Pharmacotherapy for neonatal seizures: current knowledge and future perspectives

Seizures are the most common neurological emergencies in the neonatal period and are associated with poor neurodevelopmental outcomes. Seizures affect up to five per 1000 term births and population-based studies suggest that they occur even more frequently in premature infants. Seizures are a sign of an underlying cerebral pathology, the most common of which is hypoxic-ischaemic encephalopathy in term infants. Due to a growing body of evidence that seizures exacerbate cerebral injury, effective diagnosis and treatment of neonatal seizures is of paramount importance to reduce long-term adverse outcomes. Electroencephalography is essential for the diagnosis of seizures in neonates due to their subtle clinical expression, non-specific neurological presentation and a high frequency of electro-clinical uncoupling in the neonatal period. Hypoxic-ischaemic encephalopathy may require neuroprotective therapeutic hypothermia, accompanying sedation with opioids, anticonvulsant drugs or a combination of all of these. The efficacy, safety, tolerability and pharmacokinetics of seven anticonvulsant drugs (phenobarbital, phenytoin, levetiracetam, lidocaine, midazolam, topiramate and bumetanide) are reviewed. This review is focused only on studies reporting electrographically confirmed seizures and highlights the knowledge gaps that exist in optimal treatment regimens for neonatal seizures. Randomised controlled trials are needed to establish a safe and effective treatment protocol for neonatal seizures

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Pleosporales

One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae

Identification of glucose transporters in Aspergillus nidulans

o characterize the mechanisms involved in glucose transport, in the filamentous fungus Aspergillus nidulans, we have identified four glucose transporter encoding genes hxtB-E. We evaluated the ability of hxtB-E to functionally complement the Saccharomyces cerevisiae EBY.VW4000 strain that is unable to grow on glucose, fructose, mannose or galactose as single carbon source. In S. cerevisiae HxtB-E were targeted to the plasma membrane. The expression of HxtB, HxtC and HxtE was able to restore growth on glucose, fructose, mannose or galactose, indicating that these transporters accept multiple sugars as a substrate through an energy dependent process. A tenfold excess of unlabeled maltose, galactose, fructose, and mannose were able to inhibit glucose uptake to different levels (50 to 80 %) in these s. cerevisiae complemented strains. Moreover, experiments with cyanide-m-chlorophenylhydrazone (CCCP), strongly suggest that hxtB, -C, and –E mediate glucose transport via active proton symport. The A. nidulans ΔhxtB, ΔhxtC or ΔhxtE null mutants showed ~2.5-fold reduction in the affinity for glucose, while ΔhxtB and -C also showed a 2-fold reduction in the capacity for glucose uptake. The ΔhxtD mutant had a 7.8-fold reduction in affinity, but a 3-fold increase in the capacity for glucose uptake. However, only the ΔhxtB mutant strain showed a detectable decreased rate of glucose consumption at low concentrations and an increased resistance to 2-deoxyglucose.The authors would like to thank the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Inhibition of human platelet aggregation by Choisyaternatine isolated from Choisya ternata (Rutaceae)

A newly reported alkaloid was isolated from the hexane extract of Choisya ternata Kunth. (Rutaceae) leaves, identified as 6,8-Dimethoxy-7-(3-methylbut-2-enyloxy)quinolin-2-ol (choisyaternatine) (A), together with the known compounds skimmianine (B), lup-20(29)-en-3?-ol (lupeol) (C) and tecleamaniensine A (D). Compounds C and D are reported for the first time in this species. The structures of isolated compounds were elucidated by extensive spectroscopic analyses and comparison with previously reported spectroscopic data. The structure of choisyaternatine was further confirmed based on X-ray data analysis. Anti-platelet activity of hexane extract, choisyaternatine and skimmianine was also evaluated. The extract was able to significantly inhibit collagen-induced platelet aggregation at all concentrations tested (25, 50 and 100 µg/ml). The new compound, choisyaternatine, has shown a significant inhibition of collagen-induced platelet aggregation demonstrated in a concentration dependent manner from 250 µM. The concentrations which inhibit 50% of platelet aggregation (IC50) were found to be 564 µM for skimmianine and 698 µM for choisyaternatine. This is also the first report for the antiplatelet activity for this plant and these alkaloids using human platelets

Treatment of seizures in the neonate: guidelines and consensus-based recommendations—special report from the ILAE task force on neonatal seizures

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic–ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment option

Mechanisms and therapeutic applications of electromagnetic therapy in Parkinson's disease

© 2015 Vadalà et al. Electromagnetic therapy is a non-invasive and safe approach for the management of several pathological conditions including neurodegenerative diseases. Parkinson's disease is a neurodegenerative pathology caused by abnormal degeneration of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain resulting in damage to the basal ganglia. Electromagnetic therapy has been extensively used in the clinical setting in the form of transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, high-frequency transcranial magnetic stimulation and pulsed electromagnetic field therapy which can also be used in the domestic setting. In this review, we discuss the mechanisms and therapeutic applications of electromagnetic therapy to alleviate motor and non-motor deficits that characterize Parkinson's disease

Quality assurance of teachers’ continuing professional development: design, development and pilot of a CPD quality assurance system - evaluation report

In 2018, the Wellcome Trust and the Education Endowment Foundation commissioned a project to explore the potential development of a quality assurance system for teachers’ Continuing Professional Development (CPD). This scoping work explored existing quality assurance systems and sought to test the potential for widespread, sustainable engagement in such a system. The study included stakeholder consultation, through workshops and surveys, and a review of evidence from literature and policy. We now build upon this earlier scoping study with the design, development and piloting of a quality assurance system for teacher professional development. This pilot project was commissioned by the Wellcome Trust and delivered by a consortium of the Chartered College of Teaching (CCT), the Teacher Development Trust (TDT) and Sheffield Institute of Education (SIOE) – part of Sheffield Hallam University. Full details of the design, testing and outcomes of the quality assurance system are provided in a separate report, which contains a summary of the outcomes of the scoping work, and findings and conclusions from the two cycles of design, testing and evaluation undertaken in the pilot. It also identifies key recommendations for how the quality assurance system may be utilised moving forward to increase the quality of CPD experienced by teachers, including offering guidance to support school leaders in making informed decisions about commissioning CPD which is more likely to lead to positive pupil outcomes. In this report we describe the evaluation, which was delivered in conjunction with the design, development and piloting of a quality assurance system for teacher CPD. This internal, formative evaluation ran alongside the two cycles of testing of the system of quality assurance, to inform both the development of the system during piloting and also future developments of the project beyond this pilot. In this report, we describe the evaluation aims and methodology, detail findings from each participant group, assess the effectiveness of the system, and offer recommendations for the future development of the quality assurance process

Application of a physiologically-based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate

Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates

COVID-19 : is there evidence for the use of herbal medicines as adjuvant symptomatic therapy?

Background: Current recommendations for the self-management of SARS-Cov-2 disease (COVID-19) include self-isolation, rest, hydration, and the use of NSAID in case of high fever only. It is expected that many patients will add other symptomatic/adjuvant treatments, such as herbal medicines. Aims: To provide a benefits/risks assessment of selected herbal medicines traditionally indicated for “respiratory diseases” within the current frame of the COVID-19 pandemic as an adjuvant treatment. Method: The plant selection was primarily based on species listed by the WHO and EMA, but some other herbal remedies were considered due to their widespread use in respiratory conditions. Preclinical and clinical data on their efficacy and safety were collected from authoritative sources. The target population were adults with early and mild flu symptoms without underlying conditions. These were evaluated according to a modified PrOACT-URL method with paracetamol, ibuprofen, and codeine as reference drugs. The benefits/risks balance of the treatments was classified as positive, promising, negative, and unknown. Results: A total of 39 herbal medicines were identified as very likely to appeal to the COVID-19 patient. According to our method, the benefits/risks assessment of the herbal medicines was found to be positive in 5 cases (Althaea officinalis, Commiphora molmol, Glycyrrhiza glabra, Hedera helix, and Sambucus nigra), promising in 12 cases (Allium sativum, Andrographis paniculata, Echinacea angustifolia, Echinacea purpurea, Eucalyptus globulus essential oil, Justicia pectoralis, Magnolia officinalis, Mikania glomerata, Pelargonium sidoides, Pimpinella anisum, Salix sp, Zingiber officinale), and unknown for the rest. On the same grounds, only ibuprofen resulted promising, but we could not find compelling evidence to endorse the use of paracetamol and/or codeine. Conclusions: Our work suggests that several herbal medicines have safety margins superior to those of reference drugs and enough levels of evidence to start a clinical discussion about their potential use as adjuvants in the treatment of early/mild common flu in otherwise healthy adults within the context of COVID-19. While these herbal medicines will not cure or prevent the flu, they may both improve general patient well-being and offer them an opportunity to personalize the therapeutic approaches