The potential role of DNA methylation as preventive treatment target of epileptogenesis

Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures—the process of epileptogenesis—could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis

How can antiepileptic drugs affect bone mass, structure and metabolism? Lessons from animal studies

SummaryPatients with epilepsy, treated with antiepileptic drugs (AEDs) are at increased risk of fractures. Although several commonly used AEDs reduce bone mass in patients, the mechanisms are only scarcely known. In this review, we focus on the usefulness of animal models to explore the skeletal effects of AEDs. Moreover, we report our findings from a recent study comparing the effect of levetiracetam (LEV), phenytoin (PHT) and valproate (VPA) on various aspects of bone health in actively growing female rats. Our data indicate that these AEDs act differently on bone mass, structure and metabolism. A novel finding is that LEV reduces bone strength and bone formation without altering bone mass. Based on these results we propose that epidemiological fracture studies of patients treated with LEV are needed, and that these patients should be evaluated regularly to identify possible bone-related side effects

Long-term levetiracetam treatment affects reproductive endocrine function in female Wistar rats

SummaryPurposeSeveral antiepileptic drugs (AEDs) induce changes in endocrine function in women with epilepsy. Levetiracetam (LEV) is one of the newer AEDs, and to date no endocrine side-effects have been reported in humans. However, a recent study on ovarian follicular cells from prepubertal pigs showed that LEV affected basal steroid hormone secretion. The aim of the present study was to investigate possible effects of the drug on endocrine function and ovarian morphology in non-epileptic rats.MethodsThirty female Wistar rats were fed per-orally with either 50mg/kg LEV (n=15) or 150mg/kg LEV (n=15) twice daily for 90–95 days. Twenty rats received a control solution. The rats were killed in the dioestrus phase of the oestrous cycle. Serum concentrations of testosterone, 17β-oestradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH) and LEV were measured, and the ovaries examined histologically.ResultsMean ovarian weight showed a significant, dose-dependent increase after LEV treatment. Mean numbers of ovarian follicular cysts were not changed, but the numbers of corpora lutea and secondary follicles were significantly higher in the treated animals. Serum testosterone was significantly increased in treated animals (0.50nmol/l versus 0.16nmol/l in controls, p<0.05), while oestradiol was reduced (67.4 compared to 257.5pmol/l in controls, p<0.05). The low-dose group had significantly lower serum progesterone concentrations than the control group (56.8nmol/l versus 34.7nmol/l, respectively, p<0.05). FSH was reduced in the treated animals (3.3ng/ml versus 5.5ng/ml, p<0.05) while LH was unaffected.ConclusionOur findings indicate a possible effect of LEV on the hypothalamic–pituitary–gonadal (HPG) axis and ovarian morphology in non-epileptic rats. The effects differ from those previously described for other AEDs. Caution must be taken before these results can be applied to humans

Risk of epilepsy after traumatic brain injury: a nationwide Norwegian matched cohort study

BackgroundPost-traumatic epilepsy (PTE) is a well-known complication of traumatic brain injury (TBI). Although several risk factors have been identified, prediction of PTE is difficult. Changing demographics and advances in TBI treatment may affect the risk of PTE. Our aim was to provide an up-to-date estimate of the incidence of PTE by linking multiple nationwide registers.MethodsPatients with TBI admitted to hospital 2015–2018 were identified in the Norwegian Trauma Registry and matched to trauma-free controls on sex and birth year according to a matched cohort design. They were followed up for epilepsy in nationwide registers 2015–2020. Cumulative incidence of epilepsy in TBI patients and controls was estimated taking competing risks into account. Analyses stratified by the Abbreviated Injury Scale (AIS) severity score, Glasgow Coma Scale score and age were conducted for the TBI group. Occurrence of PTE in different injury types was visualized using UpSet plots.ResultsIn total, 8,660 patients and 84,024 controls were included in the study. Of the patients, 3,029 (35%) had moderate to severe TBI. The cumulative incidence of epilepsy in the TBI group was 3.1% (95% Confidence Interval [CI] 2.8–3.5%) after 2 years and 4.0% (3.6–4.5%) after 5 years. Corresponding cumulative incidences in the control group were 0.2% (95% CI 0.2–0.3%) and 0.5% (0.5–0.6%). The highest incidence was observed in patients with severe TBI according to AIS (11.8% [95% CI 9.7–14.4%] after 2 years and 13.2% [10.8–16.0%] after 5 years) and in patients &gt;40 years of age.ConclusionPatients with TBI have significantly higher risk of developing epilepsy compared to population controls. However, PTE incidence following moderate–severe TBI was notably lower than what has been reported in several previously published studies

Why sex hormones matter for neuroscience: A very short review on sex, sex hormones, and functional brain asymmetries

Biological sex and sex hormones are known to affect functional cerebral asymmetries (FCAs). Men are generally more lateralized than women. The effect size of this sex difference is small but robust. Some of the inconsistencies in the literature may be explained by sex-related hormonal differences. Most studies focusing on neuromodulatory properties of sex hormones on FCAs have investigated women during the menstrual cycle. Although contradictions exist, these studies have typically shown that levels of estradiol and/or progesterone correlate with the degree of FCAs, suggesting that sex differences in FCAs partially depend on hormonal state and day of testing. The results indicate that FCAs are not fixed but are hormone dependent, and as such they can dynamically change within relatively short periods throughout life. Many issues raised in this Mini-Review refer not only to FCAs but also to other aspects of functional brain organization, such as functional connectivity within and between the cerebral hemispheres. Our understanding of sex differences in brain and behavior as well as their clinical relevance will improve significantly if more studies routinely take sex and sex hormones into account

Vann, juss og samfunn

Society’s use and management of water relies on professional expertise spanning diverse fields: from biology and technology to economics and law. This book examines current issues related to regulating water through chapters summarizing various sets of regulation as well as chapters that take a scientific deep dive into selected themes. The diversity of professional expertise is also reflected in the law aspect. We explore such subjects as surface runoff, natural disasters, drinking water, groundwater, salmon, hydropower, and human rights, as well as general impact assessment requirements and duty of knowledge in environmental law administration. A key objective of the book has been to provide an interdisciplinary understanding of the legal circumstances associated with water, and in addition, deliberate the pros and cons of some of the current regulations. This book will be particularly useful for those who in various ways support and facilitate procedures within the public sector at both the national and municipal levels. It will also be useful for private sector actors seeking familiarity with legal questions that can arise in relation to public administration and other private actors. From a broader perspective, we hope the book can help to throw light on conflicts between different interests and groups within society that occur, for example, when introducing fees, special injunctions against private actors, and requirements for knowledge basis. This book project is the result of legal research conducted at the Norwegian University of Life Sciences (NMBU) and is supplemented by national expertise in several areas. It has been edited by Steinar Taubøll, a professor at NMBU’s Department of Property and Law. Taubøll has a background in both law and the natural sciences, and extensive experience with interdisciplinary work.Håndtering og bruk av vann i samfunnet krever et faglig mangfold fra biologi og teknikk til økonomi og juss. Denne boken drøfter aktuelle temaer knyttet til rettslig regulering av vann, både i form av oversiktskapitler om ulike regelsett og gjennom vitenskapelige dypdykk i utvalgte temaer. Den faglige spennvidden gjenspeiler seg også innen det juridiske. I boken finner man stoff om overvannshåndtering, naturfare, drikkevann, grunnvann, villaks, kraftutbygging, menneskerettigheter, samt om generelle utredningskrav og kunnskapsplikter i miljørettsforvaltning. Et sentralt siktemål er å bygge opp tverrfaglig forståelse av gjeldende juridiske forhold knyttet til vann, og dessuten sette noen av dagens reguleringer under debatt. Boken retter seg særlig til de ressurspersonene som på ulike måter støtter saksbehandlingen i stat og kommune. Boken antas også å være nyttig for private aktører som vil gjøre seg mer kjent med rettsspørsmål som kan oppstå i forhold til forvaltningen og til andre private aktører. I et bredere perspektiv er det dessuten ønskelig at boken kan bidra til å belyse konflikter mellom ulike hensyn og grupper i samfunnet, for eksempel ved innføring av gebyrer, pålegg rettet mot private, innføring av tyngende vilkår og krav til kunnskap og faktagrunnlag. Bokprosjektet springer ut av den juridiske forskningen ved Norges miljø- og biovitenskapelige universitet, og har i tillegg knyttet til seg nasjonal spisskompetanse på mange temaer. Bokas redaktør er dosent Steinar Taubøll ved Institutt for eiendom og juss ved NMBU, som har naturfaglig og juridisk utdannelse, samt lang erfaring med tverrfaglig arbeid

Vann, juss og samfunn

Society’s use and management of water relies on professional expertise spanning diverse fields: from biology and technology to economics and law. This book examines current issues related to regulating water through chapters summarizing various sets of regulation as well as chapters that take a scientific deep dive into selected themes. The diversity of professional expertise is also reflected in the law aspect. We explore such subjects as surface runoff, natural disasters, drinking water, groundwater, salmon, hydropower, and human rights, as well as general impact assessment requirements and duty of knowledge in environmental law administration. A key objective of the book has been to provide an interdisciplinary understanding of the legal circumstances associated with water, and in addition, deliberate the pros and cons of some of the current regulations. This book will be particularly useful for those who in various ways support and facilitate procedures within the public sector at both the national and municipal levels. It will also be useful for private sector actors seeking familiarity with legal questions that can arise in relation to public administration and other private actors. From a broader perspective, we hope the book can help to throw light on conflicts between different interests and groups within society that occur, for example, when introducing fees, special injunctions against private actors, and requirements for knowledge basis. This book project is the result of legal research conducted at the Norwegian University of Life Sciences (NMBU) and is supplemented by national expertise in several areas. It has been edited by Steinar Taubøll, a professor at NMBU’s Department of Property and Law. Taubøll has a background in both law and the natural sciences, and extensive experience with interdisciplinary work

Identification of Srp9 as a febrile seizure susceptibility gene

Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. Methods: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients. Results: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE. Interpretation: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment