Celebrating the UK's incredible veterinary nurses.

Veterinary Nursing Awareness Month takes place each May and is an opportunity to celebrate these fantastic members of Team Vet. BVA media officer Charlotte Austen-Hardy shares how BVA marked the occasion.

The neurology of chronic nodding syndrome.

Nodding syndrome is an uncommon disorder of childhood onset and unknown cause, presenting with nodding seizures, and which appears to occur exclusively in clusters in sub-Saharan Africa. An endemic pattern of disease was initially described in Tanzania and in Liberia; epidemic occurrences were later reported in South Sudan and northern Uganda. Not the least significant of the many questions remaining about nodding syndrome concerns the common presence or otherwise of neurological features other than seizures-clearly relevant to the core issue of whether this is a focal, primary epileptic disease, or a multi-system CNS disorder, with, in turn implications for its aetiology. We had the opportunity to interview and clinically to examine 57 affected individuals in rural northern Uganda some 10 years after onset. In this observational cross-sectional study, nodding onset was invariably between the ages of 5 and 14, presenting with food-triggered nodding attacks in over 75% of cases; 86% went on to develop other seizure types. In 53 of 57 nodding syndrome individuals (93%), there was a definite history of the child and his or her family having resided in or been fed from an internally displaced person camp for some time prior to the onset of nodding. A half of nodding syndrome sufferers (28/57) had focal neurological abnormalities-mainly pyramidal signs (92%), often asymmetric, some with extrapyramidal abnormalities. Many individuals (28/57) were severely functionally disabled, ranging from 'sometimes can dig' to 'can do nothing at home' or 'cannot even feed herself'. Such sufferers tended more frequently to have significant burns, and clear cognitive impairment. We conclude that nodding syndrome is a unique multisystem CNS disorder of childhood onset and then slow progression over several years often followed by spontaneous stabilisation, consistent with an underlying self-limiting neurodegenerative process. We discuss the possibility that this might be triggered by food-related mycotoxins, within a fixed window of CNS vulnerability during childhood.

Nodding syndrome: a concise review.

Nodding syndrome is an uncommon epileptic disorder of childhood onset, which appears to occur exclusively in clusters in sub-Saharan Africa. It was first reported in the 1960s, in what is now southern Tanzania, then in Liberia, and later in South Sudan and northern Uganda, with both epidemic and endemic patterns described. The cause remains unknown. Here we describe the background and development of descriptions of the disorder, review its clinical features and summarize current theories and studies concerning its cause, outlining the principal remaining research questions relating to this highly unusual disease.

Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase δ.

A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.

Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma.

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease.

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.