Generierung und Charakterisierung transgener Mausmodelle zur Untersuchung und Beeinflussung neuronaler Netzwerke

Die komplexe Struktur des neuronalen Netzwerks des Gehirns bildet die Grundlage höherer Fähigkeiten wie Kognition und Verhalten. In der vorliegenden Arbeit sollte das neuronale Netzwerk über verschiedene Wege manipuliert werden und die eventuellen Auswirkungen in vivo untersucht werden. Zum einen wurde der Kalium-Chlorid-Kotransporter KCC2 in Parvalbumin(PV)-positiven Interneuronen deletiert, zum anderen wurde ein Mausmodell generiert, um den photoaktivierbaren Kationen-Kanal Channelrhodopsin-2 (ChR2) konditional in Neuronen exprimieren zu können. Die Inaktivierung von KCC2 in PV-positiven Interneuronen konnte über verschiedene molekularbiologische Methoden bestätigt werden. Knockout-Mäuse zeigten eine erhöhte Sterblichkeit, Motordefizite sowie epileptische Anfälle. Elektrophysiologisch konnte an akuten Hirnschnitten eine veränderte Plastizität sowie veränderte Netzwerkeigenschaften nachgewiesen werden. Es ist vorstellbar, dass der Knockout von KCC2 in PV-positiven Interneuronen zu einer Disinhibition dieser Zellen führt, die dadurch vermehrt GABA ausschütten. Dies könnte sich unmittelbar auf das neuronale Netzwerk auswirken. Weitere elektrophysiologische Untersuchungen an akuten Hirnschnitten der generierten Mäuse können die Funktion PV-positiver Interneurone genauer spezifizieren. Optogenetische Werkzeuge stellen eine alternative Möglichkeit dar, die Erregbarkeit von Zellen zur Untersuchung neuronaler Netzwerke selektiv zu modulieren. Im Rahmen dieser Arbeit wurde eine konditionale ChR2-Mauslinie generiert, um mithilfe lichtsensitiver Ionenkanäle selektiv Einfluss auf das Membranpotential nehmen zu können. Nach Verpaarung mit einer Cre-Deleter-Mauslinie konnte die Expression von ChR2-DNA, -RNA und -Protein verifiziert werden. Allerdings konnten Neurone nicht durch Licht moduliert werden, da offenbar die Expressionsstärke zu gering war

Morning and evening behavior in children and adolescents treated with atomoxetine once daily for Attention-Deficit/Hyperactivity Disorder (ADHD): Findings from two 24-week, open-label studies

<p>Abstract</p> <p>Background</p> <p>The impact of once daily atomoxetine treatment on symptoms in children and adolescents with ADHD may vary over the day. In order to capture such variations, two studies were undertaken in children and adolescents with ADHD using two instruments that capture morning and evening behavior and ADHD-related difficulties over the day. This secondary measure analysis builds on two primary analyses that were conducted separately for children and adolescents and also published separately.</p> <p>Methods</p> <p>In two open-label studies, ADHD patients aged 6–17 years (n = 421), received atomoxetine in the morning (target-dose 0.5–1.2 mg/kg/day) for up to 24 weeks. Morning and evening behavior was assessed using the investigator-rated Weekly Rating of Evening and Morning Behavior (WREMB-R) scale. ADHD-related difficulties at various times of the day (morning, during school, during homework, evening) were assessed using the Global Impression of Perceived Difficulties (GIPD) scale, rated by patients, parents and physicians. Data from both studies were combined for this secondary measure analysis.</p> <p>Results</p> <p>Both WREMB-R subscores decreased significantly over time, the evening subscore from 13.7 (95% CI 13.2;14.2) at baseline to 8.0 (7.4;8.5) at week 2, the morning subscore from 4.3 (4.0;4.5) to 2.4 (2.2;2.6). Scores then remained stable until week 24. All GIPD items improved correspondingly. At all times of the day, patients rated ADHD-related difficulties as less severe than parents and physicians.</p> <p>Conclusion</p> <p>These findings from two open-label studies suggest that morning and evening behavior and ADHD-related difficulties in the mornings and evenings improve over time with once daily atomoxetine treatment.</p

A 52-Week Study of Olanzapine with a Randomized Behavioral Weight Counseling Intervention in Adolescents with Schizophrenia or Bipolar I Disorder

Objectives: To evaluate the 52-week safety/tolerability of oral olanzapine for adolescents with schizophrenia or bipolar mania and compare effectiveness of a standard versus intense behavioral weight intervention in mitigating risk of weight gain. Methods: Patients 13?17 years old with schizophrenia (Brief Psychiatric Rating Scale for Children [BPRS-C] total score >30; item score ≥3 for hallucinations, delusions, or peculiar fantasies) or bipolar I disorder (manic or mixed episode; Young Mania Rating Scale [YMRS] total score ≥15) received open-label olanzapine (2.5?20?mg/day) and were randomized to standard (n?=?102; a single weight counseling session) or intense (n?=?101; weight counseling at each study visit) weight intervention. The primary outcome measure was mean change in body mass index (BMI) from baseline to 52 weeks using mixed-model repeated measures. Symptomatology was also assessed. Results: No statistically significant differences between groups were observed in mean baseline-to-52-week change in BMI (standard: +3.6?kg/m2; intense: +2.8?kg/m2; p?=?0.150) or weight (standard: +12.1?kg; intense: +9.6?kg; p?=?0.148). Percentage of patients at endpoint who had gained ≥15% of their baseline weight was 40% for the standard group and 31% for the intense group (p?=?0.187). Safety/tolerability results were generally consistent with those of previous olanzapine studies in adolescents, with the most notable exception being the finding of a mean decrease in prolactin. On symptomatology measures, patients with schizophrenia had a mean baseline-to-52-week change in BPRS-C of ?32.5 (standard deviation [SD]?=?10.8), and patients with bipolar disorder had a mean change in YMRS of ?16.7 (SD?=?8.9), with clinically and statistically significant improvement starting at 3?4 days for each. Conclusions: Long-term weight gain was high in both groups, with no statistically significant differences between the standard or intense behavioral weight interventions in BMI or weight. Safety, tolerability, and effectiveness findings were generally consistent with the known profile of olanzapine in adolescents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140324/1/cap.2016.0010.pd

Error-Aware Density-Based Clustering of Imprecise Measurement Values

Manufacturing process development is under constant pressure to achieve a good yield for stable processes. The development of new technologies, especially in the field of photomask and semiconductor development, is at its phys-ical limits. In this area, data, e.g. sensor data, has to be collected and analyzed for each process in order to ensure process quality. With increasing complexity of manufactur-ing processes, the volume of data that has to be evaluated rises accordingly. The complexity and data volume exceeds the possibility of a manual data analysis. At this point, data mining techniques become interesting. The application of current techniques is complex because most of the data is captured with sensor measurement tools. Therefore, every measured value contains a specific error. In this paper we propose an error-aware extension of the density-based al-gorithm DBSCAN. Furthermore, we present some quality measures which could be utilized for further interpretation of the determined clustering results. With this new cluster algorithm, we can ensure that masks are classified into the correct cluster with respect to the measurement errors, thus ensuring a more likely correlation between the masks

Screening for ADHD-Related Symptoms in Preschoolers Should Be Considered—Results From a Representative Sample of 5-Year-Olds From a German Metropolitan Region

Background: Early assessment and intervention are crucial to alleviate symptoms and prevent long-term negative outcomes in children suffering from Attention-deficit/hyperactivity disorder (ADHD). In Germany, at present, no standardized screening for ADHD is routinely administered. This study aims to evaluate a potential screening measure in a study population that is representative for a primary school entrance exam population in a German metropolitan region.Methods: Based on various socio-demographic variables, a sample of n = 500 5-year-old children (58% boys, 42% girls), representative of a primary school entrance exam population from a German metropolitan region, was selected. Their parents completed a written survey consisting of the CBCL and a brief screening tool for ADHD symptomatology based on the DISYPS-II questionnaire. Demographic data were also collected.Results: The subscale “Attention problems” of the CBCL/4-18 showed results in the clinical range for n = 10 (2%) participants. The ADHD screening identified n = 23 (4.6%) participants as suspect of having ADHD with a statistically significant gender difference (n = 17 boys vs. n = 6 girls, p = 0.03). In n = 5 (1%) participants, all boys, both CBCL/4-18 and the ADHD screening were indicative of ADHD.Conclusions: Results indicate that screening for ADHD in this population may be both feasible and reasonable given the high prevalence and chronic nature of this disorder and the benefit of an early initiation of treatment. Results match previously reported figures for prevalence of ADHD-related symptoms and gender differences in preschool and older pediatric populations and thus do not support the hypothesis that the prevalence of ADHD in a metropolitan region is significantly higher than in other regions

Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial

BACKGROUND: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer's dementia in a number of countries. METHODS/DESIGN: This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children's Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. DISCUSSION: This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. TRIAL REGISTRATION: EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014

Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention-deficit/hyperactivity disorder:results from a randomized, controlled trial

Lisdexamfetamine dimesylate (LDX) is a long-acting, prodrug stimulant therapy for patients with attention-deficit/hyperactivity disorder (ADHD). This randomized placebo-controlled trial of an optimized daily dose of LDX (30, 50 or 70 mg) was conducted in children and adolescents (aged 6–17 years) with ADHD. To evaluate the efficacy of LDX throughout the day, symptoms and behaviors of ADHD were evaluated using an abbreviated version of the Conners’ Parent Rating Scale-Revised (CPRS-R) at 1000, 1400 and 1800 hours following early morning dosing (0700 hours). Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment, but the study was not designed to support a statistical comparison between LDX and OROS-MPH. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107). At baseline, CPRS-R total scores were similar across treatment groups. At endpoint, differences (active treatment − placebo) in least squares (LS) mean change from baseline CPRS-R total scores were statistically significant (P < 0.001) throughout the day for LDX (effect sizes: 1000 hours, 1.42; 1400 hours, 1.41; 1800 hours, 1.30) and OROS-MPH (effect sizes: 1000 hours, 1.04; 1400 hours, 0.98; 1800 hours, 0.92). Differences in LS mean change from baseline to endpoint were statistically significant (P < 0.001) for both active treatments in all four subscales of the CPRS-R (ADHD index, oppositional, hyperactivity and cognitive). In conclusion, improvements relative to placebo in ADHD-related symptoms and behaviors in children and adolescents receiving a single morning dose of LDX or OROS-MPH were maintained throughout the day and were ongoing at the last measurement in the evening (1800 hours)

Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder

The Author(s) 2014. This article is published with open access at Springerlink.com Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and ato-moxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactiv-ity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. Methods In this 9-week, double-blind, active-controlled study, patients aged 6–17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients \70 kg: 0.5–1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients C70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (C25, C30 or C50 %) or a Clinical Global Impressions (CGI)–Improvement (CGI–I) score of 1 or 2 throughout weeks 4–9. CGI– Severity (CGI–S) scores were also assessed, as an indicator of remission. Results A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p \ 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also signifi-cantly (p \ 0.05) higher among LDX-treated patient