Relationship between atomoxetine plasma concentration, treatment response and tolerability in attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder

The purpose of this study was to examine whether atomoxetine plasma concentration predicts attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) response. This post-hoc analysis assessed the relationship between atomoxetine plasma concentration and ADHD and ODD symptoms in patients (with ADHD and comorbid ODD) aged 6–12 years. Patients were randomly assigned to atomoxetine 1.2 mg/kg/day (n = 156) or placebo (n = 70) for 8 weeks (Study Period II). At the end of 8 weeks, ODD non-remitters (score >9 on the SNAP-IV ODD subscale and CGI-I > 2) with atomoxetine plasma concentration <800 ng/ml at 2 weeks were re-randomized to either atomoxetine 1.2 mg/kg/day or 2.4 mg/kg/day for an additional 4 weeks (Study Period III). ODD remitters and non-remitters with plasma atomoxetine ≥800 ng/ml remained on 1.2 mg/kg/day atomoxetine for 4 weeks. Patients who received atomoxetine, completed Study Period II, and entered Study Period III were included in these analyses. All the groups demonstrated improvement on the SNAP-IV ODD and ADHD-combined subscales (P < .001). At the end of Study Periods II and III, ODD and ADHD improvement was significantly greater in the remitter group compared with the non-remitter groups. Symptom improvement was numerically greater in the non-remitter (2.4 mg/kg/day compared with the non-remitter 1.2 mg/kg/day) group. Atomoxetine plasma concentration was not indicative of ODD and ADHD improvement after 12 weeks of treatment. ADHD and ODD symptoms improved in all the groups with longer duration on atomoxetine. Results suggest atomoxetine plasma concentration does not predict ODD and ADHD symptom improvement. However, a higher atomoxetine dose may benefit some patients

ADHD and EEG-neurofeedback: a double-blind randomized placebo-controlled feasibility study

Electroencephalography (EEG)-neurofeedback has been shown to offer therapeutic benefits to patients with attention-deficit/hyperactivity disorder (ADHD) in several, mostly uncontrolled studies. This pilot study is designed to test the feasibility and safety of using a double-blind placebo feedback-controlled design and to explore the initial efficacy of individualized EEG-neurofeedback training in children with ADHD. Fourteen children (8–15 years) with ADHD defined according to the DSM-IV-TR criteria were randomly allocated to 30 sessions of EEG-neurofeedback (n = 8) or placebo feedback (n = 6). Safety measures (adverse events and sleep problems), ADHD symptoms and global improvement were monitored. With respect to feasibility, all children completed the study and attended all study visits and training sessions. No significant adverse effects or sleep problems were reported. Regarding the expectancy, 75% of children and their parent(s) in the active neurofeedback group and 50% of children and their parent(s) in the placebo feedback group thought they received placebo feedback training. Analyses revealed significant improvements of ADHD symptoms over time, but changes were similar for both groups. This pilot study shows that it is feasible to conduct a rigorous placebo-controlled trial to investigate the efficacy of neurofeedback training in children with ADHD. However, a double-blind design may not be feasible since using automatic adjusted reward thresholds may not work as effective as manually adjusted reward thresholds. Additionally, implementation of active learning strategies may be an important factor for the efficacy of EEG-neurofeedback training. Based on the results of this pilot study, changes are made in the design of the ongoing study

Proportions of CD4+ memory T cells are altered in individuals chronically infected with Schistosoma haematobium

Characterisation of protective helminth acquired immunity in humans or experimental models has focused on effector responses with little work conducted on memory responses. Here we show for the first time, that human helminth infection is associated with altered proportions of the CD4+ memory T cells, with an associated alteration of TH1 responses. The reduced CD4+ memory T cell proportions are associated with a significantly lower ratio of schistosome-specific IgE/IgG4 (marker for resistance to infection/re-infection) in uninfected older people. Helminth infection does not affect the CD8+ memory T cell pool. Furthermore, we show for the first time in a helminth infection that the CD4+ memory T cell proportions decline following curative anti-helminthic treatment despite increased CD4+ memory cell replication. Reduced accumulation of the CD4+ memory T cells in schistosome-infected people has implications for the development of natural or vaccine induced schistosome-specific protective immunity as well as for unrelated pathogens

Current issues around the pharmacotherapy of ADHD in children and adults

Background New drugs and new formulations enter the growing market for ADHD medication. The growing awareness of possible persistence of ADHD impairment beyond childhood and adolescence resulting in increased pharmacotherapy of ADHD in adults, is also a good reason for making an inventory of the what is generally known about pharmacotherapy in ADHD. Aim To discuss current issues in the possible pharmacotherapy treatment of ADHD in children, adolescents and adults with respect to the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used. Methods A search of the literature with an emphasis on the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used in pharmacotherapy. Results According to the guidelines, the treatment of ADHD in children consists of psychosocial interventions in combination with pharmacotherapy when needed. Stimulants are the first-choice drugs in the pharmacological treatment of ADHD in children despite a number of well known and frequently reported side effects like sleep disorders and loss of appetite. With regard to the treatment of adults, stimulant treatment was recommended as the first-choice pharmacotherapy in the single guideline available. Both in children and adults, there appears to be an additional though limited role for the nonadrenergic drug atomoxetine. The increase of ADHD medication use, in children, adolescents and in adults, can not only be interpreted as a sign of overdiagnosis of ADHD. Despite the frequent use of stimulants, there is still a lack of clarity on the effects of long-term use on growth and nutritional status of children. Cardiovascular effects of both stimulants and atomoxetine are rare but can be severe. The literature suggests that atomoxetine may be associated with suicidal ideation in children. Conclusion Although pharmacotherapy is increasing common in the treatment of ADHD in both children and adults, there are still a lot of questions about side effects and how best to counter them. This suggests an important role for close monitoring of children and adults treated with stimulants or atomoxetine

Time series analysis of dengue incidence in Guadeloupe, French West Indies: Forecasting models using climate variables as predictors

BACKGROUND: During the last decades, dengue viruses have spread throughout the Americas region, with an increase in the number of severe forms of dengue. The surveillance system in Guadeloupe (French West Indies) is currently operational for the detection of early outbreaks of dengue. The goal of the study was to improve this surveillance system by assessing a modelling tool to predict the occurrence of dengue epidemics few months ahead and thus to help an efficient dengue control. METHODS: The Box-Jenkins approach allowed us to fit a Seasonal Autoregressive Integrated Moving Average (SARIMA) model of dengue incidence from 2000 to 2006 using clinical suspected cases. Then, this model was used for calculating dengue incidence for the year 2007 compared with observed data, using three different approaches: 1 year-ahead, 3 months-ahead and 1 month-ahead. Finally, we assessed the impact of meteorological variables (rainfall, temperature and relative humidity) on the prediction of dengue incidence and outbreaks, incorporating them in the model fitting the best. RESULTS: The 3 months-ahead approach was the most appropriate for an effective and operational public health response, and the most accurate (Root Mean Square Error, RMSE = 0.85). Relative humidity at lag-7 weeks, minimum temperature at lag-5 weeks and average temperature at lag-11 weeks were variables the most positively correlated to dengue incidence in Guadeloupe, meanwhile rainfall was not. The predictive power of SARIMA models was enhanced by the inclusion of climatic variables as external regressors to forecast the year 2007. Temperature significantly affected the model for better dengue incidence forecasting (p-value = 0.03 for minimum temperature lag-5, p-value = 0.02 for average temperature lag-11) but not humidity. Minimum temperature at lag-5 weeks was the best climatic variable for predicting dengue outbreaks (RMSE = 0.72). CONCLUSION: Temperature improves dengue outbreaks forecasts better than humidity and rainfall. SARIMA models using climatic data as independent variables could be easily incorporated into an early (3 months-ahead) and reliably monitoring system of dengue outbreaks. This approach which is practicable for a surveillance system has public health implications in helping the prediction of dengue epidemic and therefore the timely appropriate and efficient implementation of prevention activities

Silencing Nuclear Pore Protein Tpr Elicits a Senescent-Like Phenotype in Cancer Cells

Background: Tpr is a large coiled-coil protein located in the nuclear basket of the nuclear pore complex for which many different functions were proposed from yeast to human. Methodology/Principal Findings: Here we show that depletion of Tpr by RNA interference triggers G0–G1 arrest and ultimately induces a senescent-like phenotype dependent on the presence of p53. We also found that Tpr depletion impairs the NES [nuclear export sequence]-dependent nuclear export of proteins and causes partial co-depletion of Nup153. In addition Tpr depletion impacts on level and function of the SUMO-protease SENP2 thus affecting SUMOylation regulation at the nuclear pore and overall SUMOylation in the cell. Conclusions: Our data for the first time provide evidence that a nuclear pore component plays a role in controlling cellular senescence. Our findings also point to new roles for Tpr in the regulation of SUMO-1 conjugation at the nuclear pore and directly confirm Tpr involvement in the nuclear export of NES-proteins

A strategy to discover new organizers identifies a putative heart organizer

Organizers are regions of the embryo that can both induce new fates and impart pattern on other regions. So far, surprisingly few organizers have been discovered, considering the number of patterned tissue types generated during development. This may be because their discovery has relied on transplantation and ablation experiments. Here we describe a new approach, using chick embryos, to discover organizers based on a common gene expression signature, and use it to uncover the anterior intestinal portal (AIP) endoderm as a putative heart organizer. We show that the AIP can induce cardiac identity from non-cardiac mesoderm and that it can pattern this by specifying ventricular and suppressing atrial regional identity. We also uncover some of the signals responsible. The method holds promise as a tool to discover other novel organizers acting during development

Bright light therapy versus physical exercise to prevent co-morbid depression and obesity in adolescents and young adults with attention-deficit/hyperactivity disorder: study protocol for a randomized controlled trial

Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day– night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD. Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up. This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.The trial is funded by the EU Framework Programme for Research and Innovation, Horizon 2020 (Project no. 667302). Funding period: January 2016–December 2020. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Some local funds additionally contributed to carry out this study, especially for the preparation of the interventions: FBO research activity is by the Spanish Ministry of Economy and Competitiveness – MINECO (RYC-2011-09011) and by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Unit of Excellence on Exercise and Health (UCEES)