Testing Gait with Ankle-Foot Orthoses in Children with Cerebral Palsy by Using Functional Mixed-Effects Analysis of Variance

Dr Morrissey is part funded by the NIHR/HEE Senior Clinical Lecturer scheme. Tis report presents independent research part-funded by the National Institute for Health Research (NIHR) CAT SCL-2013-04-00

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway

Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for Clostridium difficile

John P Hegarty,1 Jacek Krzeminski,2 Arun K Sharma,2 Diana Guzman-Villanueva,3 Volkmar Weissig,3 David B Stewart Sr1 1Deparment of Surgery, Pennsylvania State University College of Medicine Hershey, PA, USA; 2Department of Pharmacology, Penn State Hershey Cancer Institute, Hershey, PA, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, Nanomedicine Center of Excellence in Translational Research, Midwestern University, Glendale, AZ, USA Abstract: Despite being a conceptually appealing alternative to conventional antibiotics, a major challenge toward the successful implementation of antisense treatments for bacterial infections is the development of efficient oligonucleotide delivery systems. Cationic vesicles (bolasomes) composed of dequalinium chloride (“DQAsomes”) have been used to deliver plasmid DNA across the cardiolipin-rich inner membrane of mitochondria. As cardiolipin is also a component of many bacterial membranes, we investigated the application of cationic bolasomes to bacteria as an oligonucleotide delivery system. Antisense sequences designed in silico to target the expression of essential genes of the bacterial pathogen, Clostridium difficile, were synthesized as 2'-O-methyl phosphorothioate gapmer antisense oligonucleotides (ASO). These antisense gapmers were quantitatively assessed for their ability to block mRNA translation using luciferase reporter and C. difficile protein expression plasmid constructs in a coupled transcription–translation system. Cationic bolaamphiphile compounds (dequalinium derivatives) of varying alkyl chain length were synthesized and bolasomes were prepared via probe sonication of an aqueous suspension. Bolasomes were characterized by particle size distribution, zeta potential, and binding capacities for anionic oligonucleotide. Bolasomes and antisense gapmers were combined to form antisense nanocomplexes. Anaerobic C. difficile log phase cultures were treated with serial doses of gapmer nanocomplexes or equivalent amounts of empty bolasomes for 24 hours. Antisense gapmers for four gene targets achieved nanomolar minimum inhibitory concentrations for C. difficile, with the lowest values observed for oligonucleotides targeting polymerase genes rpoB and dnaE. No inhibition of bacterial growth was observed from treatments at matched dosages of scrambled gapmer nanocomplexes or plain, oligonucleotide-free bolasomes compared to untreated control cultures. We describe the novel application of cationic bolasomes to deliver ASOs into bacteria. We also report the first successful in vitro antisense treatment to inhibit the growth of C. difficile. Keywords: cationic bolaamphiphiles, dequalinium derivatives, nanocomplex, antisense, gapmers, Clostridium difficile, bacteri

Antipsychotic polypharmacy in a regional health service: a population-based study

Background To analyse the extent and profile of outpatient regular dispensation of antipsychotics, both in combination and monotherapy, in the Barcelona Health Region (Spain), focusing on the use of clozapine and long-acting injections (LAI). Methods Antipsychotic drugs dispensed for people older than 18 and processed by the Catalan Health Service during 2007 were retrospectively reviewed. First and second generation antipsychotic drugs (FGA and SGA) from the Anatomical Therapeutic Chemical classification (ATC) code N05A (except lithium) were included. A patient selection algorithm was designed to identify prescriptions regularly dispensed. Variables included were age, gender, antipsychotic type, route of administration and number of packages dispensed. Results A total of 117,811 patients were given any antipsychotic, of whom 71,004 regularly received such drugs. Among the latter, 9,855 (13.9%) corresponded to an antipsychotic combination, 47,386 (66.7%) to monotherapy and 13,763 (19.4%) to unspecified combinations. Of the patients given antipsychotics in association, 58% were men. Olanzapine (37.1%) and oral risperidone (36.4%) were the most common dispensations. Analysis of the patients dispensed two antipsychotics (57.8%) revealed 198 different combinations, the most frequent being the association of FGA and SGA (62.0%). Clozapine was dispensed to 2.3% of patients. Of those who were receiving antipsychotics in combination, 6.6% were given clozapine, being clozapine plus amisulpride the most frequent association (22.8%). A total of 3.800 patients (5.4%) were given LAI antipsychotics, and 2.662 of these (70.1%) were in combination. Risperidone was the most widely used LAI. Conclusions The scant evidence available regarding the efficacy of combining different antipsychotics contrasts with the high number and variety of combinations prescribed to outpatients, as well as with the limited use of clozapine. Background To analyse the extent and profile of outpatient regular dispensation of antipsychotics, both in combination and monotherapy, in the Barcelona Health Region (Spain), focusing on the use of clozapine and long-acting injections (LAI). Methods Antipsychotic drugs dispensed for people older than 18 and processed by the Catalan Health Service during 2007 were retrospectively reviewed. First and second generation antipsychotic drugs (FGA and SGA) from the Anatomical Therapeutic Chemical classification (ATC) code N05A (except lithium) were included. A patient selection algorithm was designed to identify prescriptions regularly dispensed. Variables included were age, gender, antipsychotic type, route of administration and number of packages dispensed. Results A total of 117,811 patients were given any antipsychotic, of whom 71,004 regularly received such drugs. Among the latter, 9,855 (13.9%) corresponded to an antipsychotic combination, 47,386 (66.7%) to monotherapy and 13,763 (19.4%) to unspecified combinations. Of the patients given antipsychotics in association, 58% were men. Olanzapine (37.1%) and oral risperidone (36.4%) were the most common dispensations. Analysis of the patients dispensed two antipsychotics (57.8%) revealed 198 different combinations, the most frequent being the association of FGA and SGA (62.0%). Clozapine was dispensed to 2.3% of patients. Of those who were receiving antipsychotics in combination, 6.6% were given clozapine, being clozapine plus amisulpride the most frequent association (22.8%). A total of 3.800 patients (5.4%) were given LAI antipsychotics, and 2.662 of these (70.1%) were in combination. Risperidone was the most widely used LAI. Conclusions The scant evidence available regarding the efficacy of combining different antipsychotics contrasts with the high number and variety of combinations prescribed to outpatients, as well as with the limited use of clozapine

Correction to: Decision making with visualizations: a cognitive framework across disciplines

The original article (Padilla et al., 2018) contained a formatting error in Table 2; this has now been corrected with the appropriate boxes marked clearly