The phorbol derivatives thymeleatoxin and 12-deoxyphorbol-13-O-phenylacetate-10-acetate cause translocation and down-regulation of multiple protein kinase C isozymes

AbstractPhorbol esters such as phorbol 12-myristate,13-acetate (PMA) are potent activators of protein kinase C (PKC), and activate all PKC isozymes except ζ, and λ. Recently, 12-deoxyphorbol-13-O-phenylacetate-20-acetate (dPPA) and thymeleatoxin (Tx) were reported to selectively activate PKCβ1 (dPPA) and PKCα, -β, and -γ (Tx), but not PKCδ or PKCϵ in vitro. We examined the ability of these phorbol derivatives to translocate and down-regulate PKC isozymes in intact cells. Our findings demonstrate that dPPA and Tx cause translocation and down-regulation of multiple PKC isozymes, including δ and ϵ

Dravet’n oireyhtymä - vaikea neurologinen harvinaissairaus

VertaisarvioituDravet’n oireyhtymä on harvinainen, mutta todennäköisesti alidiagnosoitu sairaus. Sen tavallisin syy on hermosolujen natriumkanavien toimintaa säätelevän SCN1A-geenin virhe. Sairaus alkaa infektioon, rokotukseen tai muuhun lämmönnousuun liittyvillä pitkittyneillä kuumekouristuksilla ensimmäisen ikävuoden aikana. Vaikea epilepsia on tunnetuin oire, mutta useimmilla on myös vaikeita kognitiivisia ja motorisia häiriöitä. Diagnoosilla on merkitystä, koska epilepsialääkkeiden oikealla valinnalla voidaan estää sarjakohtaukset ja lievittää oireita. Lapset tulee rokottaa normaalisti diagnoosista huolimatta.Peer reviewe

Epilepsiapotilas päivystyksessä

Vertaisarvioitu. English summaryEpilepsiapotilaat ohjautuvat päivystykseen ensimmäisen, pitkittyneen, tiheästi toistuvan tai komplisoituneen kohtauksensa vuoksi. Nopea ja oikein kohdennettu hoito parhaassa tapauksessa estää kohtauksen vaikeutumisen status epilepticukseksi. Hoitoketjun eri vaiheiden saumaton eteneminen selkeän hoitoprotokollan mukaan on pitkittyneen epilepsiakohtauksen saaneen potilaan ennusteen kannalta keskeistä. Viiveettömän hoidon toteutuksen lisäksi lääkehoidon valinnassa tulisi huomioida epilepsian ja pitkittyneen kohtauksen tyyppi, etiologia ja niihin liittyvät epävarmuustekijät. Aikuispotilaiden osalta korostuvat liitännäissairaudet, niihin liittyvät hoidot ja kohtaustilanteen vaikeutumisen muut syyt. Vaikeassa kohtaustilanteessa epileptologisen yksikön konsultoiminen on tarpeen. Jos potilaan status epilepticus on vaikeahoitoinen, konsultaation tulisi toteutua kiireellisesti. Päivystyspisteiden osuus on merkittävä paitsi viiveettömässä kohtausten hoidossa myös jatkohoidon toteutuksessa ja ohjauksessa.Peer reviewe

Feasibility of video/audio monitoring in the analysis of motion and treatment effects on night-time seizures - Interventional study

The aim of the study: This pilot study assessed the ability of a video/audio-based seizure monitoring system to evaluate (I) baseline frequency and severity of nocturnal seizures with motor features in patients with drugresistant epilepsy (DRE) and (II) the individual effect of brivaracetam (BRV) treatment on number, duration and movement intensity of these seizure types. Algorithmic feature analysis was developed for assessment of qualitative changes in movement intensity measurements within seizure types before and after BRV intervention. Materials and methods: Night-time motor seizures of recruited patients were recorded in two separate four-week monitoring periods. The first period defined a prescreening phase (n = 13 patients) to establish a baseline, and the second period defined the intervention phase (n = 9 patients), with BRV initiated during the second week of the second monitoring period. All recorded nights were analyzed by an expert video reviewer, and all unequivocal seizures were classified by an epileptologist. Seizure frequencies using both seizure diaries and video monitoring were compared. The effect of BRV on both seizure duration and movement intensity was assessed by numerical comparison of visual features calculated from motion characteristics of the video, as well as spectral features from the recorded audio. The statistical significance of changes in seizure duration and intensity before and after the intervention were investigated by Wilcoxon rank-sum test and visual inspection of Kernel density estimation. Results: 8 patients marked seizures in their seizure diaries during the prescreening phase. During the three-week follow-up, three patients achieved > 50% seizure decrease, four patients did not respond to treatment, and two patients experienced worsening of seizures. Five patients were able to document 40-70% of their seizures compared to the video/audio monitoring system. According to the signal feature analysis the intervention decreased movement intensity with clear clinical significance in three patients, whereas statistically significant differences in features appeared in 8 out of 9 patients. Conclusions: The novel video/audio monitoring system improved the evaluation of treatment effect compared to the seizure diaries and succeeded in providing a comparative intra-patient assessment of the movement intensity and duration of the recorded seizures.Peer reviewe

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs

Introduction: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developitiental aberrations associated with prenatal AED exposure-could be-detected already in infancy and whether effects on visual attention can be observed at this early age. Material and methods: We compared a prospective cohort of infants with in utero exposure to AED (n = 56) with infants without drug exposures (n = 62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. Results: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. Discussion: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds

Introduction: Prenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. Material and methods: Data on AED exposure. pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. Results: Frontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. Conclusions: These preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Feasibility of video/audio monitoring in the analysis of motion and treatment effects on night-time seizures - Interventional study

The aim of the study: This pilot study assessed the ability of a video/audio-based seizure monitoring system to evaluate (I) baseline frequency and severity of nocturnal seizures with motor features in patients with drugresistant epilepsy (DRE) and (II) the individual effect of brivaracetam (BRV) treatment on number, duration and movement intensity of these seizure types. Algorithmic feature analysis was developed for assessment of qualitative changes in movement intensity measurements within seizure types before and after BRV intervention.Materials and methods: Night-time motor seizures of recruited patients were recorded in two separate four-week monitoring periods. The first period defined a prescreening phase (n = 13 patients) to establish a baseline, and the second period defined the intervention phase (n = 9 patients), with BRV initiated during the second week of the second monitoring period. All recorded nights were analyzed by an expert video reviewer, and all unequivocal seizures were classified by an epileptologist.Seizure frequencies using both seizure diaries and video monitoring were compared.The effect of BRV on both seizure duration and movement intensity was assessed by numerical comparison of visual features calculated from motion characteristics of the video, as well as spectral features from the recorded audio. The statistical significance of changes in seizure duration and intensity before and after the intervention were investigated by Wilcoxon rank-sum test and visual inspection of Kernel density estimation.Results: 8 patients marked seizures in their seizure diaries during the prescreening phase. During the three-week follow-up, three patients achieved > 50% seizure decrease, four patients did not respond to treatment, and two patients experienced worsening of seizures. Five patients were able to document 40-70% of their seizures compared to the video/audio monitoring system. According to the signal feature analysis the intervention decreased movement intensity with clear clinical significance in three patients, whereas statistically significant differences in features appeared in 8 out of 9 patients.Conclusions: The novel video/audio monitoring system improved the evaluation of treatment effect compared to the seizure diaries and succeeded in providing a comparative intra-patient assessment of the movement intensity and duration of the recorded seizures