Expression of circ_Satb1 is decreased in mesial temporal lobe epilepsy and regulates dendritic spine morphology

Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis

Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine

Rationale: Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine. Objective: This study aims to evaluate the role of mGlu5 and dopamine receptors in the development of cocaine- and morphine-induced conditioned place preference (CPP) and psychomotor sensitization. Materials and methods: Rats were treated with the mGlu5 receptor antagonist MTEP (0, 1, 3, and 10 mg/kg, i.p.) or the dopamine receptor antagonist α-flupenthixol (0, 0.125, 0.25, and 0.5 mg/kg, i.p.) during place conditioning with either morphine (3 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). Furthermore, MTEP (1 mg/kg, i.p.) or α-flupenthixol (0.5 mg/kg, i.p.) was co-administered during cocaine (30 mg/kg, i.p.) or morphine (3.0 mg/kg, s.c.) pretreatment and psychomotor sensitization was tested 3 weeks post-treatment. Results: MTEP attenuated the development of morphine- but not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine- but not morphine-induced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine- and morphine-induced CPP but did not affect the development of sensitization to either drug. Conclusion: Dopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific

Prognosetafel AG2014

Met de publicatie van de Prognosetafel AG2014 presenteert het AG de meest recente inschatting van de toekomstige sterfte voor de Nederlandse bevolking. Deze inschatting is gebaseerd op zowel Nederlandse sterftedata als sterftedata van Europese landen met een vergelijkbare welvaart als in Nederland. De Prognosetafel AG2014 is de eerste AGprognosetafel die is gebaseerd op een onderliggend stochastisch model. Ook heeft de Prognosetafel AG2014 een langere horizon dan de 51 jaar van de vorige prognosetafel (Prognosetafel AG2012-2062). De Prognosetafel AG2014 vervangt de Prognosetafel AG2012-2062 die in september 2012 door het AG werd gepubliceerd. Uit de Prognosetafel AG2014 blijkt dat de sterftekansen voor zowel vrouwen als mannen nog steeds dalen en dat de levensverwachting blijft stijgen. Met het nieuwe stochastische model, waarin sterftekansen van vergelijkbare Europese landen zijn meegenomen, is een vervolgstap gezet om de sterftekansen voor de Nederlandse bevolking beter in te schatten. Op basis van de laatste inzichten bedraagt de levensverwachting van een in 2014 geboren vrouw 92,2 jaar en van een in 2014 geboren man 89,9 jaar. Deze levensverwachting is berekend op basis van de definitie van cohortlevensverwachting. Naar verwachting stijgt de levensverwachting van jongens en meisjes die in de komende 50 jaar worden geboren verder met 3 à 4 jaar. Pensioenfondsen en verzekeraars kunnen de Prognosetafel AG2014 gebruiken voor het vaststellen en toetsen van hun technische voorzieningen en hun premies. De effecten zullen niet voor alle pensioenfondsen en pensioenportefeuilles hetzelfde zijn. Verschillen in effecten zijn vooral afhankelijk van de verhouding in aantallen tussen jonge en oude deelnemers, van de verhouding tussen mannen en vrouwen en van de samenstelling van de pensioenverplichtingen binnen de genoemde fondsen en portefeuilles. Algemeen kan worden gesteld dat bij pensioenfondsen en pensioenportefeuilles met relatief veel ouderen en relatief veel mannen, de technische voorzieningen iets zullen dalen en dat bij pensioenfondsen en pensioenportefeuilles met relatief veel jongeren en relatief veel vrouwen de technische voorzieningen iets zullen stijgen. Op geaggregeerd niveau is het verschil in uitkomsten tussen de Prognosetafel AG2014 en de Prognosetafel AG2012-2062 op de technische voorziening naar verwachting beperkt. Indien de Prognosetafel AG2014 wordt gebruikt voor de eerstvolgende vaststelling (2019) van de AOW-leeftijd dan is er op basis van de huidige wetgeving naar verwachting geen reden de AOW-leeftijd in 2024 verder te verhogen

Factors associated with presenting late or with advanced HIV disease in the Netherlands, 1996 2014: Results from a national observational cohort

Objectives: Early testing for HIV and entry into care are crucial to optimise treatment outcomes of HIV-infected patients and to prevent spread of HIV. We examined risk factors for presentation with late or advanced disease in HIV-infected patients in the Netherlands. Methods: HIV-infected patients registered in care between January 1996 and June 2014 were selected from the ATHENA national observational HIV cohort. Risk factors for late presentation and advanced disease were analysed by multivariable logistic regression. Furthermore, geographical differences and time trends were examined. Results: Of 20 965 patients, 53% presented with latestage HIV infection, and 35% had advanced disease. Late presentation decreased from 62% (1996) to 42% (2013), while advanced disease decreased from 46% to 26%. Late presentation only declined significantly among men having sex with men (MSM; p <0.001), but not among heterosexual males (p=0.08) and females (p=0.73). Factors associated with late presentation were: heterosexual male (adjusted OR (aOR), 1.59; 95% CI 1.44 to 1.75 vs MSM), injecting drug use (2.00; CI 1.69 to 2.38), age .50 years (1.46; CI 1.33 to 1.60 vs 30.49 years), region of origin (South-East Asia 2.14; 1.80 to 2.54, sub-Saharan Africa 2.11; 1.88 to 2.36, Surinam 1.59; 1.37 to 1.84, Caribbean 1.31; 1.13 to 1.53, Latin America 1.23; 1.04 to 1.46 vs the Netherlands), and location of HIV diagnosis (hospital 3.27; 2.94 to 3.63, general practitioner 1.66; 1.50 to 1.83, antenatal screening 1.76; 1.38 to 2.34 vs sexually transmitted infection clinic). No association was found for socioeconomic status or level of urbanisation. Compared with Amsterdam, 2 regions had higher adjusted odds and 2 regions had lower odds of late presentation. Results were highly similar for advanced disease. Conclusions: Although the overall rate of late presentation is declining in the Netherlands, targeted programmes to reduce late HIV diagnoses remain needed for all risk groups, but should be prioritised for heterosexual males, migrant populations, people aged ≥50 years and certain regions in the Netherlands