In vitro and in vivo (cyto)toxicity assays using PVC and LDPE as model materials.

The choice for a biomaterial is partly based on the outcome of (cyto)toxicity assays. The rationales behind the selection of certain parameters, such as cell lines, controls, and animals, were evaluated using a positive and a negative control, and one experimental sample designed to induce intermediate toxicity. Extraction and direct contact assays were performed using human epidermal keratinocytes and mouse fibroblasts and mouse epithelial cells. Cell survival was measured with the tetrazolium salt (MTT) reduction assay. In addition, local implantation studies were performed in mice and rats. The positive control induced a high degree of toxicity in all in vitro tests performed, indicating that the toxicity observed in the direct contact assay was due to in situ extraction of toxic components. In the direct contact assay the negative control tested on the mouse fibroblasts resulted in a significant reduction of cell survival. No decrease in cell survival was found using the experimental sample. Subcutaneous implantation studies in mice showed that the positive control material induced a severe degeneration in mice. However, in rats just minimal alterations were noted. The experimental material induced moderate responses only in mice. Our results indicate that the direct contact assay provides limited additional information on the cytotoxicity of materials if certain limitations are not taken into account. For the in vivo implantation assay mice were superior to rats in detecting local toxic responses

The effect of transcutaneous vagus nerve stimulation on fear generalization and subsequent fear extinction

Fear overgeneralization is thought to be one of the cardinal processes underlying anxiety disorders, and a determinant of the onset, maintenance and recurrence of these disorders. Animal studies have shown that stimulating the vagus nerve (VNS) affects neuronal pathways implicated in pattern separation and completion, suggesting it may reduce the generalization of a fear memory to novel situations. In a one-day study, 58 healthy students were subjected to a fear conditioning, fear generalization, and fear extinction paradigm. Participants were randomly assigned to receive either transcutaneous auricular VNS (tVNS; final N = 29) or sham stimulation (final N = 29) during the generalization and extinction phases. tVNS did not affect fear generalization, as reflected by US expectancy ratings and fear potentiated startle responses. However, participants who received tVNS reported lower US expectancy ratings to the CS + during the extinction phase, possibly reflecting a stronger declarative extinction of fear. No effects of tVNS on fear potentiated startle responses during extinction were found. The pattern of findings regarding extinction of declarative fear suggest a facilitating effect of tVNS.Stress-related psychiatric disorders across the life spa

De bepaling van androstenon in varkensvet in het kader van de controle op berevlees : overzicht van de Nederlandse bevindingen in de periode januari t/m oktober 1988 en de herkeuringsproblematiek van Duitse monsters

In Duitsland wordt geïmporteerd varkensvlees, dat van zeugen en borgen afkomstig moet zijn, onderzocht op de mogelijke aanwezigheid van berevlees, dat in sommige gevallen tot beregeur aanleiding geeft. Bij de sinds 1987 uitgevoerde steekproeven wordt het gehalte aan androstenon, een voornamelijk bij (niet gecastreerde) mannelijke dieren (beren) geproduceerd steroidhormoon, in vet gemeten. Indien dit gehalte hoger is dan 0.3 Mg/g acht men bewezen dat het bemonsterde dier inderdaad een beer was, terwijl bij vrouwelijke (zeugen) en bij gecastreerde mannelijke dieren (borgen) waarden lager dan 0.1 Mg/g worden gemeten. Inventariserend onderzoek binnen het RIKILT heeft uitgewezen dat de in Duitsland gehanteerde beslisgrens ook voor Nederlandse mestvarkens toepasbaar is. De in Duitsland toegepaste methode is een immunochemische methode; enigszins vergelijkbaar met de tot voor kort in Nederland uitgevoerde radioimmunochemische DES bepaling (RIA-DES). Als screeningsmethode is deze techniek geschikt voor een snelle analyse van een groot monsteraanbod, maar de specificiteit is afhankelijk van het gebruikte antiserum en de monstervoorbewerking, zodat de mogelijkheid bestaat dat andere in het vet aanwezige verbindingen het resultaat van de meting kunnen beïnvloeden. Bij de tot nu toe in Duitsland door Prof. Claus, Universiteit Hohenheim, Stuttgart, verrichte metingen zijn hiervoor echter nooit aanwijzingen gevonden. De door het RIKILT ontwikkelde methode berust op gaschromatografiemassaspectrometrie (GCMS), waardoor de specificiteit veel hoger is en deze methode als bevestigingsmethode kan worden toegepast. Uit onderzoek van wederzijds ter beschikking gestelde monsters varkensspek en het onderzoek van een serie monsters in het kader van een ringonderzoek, bleek dat de resultaten, het herkennen van beren, bij beide methoden overeenkwamen. De gemeten androstenongehalten verschillen daarbij wel in absolute zin. In tegenstelling tot bovengenoemde monsters bleken bij herkeuring door het RIKILT van in Duitsland "positief" bevonden monsters, deze monsters, ook na herhaald onderzoek, geen androstenon te bevatten. Helaas werden bij de monstername in Duitsland geen verzegelde en goed gedocumenteerde contra-monsters genomen

Treatment and Coronary Artery Aneurysm Formation in Kawasaki Disease: A Per-Day Risk Analysis

Objective: To assess whether ‘treatment day’ is a significant predicting factor in Kawasaki disease and imposes a risk for coronary artery aneurysms (CAAs) in a per-day analysis. CAA formation can be reduced from 25% to 10% when treated with intravenous immunoglobulin (IVIG). Study design: Patient data from (n = 1016) a single center were collected for an observational cohort study. After exclusions, we retrospectively analyzed 776 patients in total. A multivariate analysis was performed with treatment day as a continuous variable (n = 691). Patients were categorized as no enlargement, small CAA, medium CAA, and giant CAA. Results: Late treatment per-day was a significant predicting factor for the development of larger CAAs. ORs for medium and giant CAAs per delayed day were 1.1 (95% CI 1.1-1.2) P < .05 and 1.2 (95% CI 1.1-1.2) P < .05, respectively. Conclusion: We showed that every day of delay in treatment of patients with Kawasaki disease inherently carries a risk of medium and giant aneurysm formation. There was no cut-off point for treatment day that could mark a safe zone

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies.

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial