Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-&amp;#x03BA;B (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK&lt;sup&gt;-/-&lt;/sup&gt; BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.</jats:p

Dissociative symptoms and sleep parameters: an all-night polysomnography study in patients with insomnia

AbstractBackgroundDissociative disorders encompass a range of symptoms varying from severe absent-mindedness and memory problems to confusion about one's own identity. Recent studies suggest that these symptoms may be the by-products of a labile sleep–wake cycle.MethodsIn the current study, we explored this issue in patients suffering from insomnia (N=46). We investigated whether these patients have raised levels of dissociative symptoms and whether these are related to objective sleep parameters. Patients stayed for at least one night in a specialized sleep clinic, while sleep EEG data were obtained. In addition, they completed self-report measures on dissociative symptoms, psychological problems, and sleep characteristics.ResultsDissociative symptom levels were elevated in patients suffering from insomnia, and were correlated with unusual sleep experiences and poor sleep quality. Longer REM sleep periods and less time spent awake during the night were predictive of dissociation.ConclusionsThis is the first study to show that insomnia patients have raised dissociative symptom levels and that their dissociative symptoms are related to objective EEG parameters. These findings are important because they may inspire sleep-related treatment methods for dissociative disorders

De consultatie-liaisonpsychiatrie in de Belgische ziekenhuizen van de eenentwintigste eeuw : quo vadis?

In een tijd waarin de geneeskunde zich uitsplitst in een groeiend aantal specialismen, subspecialismen en superspecialismen is er in de algemene en de universitaire ziekenhuizen een toenemende nood aan multidisciplinaire samenwerking. Deze vorm van samenwerking is nodig om hoogstaande holistische zorg te blijven verlenen aan de patiënt als centrale figuur in het zorgproces. De technologische mogelijkheden in de geneeskundige zorg nemen toe, maar er is een belangrijke comorbiditeit tussen de medische aandoeningen. De consultatie-liaisonpsychiatrie (CLP) is een van de disciplines die hierop inspeelt. Deze discipline focust vanuit een multidisciplinaire en integrale zorgvisie op de psychiatrische diagnostiek en behandeling van patiënten met psychiatrische en somatische comorbiditeit die hiervoor behandeld en opgevolgd worden in een algemeen ziekenhuis. Dit artikel wil een overzicht geven van de functies van de CLP zowel binnen als buiten het ziekenhuis en licht het historische en huidige Belgische beleid en de wetgeving ter zake toe. Er worden ook aanbevelingen geformuleerd voor de toekomst en men pleit voor de implementatie van de CLP als een volwaardige en structurele klinische activiteit en opdracht in de algemene ziekenhuizen

Structural and Functional Brain Abnormalities Associated With Exposure to Different Childhood Trauma Subtypes: A Systematic Review of Neuroimaging Findings

Background: Childhood trauma subtypes sexual abuse, physical abuse, emotional maltreatment, and neglect may have differential effects on the brain that persist into adulthood. A systematic review of neuroimaging findings supporting these differential effects is as yet lacking.Objectives: The present systematic review aims to summarize the findings of controlled neuroimaging trials regarding long-term differential effects of trauma subtypes on the human brain.Methods: A systematic literature search was performed using the PubMed and PsycINFO databases from January 2017 up to and including January 2018. Additional papers were identified by a manual search in the reference lists of selected papers and of relevant review articles retrieved by the initial database search. Studies were then assessed for eligibility by the first author. Only original human studies directly comparing neuroimaging findings of exposed and unexposed individuals to well-defined emotional, physical or sexual childhood maltreatment while controlling for the effects of other subtypes were included. A visual summary of extracted data was made for neuroimaging modalities for which comparison between trauma subtypes was feasible, taking the studies' numbers and sample sizes into account.Results: The systematic literature search yielded 25 publications. Sexual abuse was associated with structural deficits in the reward circuit and genitosensory cortex and amygdalar hyperreactivity during sad autobiographic memory recall. Emotional maltreatment correlated with abnormalities in fronto-limbic socioemotional networks. In neglected individuals, white matter integrity and connectivity were disturbed in several brain networks involved in a variety of functions. Other abnormalities, such as reduced frontal cortical volume, were common to all maltreatment types.Conclusions: There is some evidence for long-term differential effects of trauma subtypes on the human brain. The observed alterations may result from both protective adaptation of and damage to the brain following exposure to threatening life events. Though promising, the current evidence is incomplete, with few brain regions and neuroimaging modalities having been investigated in all subtypes. The comparability of the available evidence is further limited by the heterogeneity of study populations regarding gender, age and comorbid psychopathology. Future neuroimaging studies should take this potentially differential role of childhood trauma subtypes into account

Multiplicity and Diversity of Plasmodium vivax Infections in a Highly Endemic Region in Papua New Guinea

Plasmodium vivax is highly endemic in the lowlands of Papua New Guinea and accounts for a large proportion of the malaria cases in children less than 5 years of age. We collected 2117 blood samples at 2-monthly intervals from a cohort of 268 children aged 1 to 4.5 years and estimated the diversity and multiplicity of P. vivax infection. All P. vivax clones were genotyped using the merozoite surface protein 1 F3 fragment (msp1F3) and the microsatellite MS16 as molecular markers. High diversity was observed with msp1F3 (HE = 88.1%) and MS16 (HE = 97.8%). Of the 1162 P. vivax positive samples, 74% harbored multi-clone infections with a mean multiplicity of 2.7 (IQR = 1–3). The multiplicity of P. vivax infection increased slightly with age (P = 0.02), with the strongest increase in very young children. Intensified efforts to control malaria can benefit from knowledge of the diversity and MOI both for assessing the endemic situation and monitoring the effects of interventions

Use of pJANUS™-02-001 as a calibrator plasmid for Roundup Ready soybean event GTS-40-3-2 detection: an interlaboratory trial assessment

Owing to the labelling requirements of food and feed products containing materials derived from genetically modified organisms, quantitative detection methods have to be developed for this purpose, including the necessary certified reference materials and calibrator standards. To date, for most genetically modified organisms authorized in the European Union, certified reference materials derived from seed powders are being developed. Here, an assessment has been made on the feasibility of using plasmid DNA as an alternative calibrator for the quantitative detection of genetically modified organisms. For this, a dual-target plasmid, designated as pJANUS™-02-001, comprising part of a junction region of genetically modified soybean event GTS-40-3-2 and the endogenous soybean-specific lectin gene was constructed. The dynamic range, efficiency and limit of detection for the soybean event GTS-40-3-2 real-time quantitative polymerase chain reaction (Q-PCR) system described by Terry et al. (J AOAC Int 85(4):938–944, 2002) were shown to be similar for in house produced homozygous genomic DNA from leaf tissue of soybean event GTS-40-3-2 and for plasmid pJANUS™-02-001 DNA backgrounds. The performance of this real-time Q-PCR system using both types of DNA templates as calibrator standards in quantitative DNA analysis was further assessed in an interlaboratory trial. Statistical analysis and fuzzy-logic-based interpretation were performed on critical method parameters (as defined by the European Network of GMO Laboratories and the Community Reference Laboratory for GM Food and Feed guidelines) and demonstrated that the plasmid pJANUS™-02-001 DNA represents a valuable alternative to genomic DNA as a calibrator for the quantification of soybean event GTS-40-3-2 in food and feed products

A New Single-Step PCR Assay for the Detection of the Zoonotic Malaria Parasite Plasmodium knowlesi

Recent studies in Southeast Asia have demonstrated substantial zoonotic transmission of Plasmodium knowlesi to humans. Microscopically, P. knowlesi exhibits several stage-dependent morphological similarities to P. malariae and P. falciparum. These similarities often lead to misdiagnosis of P. knowlesi as either P. malariae or P. falciparum and PCR-based molecular diagnostic tests are required to accurately detect P. knowlesi in humans. The most commonly used PCR test has been found to give false positive results, especially with a proportion of P. vivax isolates. To address the need for more sensitive and specific diagnostic tests for the accurate diagnosis of P. knowlesi, we report development of a new single-step PCR assay that uses novel genomic targets to accurately detect this infection.We have developed a bioinformatics approach to search the available malaria parasite genome database for the identification of suitable DNA sequences relevant for molecular diagnostic tests. Using this approach, we have identified multi-copy DNA sequences distributed in the P. knowlesi genome. We designed and tested several novel primers specific to new target sequences in a single-tube, non-nested PCR assay and identified one set of primers that accurately detects P. knowlesi. We show that this primer set has 100% specificity for the detection of P. knowlesi using three different strains (Nuri, H, and Hackeri), and one human case of malaria caused by P. knowlesi. This test did not show cross reactivity with any of the four human malaria parasite species including 11 different strains of P. vivax as well as 5 additional species of simian malaria parasites.The new PCR assay based on novel P. knowlesi genomic sequence targets was able to accurately detect P. knowlesi. Additional laboratory and field-based testing of this assay will be necessary to further validate its utility for clinical diagnosis of P. knowlesi