Peripubertal stress-induced behavioral changes are associated with altered expression of genes involved in excitation and inhibition in the amygdala

Early-life stress is a critical risk factor for developing psychopathological alterations later in life. This early adverse environment has been modeled in rats by exposure to stress during the peripubertal period-that is, corresponding to childhood and puberty-and has been shown to lead to increased emotionality, decreased sociability and pathological aggression. The amygdala, particularly its central nucleus (CeA), is hyperactivated in this model, consistent with evidence implicating this nucleus in the regulation of social and aggressive behaviors. Here, we investigated potential changes in the gene expression of molecular markers of excitatory and inhibitory neurotransmission in the CeA. We found that peripubertal stress led to an increase in the expression of mRNA encoding NR1 (the obligatory subunit of the N-methyl D-aspartate (NMDA) receptor) but to a reduction in the level of mRNA encoding glutamic acid decarboxylase 67 (GAD67), an enzyme that is critically involved in the activity-dependent synthesis of GABA, and to an increase in the vesicular glutamate transporter 1 (VGLUT1)/vesicular GABA transporter (VGAT) ratio in the CeA. These molecular alterations were present in addition to increased novelty reactivity, sociability deficits and increased aggression. Our results also showed that the full extent of the peripubertal protocol was required for the observed behavioral and neurobiological effects because exposure during only the childhood/prepubertal period (Juvenile Stress) or the male pubertal period (Puberty Stress) was insufficient to elicit the same effects. These findings highlight peripuberty as a period in which stress can lead to long-term programming of the genes involved in excitatory and inhibitory neurotransmission in the CeA

Epidemiology, Prehospital Characteristics and Outcomes of Severe Traumatic Brain Injury in The Netherlands:The BRAIN-PROTECT Study

Objective: A thorough understanding of the epidemiology, patient characteristics, trauma mechanisms, and current outcomes among patients with severe traumatic brain injury (TBI) is important as it may inform potential strategies to improve prehospital emergency care. The aim of this study is to describe the prehospital epidemiology, characteristics and outcome of (suspected) severe TBI in the Netherlands. Methods: The BRAIN-PROTECT study is a prospective observational study on prehospital management of patients with severe TBI in the Netherlands. The study population comprised all consecutive patients with clinical suspicion of TBI and a prehospital GCS score ≤ 8, who were managed by one of the 4 Helicopter Emergency Medical Services (HEMS). Patients were followed-up in 9 trauma centers until 1 year after injury. Planned sub-analyses were performed for patients with “confirmed” and “isolated” TBI. Results: Data from 2,589 patients, of whom 2,117 (81.8%) were transferred to a participating trauma center, were analyzed. The incidence rate of prehospitally suspected and confirmed severe TBI were 3.2 (95% CI: 3.1;3.4) and 2.7 (95% CI: 2.5;2.8) per 100,000 inhabitants per year, respectively. Median patient age was 46 years, 58.4% were involved in traffic crashes, of which 37.4% were bicycle related. 47.6% presented with an initial GCS of 3. The median time from HEMS dispatch to hospital arrival was 54 minutes. The overall 30-day mortality was 39.0% (95% CI: 36.8;41.2). Conclusion: This article summarizes the prehospital epidemiology, characteristics and outcome of severe TBI in the Netherlands, and highlights areas in which primary prevention and prehospital care can be improved

Onderzoek beleidsaanpak MKB-financieringsmarkt

__De vraagstelling van het onderzoek luidt als volgt:__ _Voorziet het overheidsbeleid, specifiek het EZK MKB financieringsbeleid en het samenspel van de diverse instrumenten, nog steeds in het effectief wegnemen van de knelpunten op de kapitaalmarkt die de beschikbaarheid van passende financieringsarrangementen voor ondernemingen belemmeren en waarin de markt zelf niet voorziet?

Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended