Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors

Nuclear egress is an essential process in the replication of human cytomegalovirus (HCMV), as it enables the migration of newly formed viral capsids from the nucleus into the cytoplasm. Inhibition of the HCMV core nuclear egress complex (core NEC), composed of viral proteins pUL50 and pUL53, has been proposed as a potential new target for the treatment of HCMV infection and disease. Here, we present a new type of small molecule inhibitors of HCMV core NEC formation, which inhibit the pUL50-pUL53 interaction at nanomolar concentrations. These inhibitors, i.e., verteporfin and merbromin, were identified through the screening of the Prestwick Chemical Library® of approved drug compounds. The inhibitory effect of merbromin is both compound- and target-specific, as no inhibition was seen for other mercury-organic compounds. Furthermore, merbromin does not inhibit an unrelated protein–protein interaction either. More importantly, merbromin was found to inhibit HCMV infection of cells in three different assays, as well as to disrupt HCMV NEC nuclear rim formation. Thus, while not being an ideal drug candidate by itself, merbromin may serve as a blueprint for small molecules with high HCMV core NEC inhibitory potential, as candidates for novel anti-herpesviral drugs

Genetische und pathologische Linkshändigkeit als möglicher ursächlicher und prognostischer Faktor für Stottern

Für das Auftreten von Stottern sind disponierende, auslösende und chronifizierende Faktoren bedeutungsvoll. Unter den Dispositionen werden in der Literatur immer wieder veränderte cerebrale Dominanzverhältnisse diskutiert. Dies stützt sich unter anderem auf die Beobachtung zahlreicher Forscher über eine erhöhte Inzidenz von Linkshändigkeit bei Stotterern, denn Linkshändigkeit ist das am leichtesten erfassbare Beispiel für veränderte cerebrale Dominanz. In der hier vorgestellten Studie wurden die Fragen untersucht, ob Links- bzw. Nichtrechtshändigkeit auch vermehrt bei entwicklungsunflüssigen bzw. stotternden Kindern im Vorschulalter auftritt, diese pathologischer oder genetischer Natur ist und ob Handpräferenzen Rückschlüsse auf die Manifestation von chronischem Stottern im Kindesalter zulassen

Welche Hör- und Sprachbefunde verbergen sich hinter der Verdachtsdiagnose AVS?

Hintergrund: Die Häufigkeit und Symptomzusammensetzung von Kindern mit dem Verdacht auf eine auditive Verarbeitungsstörung sind nach wie vor unklar.Material und Methoden: In der vorliegenden Arbeit wurden 106 Kinder (5-14 Jahre) mit der Überweisungsdiagnose "auditive Verarbeitungsstörung" (AVS) nach den Vorgaben der aktuellen Leitlinie untersucht. Pathologien im Sinne umschriebener Entwicklungsstörungen des Sprechens und der Sprache, tiefgreifende Entwicklungsstörungen wie Autismusspektrumstörungen oder hyperkinetische Störungen sowie eine unterdurchschnittliche Intelligenz wurden vor Beginn der Testung ausgeschlossen.Ergebnisse: Signifikant auffällige Testergebnisse zeigten sich der Häufigkeit nach vor allem in den Teilbereichen dichotische Signalverarbeitung (36,4%), Lautdifferenzierung (34,9%), phonologische Verarbeitung und Bewusstheit (22,8%) sowie der auditiven Merkspanne und Gedächtnis (22,6%). Defizite in den Teilleistungsgebieten auditive Reizfilterung (10,0%), Sprach- und Grammatikverständnis (7,4%), lautgetreues Schreiben (5,2%) und Wortschatzdefizit/Wortfindungsstörung (1,1%) waren demgegenüber deutlich seltener. Auffällig im Sinne der für die Diagnose AVS geforderten Testergebnisse waren 33 der untersuchten 106 Kinder (31,1%).Diskussion: Bei 87,7% der Kinder im Gesamtkollektiv wurden Reste einer Sprachentwicklungsstörung gesehen, bei 54,7% wurde eine Legasthenie diagnostiziert. Zwei Drittel (66,6%) der 33 mit AVS diagnostizierten Kinder hatten Defizite in der phonologische Verarbeitung/Bewusstheit sowie der auditiven Merkspanne/Gedächtnis, etwa die Hälfte hatte Probleme mit der Lautdifferenzierung (54,5%) und der beidohrigen Signalverarbeitung (48,5%).Fazit: Somit überwiegen bei einem Großteil der Kinder mit V.a. AVS sprachsystematische Probleme, die entsprechend aufzuarbeiten sind

Pharmacotherapy for ADHD in children and adolescents:A summary and overview of different European guidelines

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. It is the most common neurodevelopmental disorder presenting to pediatric services, and pediatricians are often involved in the early assessment, diagnosis, and treatment of children with ADHD. The treatment of ADHD typically involves a multimodal approach that encompasses a combination of psychoeducation, parent/teacher training, psychosocial/psychotherapeutic interventions, and pharmacotherapy. Concerning pharmacotherapy, guidelines vary in drug choice and sequencing, with psychostimulants, such as methylphenidate and (lis)dexamfetamine, generally being the favored initial treatment. Alternatives include atomoxetine and guanfacine. Pharmacotherapy has been proven effective, but close follow-up focusing on physical growth, cardiovascular monitoring, and the surveillance of potential side effects including tics, mood fluctuations, and psychotic symptoms, is essential. This paper presents an overview of current pharmacological treatment options for ADHD and explores disparities in treatment guidelines across different European countries. Conclusion: Pharmacological treatment options for ADHD in children and adolescents are effective and generally well-tolerated. Pharmacotherapy for ADHD is always part of a multimodal approach. While there is a considerable consensus among European guidelines on pharmacotherapy for ADHD, notable differences exist, particularly concerning the selection and sequencing of various medications. (Table presented.)</p

Pharmacotherapy for ADHD in children and adolescents:A summary and overview of different European guidelines

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. It is the most common neurodevelopmental disorder presenting to pediatric services, and pediatricians are often involved in the early assessment, diagnosis, and treatment of children with ADHD. The treatment of ADHD typically involves a multimodal approach that encompasses a combination of psychoeducation, parent/teacher training, psychosocial/psychotherapeutic interventions, and pharmacotherapy. Concerning pharmacotherapy, guidelines vary in drug choice and sequencing, with psychostimulants, such as methylphenidate and (lis)dexamfetamine, generally being the favored initial treatment. Alternatives include atomoxetine and guanfacine. Pharmacotherapy has been proven effective, but close follow-up focusing on physical growth, cardiovascular monitoring, and the surveillance of potential side effects including tics, mood fluctuations, and psychotic symptoms, is essential. This paper presents an overview of current pharmacological treatment options for ADHD and explores disparities in treatment guidelines across different European countries. Conclusion: Pharmacological treatment options for ADHD in children and adolescents are effective and generally well-tolerated. Pharmacotherapy for ADHD is always part of a multimodal approach. While there is a considerable consensus among European guidelines on pharmacotherapy for ADHD, notable differences exist, particularly concerning the selection and sequencing of various medications. What is Known: • There is a significant base of evidence for pharmacological treatment for ADHD in children and adolescents. • Pediatricians are often involved in assessment, diagnosis and management of children with ADHD. What is New: • Our overview of different European guidelines reveals significant agreement in the context of pharmacotherapy for ADHD in children and adolescents. • Discrepancies exist primarily in terms of selection and sequencing of different medications.</p

"Include me if you can"-reasons for low enrollment of pediatric patients in a psychopharmacological trial

BACKGROUND: Low recruitment in clinical trials is a common and costly problem which undermines medical research. This study aimed to investigate the challenges faced in recruiting children and adolescents with obsessive-compulsive disorder and autism spectrum disorder for a randomized, double-blind, placebo-controlled clinical trial and to analyze reasons for non-participation. The trial was part of the EU FP7 project TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes). METHODS: Demographic data on pre-screening patients were collected systematically, including documented reasons for non-participation. Findings were grouped according to content, and descriptive statistical analyses of the data were performed. RESULTS: In total, n = 173 patients were pre-screened for potential participation in the clinical trial. Of these, only five (2.9%) were eventually enrolled. The main reasons for non-inclusion were as follows: failure to meet all inclusion criteria/meeting one or more of the exclusion criteria (n = 73; 42.2%), no interest in the trial or trials in general (n = 40; 23.1%), and not wanting changes to current therapy/medication (n = 14; 8.1%). CONCLUSIONS: The findings from this study add valuable information to the existing knowledge on reasons for low clinical trial recruitment rates in pediatric psychiatric populations. Low enrollment and high exclusion rates raise the question of whether such selective study populations are representative of clinical patient cohorts. Consequently, the generalizability of the results of such trials may be limited. The present findings will be useful in the development of improved recruitment strategies and may guide future research in establishing the measurement of representativeness to ensure enhanced external validity in psychopharmacological clinical trials in pediatric populations. TRIAL REGISTRATION: EudraCT 2014-003080-38 . Registered on 14 July 2014