MicroRNAs in the pathophysiology and treatment of status epilepticus

MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis

Hippocampal astrogliosis and neuronal cell loss in an experimental P10 neonatal model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of intractable seizure disorder in adults. It is associated with an asymmetrical pattern of neuron loss within the hilus and CA1 hippocampal subfields, with relative sparing of the dentate granule neurons and the CA2 subfields. The amygdalar nuclei and the cortical neurons are other areas that are rarely involved in MTLE.1 The neuropathological changes that bring about focally evoked seizures in the adult are thought to begin in the early stages of neonatal life. A wide range of factors have been implicated in the causation of MTLE, such as febrile seizures and traumatic brain injury.2 Some studies indicate that up to 74% of those who experience early life status epilepticus develop epilepsy at a later stage.2 The objective of this study is to investigate the neuropathological changes induced by intra-amygdalar kainic acid (KA) microinjection in a postnatal day 10 (P10) rat model of MTLE.

The value of nurse mentoring relationships: Lessons learnt from a work-based resilience enhancement programme for nurses working in the forensic setting.

This study aimed to evaluate a mentoring programme embedded in a work-based personal resilience enhancement intervention for forensic nurses. This qualitative study formed part of a wider mixed-methods study that aimed to implement and evaluate the intervention. Twenty-four semistructured interviews were carried out with forensic nurse mentees and senior nurse mentors; these explored their experiences of the mentoring programme and any benefits and challenges involved in constructing and maintaining a mentor-mentee relationship. Qualitative data were analysed thematically using the Framework Method. Four key themes relating to the initiation and maintenance of mentor-mentee relationships were identified: finding time and space to arrange mentoring sessions; building rapport and developing the relationship; setting expectations of the mentoring relationship and the commitment required; and the impact of the mentoring relationship for both mentees and mentors. Study findings highlight the benefits of senior nurses mentoring junior staff and provide evidence to support the integration of mentoring programmes within wider work-based resilience enhancement interventions. Effective mentoring can lead to the expansion of professional networks, career development opportunities, increased confidence and competence at problem-solving, and higher levels of resilience, well-being, and self-confidence

Detection of 14-3-3zeta in cerebrospinal fluid following experimentally evoked seizures.

Surrogate and peripheral (bio)markers of neuronal injury may be of value in assessing effects of seizures on the brain or epilepsy development following trauma. The presence of 14-3-3 isoforms in cerebrospinal fluid (CSF) is a diagnostic indicator of Creutzfeldt-Jakob disease but these proteins may also be present following acute neurological insults. Here, we examined neuronal and 14-3-3 proteins in CSF from rats after seizures. Seizures induced by intra-amygdala microinjection of 0.1 microg kainic acid (KA) caused damage which was mainly restricted to the ipsilateral CA3 subfield of the hippocampus. 14-3-3zeta was detected at significant levels in CSF sampled 4 h after seizures compared with near absence in control CSF. Neuron-specific nuclear protein (NeuN) was also elevated in CSF in seizure rats. CSF 14-3-3zeta levels were significantly lower in rats treated with 0.01 microg KA. These data suggest the presence of 14-3-3zeta within CSF may be a biomarker of acute seizure damage

Mixed methods case study exploring primary care antibiotic prescribing practices and maternal expectations of using antibiotics in children.

BackgroundOveruse of antibiotics and inappropriate prescribing has resulted in rapid development of antimicrobial resistance. Most antibiotics in the United Kingdom (71.4%) are prescribed in primary care by general practitioners, with about half prescribed for viral rather than bacterial illnesses.AimsTo explore antibiotic prescribing and factors which may influence maternal decision making to seek antibiotics for their young children.MethodsData for children under five years was gathered using a mixed methods case study approach. Quantitative general practice antibiotic prescribing data (n = 697 children) was statistically analysed and these results were further explored in six focus groups with mothers (n=19) of children under five. The qualitative data was thematically analysed.ResultsQuantitative data identified nearly half of children received antibiotics. Children under one were prescribed the fewest antibiotics. Qualitative focus group data showed mothers trusted their general practitioner to provide expert care for their child and often wanted convenient and timely access to advice and reassurance, rather than treatment.ConclusionAntibiotics are frequently prescribed for young children in primary care. Healthcare professionals need to understand the maternal influences contributing to antibiotic use in children and consider strategies and interventions to reduce unnecessary antibiotic prescriptions.Impact statement- implications for research/practiceNurses and health visitors should have a greater role in supporting maternal decision making for managing their children's illnesses

miRNA-Mediated Regulation of Adult Hippocampal Neurogenesis; Implications for Epilepsy

Hippocampal neural stem/progenitor cells (NSPCs) proliferate and differentiate to generate new neurons across the life span of most mammals, including humans. This process takes place within a characteristic local microenvironment where NSPCs interact with a variety of other cell types and encounter systemic regulatory factors. Within this microenvironment, cell intrinsic gene expression programs are modulated by cell extrinsic signals through complex interactions, in many cases involving short non-coding RNA molecules, such as miRNAs. Here we review the regulation of gene expression in NSPCs by miRNAs and its possible implications for epilepsy, which has been linked to alterations in adult hippocampal neurogenesis

Kainic acid-induced seizures modulate Akt (SER473) phosphorylation in the hippocampus of dopamine D2 receptor knockout mice.

Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death. D2R knockout (D2R-/-) mice are more susceptible to kainic acid (KA)-induced excitotoxicity, displaying cell death in the CA3 subfield of the hippocampus at KA doses not damaging in wild-type (WT) animals. Absence of D2R signalling in the hippocampus leads to activation (dephosphorylation) of glycogen synthase kinase 3β (GSK-3β) after KA (20 mg/kg), which is not associated with a change in the phosphorylation of the GSK-3β regulator Akt at the canonical threonine 308 residue. In the present study, we investigated alternative pathways responsible for the activation of GSK-3β in the hippocampus of the D2R-/- mice 24 h following KA-induced seizures. Here, we show that phosphorylation of Akt occurs at serine 473 (Ser473) in the CA3 region of WT but not D2R-/- mice following KA. Moreover, the CA1 subregion, which does not undergo neurodegeneration in either WT or D2R-/- mice, displays a strong induction of Akt (Ser473) phosphorylation after KA. Additionally, the vulnerability in the CA3 is not associated with changes to p38MAPK and Dishevelled activation, and β-catenin does not appear to be a downstream target of the GSK-3β. Thus, we propose that GSK-3β phosphorylation-mediated hippocampal cell survival may depend on Akt (Ser473) phosphorylation; loss of D2R-mediated signalling in the CA3 region of D2R-/- mice leads to reduced Akt (Ser473) phosphorylation rendering neurons more vulnerable to apoptosis. Further investigation is required to fully elucidate the GSK-3β targets involved in D2R-dependent response to excitotoxicity

Dynamic Field Programmable Logic-Driven Soft Exosuit

The next generation of etextiles foresees an era of smart wearable garments where embedded seamless intelligence provides the ability to sense, process and perform. Core to this vision is embedded textile functionality enabling dynamic configuration. In this paper we detail a methodology, design and implementation of a dynamic field programmable logic-driven fabric soft exosuit. Dynamic field programmability allows the soft exosuit to alter its functionality and adapt to specific exercise programs depending on the wearers need. The dynamic field programmability is enabled through motion based control arm movements of the soft exosuit triggering momentary sensors embedded in the fabric exosuit at specific joint placement points (right arm: wrist, elbow).The embedded circuitry in the fabric exosuit is implemented using a layered and interchangeable approach. This includes logic gate patches (AND,OR,NOT) and a layered textile interconnection panel. This modular and interchangeable design enhances the soft exosuits flexibility and adaptability. A truth table aligning to a rehabilitation healthcare use case was utilised. Tests were completed validating the field programmability of the soft exosuit and its capability to switch between its embedded logic driven circuitry and its operational and functionality options controlled by motion movement of the wearers right arm (elbow and wrist). Iterative exercise movement and acceleration based tests were completed to validate the functionality of the field programmable logic driven fabric exosuit. We demonstrate a working soft exosuit prototype with motion controlled operational functionality that can be applied to rehabilitation applications.Comment: 20 pages, 9 figure

P2X receptors as targets for the treatment of status epilepticus.

Prolonged seizures are amongst the most common neurological emergencies. Status epilepticus is a state of continuous seizures that is life-threatening and prompt termination of status epilepticus is critical to protect the brain from permanent damage. Frontline treatment comprises parenteral administration of anticonvulsants such as lorazepam that facilitate γ-amino butyric acid (GABA) transmission. Because status epilepticus can become refractory to anticonvulsants in a significant proportion of patients, drugs which act on different neurotransmitter systems may represent potential adjunctive treatments. P2X receptors are a class of ligand-gated ion channel activated by ATP that contributes to neuro- and glio-transmission. P2X receptors are expressed by both neurons and glia in various brain regions, including the hippocampus. Electrophysiology, pharmacology and genetic studies suggest certain P2X receptors are activated during pathologic brain activity. Expression of several members of the family including P2X2, P2X4, and P2X7 receptors has been reported to be altered in the hippocampus following status epilepticus. Recent studies have shown that ligands of the P2X7 receptor can have potent effects on seizure severity during status epilepticus and mice lacking this receptor display altered seizures in response to chemoconvulsants. Antagonists of the P2X7 receptor also modulate neuronal death, microglial responses and neuroinflammatory signaling. Recent work also found altered neuronal injury and inflammation after status epilepticus in mice lacking the P2X4 receptor. In summary, members of the P2X receptor family may serve important roles in the pathophysiology of status epilepticus and represent novel targets for seizure control and neuroprotection