It is generally caused by mutations in the MECP2 gene. Rett Syndrome has a prevalence ranging from 10-20 000 females. Specific treatment is not available, but patients need a careful planning for long-term care, with multidisciplinary approaches.

Clinical Experience of the Efficacy and Safety of Low-dose Tolvaptan Therapy in a UK Tertiary Oncology Setting.

CONTEXT: In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy. OBJECTIVE: To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy. METHODS: Retrospective evaluation in a tertiary cancer center. RESULTS: Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ±â€…4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ±â€…9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01). CONCLUSION: In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.

[The mobile: a new addiction upon adolescents]. / Le téléphone portable: une nouvelle addiction chez les adolescents.

AIM: This survey was conducted to investigate mobile phone use and dependence in Tunisian high school students. METHODS: Questionnaires were anonymously distributed to 120 adolescents looking for the modalities of use of mobiles. SMS dependency was assessed with the French version of the Igarashi scale. RESULTS: The two most used means for communication were SMS and missing calls. 83.2% of the sample sent more than 6 missing calls per day. According to the Igarashi scale, adolescents reported perception of excessive use in 31. Seven percent of cases, emotional reaction in 33.4% of cases and exclusive relationship maintenance thanks to mobile in 18% of cases. CONCLUSION: This study demonstrated a anew addictgion to mobile phone among tunisian high school students.

[Profile of a population of consultants in child psychiatry and access to care by gender]. / Profil d'une population de consultants en pédopsychiatrie et accès aux soins selon le genre.

BACKGROUND: Access to care in mental health is a fundamental element in the monitoring and care of children and adolescents. AIM: The objective of this work was to draw up the demographic and clinical characteristics of a population of consultants in child psychiatry and to investigate possible gender inequalities in access to care. METHODS: This is a descriptive cross-sectional study concerning a sample of 730 children and adolescents having consulted child psychiatry department in Tunis and Monastir during a period of 4 months (April-July on 2006). Data were collected through a questionnaire administered to the relatives of patients consulting these various structures. RESULTS: 66 % of consulting were boys. In 55 % of cases, the mother, alone, accompanied the child to the consultation. The request of care emanated in the majority of the cases from parents and doctors. On average ran out 18 months before the first medical visit and 26 months before the first psychiatric consultation. Multiple medical consultations precede the meeting with the child psychiatrist. We have not found difference in the care of children and adolescents according to gender. Only the period preceding the first medical consultation for psychiatric symptoms was longer in girls compared to boys. CONCLUSION: Access to care structures was easy and even in cases of geographical remoteness parents did not seem to privilege boys over girls.

[The diagnosis of temporal epilepsy in child psychiatry: a report of 7 cases]. / Le diagnostic d'epilepsie temporale en pedopsychiatrie: a propos de 7 cas.

AIM: This paper attempts to describe the features of temporal epilepsy in patients firstly considered as having psychiatric disorders. METHODS: The cases of seven patients followed between 2005 and 2008 at the Child and Adolescent Psychiatry Department of Razi Hospital, aged 11 to 15 years are treated. RESULTS: All the patients showed complex partial seizures, and some of them showed secondarily generalized tonic-clonic seizures. Seizures were predominantly made of psychic symptoms (delusion, fear, aggressiveness) but also associated sensory, motor and vegetative features. In 5 cases, epilepsy was idiopathic, and symptomatic of brain anomaly in 2 cases. CONCLUSION: Careful attention must be paid to paroxystic symptoms in children.

[Memory impairments during child and adolescent depression]. / Les troubles mnesiques dans la depression de l'enfant et de l'adolescent.

AIM: This study aimed to evaluate basic performances on verbal memory in treatment-naïve children and adolescents with depression and in healthy control subjects. METHODS: 34 children and adolescents aged 6-16 years, suffering from a first major depressive disorder (DSM IV) and 34 controls matched on sex, age and cognitive ability were evaluated. Psychiatric diagnosis was assessed with the K-SADS-PL. The Child Depression Rating Scale (CDRS) was used to assess the severity of depression. Progressive matrices of Raven were used to evaluate intelligence. Two different cognitive tasks were administered to assess semantic and working memory: digit span test, and semantic and phonemic verbal fluency. RESULTS: A significant effect of diagnosis was found for digit span: patients showed lower performance on forward (p=0,015) and backward (p=0,002) digits. No difference was found between patients and controls on verbal fluency. The young age of the sample and the first depressive episode criteria may explain the absence of severe impairment of this type of semantic and working memory. CONCLUSION: These results support the hypothesis that memory deficits in depressive disorders are partly the result of poor encoding caused by a deficit in attention.

[The Usefulness of Clonazepam as an Augmentative Treatment in a Case of Severe Childhood Onset Obsessive-Compulsive Disorder]. / Siddetli Bir Çocukluk Çagi Baslangiçli Obsesif Kompulsif Bozukluk Olgusunda Güçlendirme Tedavisi Olarak Klonazepam.

The goal of this study is to report on the treatment of obsessive-compulsive disorder (OCD), a chronic disabling condition that often presents during childhood and adolescence. Reports on adults using clonazepam for the treatment of OCD are more numerous than on children. Clonazepam as an augmentative treatment in OCD is still controversial. Our aim is to illustrate in a case report the efficacy of clonazepam as an augmentative treatment for severe childhood onset OCD. We report on the case of a young teenage girl with an extremely severe form of obsessive-compulsive disorder (score of 32 on the Children's Yale-Brown Obsessive Compulsive Scale), who, after a mild improvement with a combination of serotonin recapture inhibitors and second generation antipsychotics at high doses, has responded to clonazepam (3mg/day) augmentation of sertraline (200mg/day) and olanzapine (15mg/day). Clonazepam was effective not only in reducing anxiety symptoms, but also in lowering compulsions and obsessions frequency within 6 weeks with a drop in the Children's Yale-Brown Obsessive Compulsive Scale of 16 points. It may be asserted that clonazepam could be useful in the initial stage for severe OCD in young patients.