Microglial Immunoreceptor Tyrosine-Based Activation and Inhibition Motif Signaling in Neuroinflammation

Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12-associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-β1, and complement receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAM-signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic activity of microglia via ITIM signaling. Moreover, microglial neurotoxicity is alleviated via interaction of Siglec-11 with sialic acids on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration triggered by chronic inflammation

Postwar Bargains? German Librarians and the Abandoned Collections of Nazi Loot

Ce colloque s’est tenu les jeudi et vendredi 23 et 24 mars 2017, à la Bibliothèque universitaire des langues et civilisations et à la Bibliothèque nationale de France, Il a été organisé par le Centre Gabriel Naudé de l\u27Ecole nationale supérieure des sciences de l\u27information et des bibliothèques (ENSSIB), l\u27Institut d\u27histoire du temps présent (IHTP, UMR CNRS Paris 8) et l\u27Université Paris Diderot (EA Identités, cultures, territoires), avec le soutien de la Bibliothèque nationale de France, de la Bibliothèque universitaire des langues et civilisations (BULAC), de la Fondation pour la Mémoire de la Shoah, de la Claims Foundation, de la Fondation Maison des Sciences de l\u27Homme et du Deutscher Akademischer Austauschdienst. Au cours de ce colloque, une douzaine de livres, datant du XVIIe siècle et retrouvés dans ses collections par la Bibliothèque centrale et régionale de Berlin (Zentral -und Landesbibliothek) ont été restitués à trois ministères français (ministère des Affaires étrangères, ministère de l\u27Intérieur, ministère de la Justice) auxquels ils avaient été spoliées en juin 1940. Un registre manuscrit d\u27état civil des années 1751-1771, spolié à la commune de Verpel (Ardennes) lui sera également restitué. Associé à ce colloque en ligne, les Presses de l’Enssib proposent Où sont les bibliothèques françaises spoliées par les nazis ? ouvrage coordonné par Martine Poulain qui a rassemblé les contributions, enrichies, concernant particulièrement l’histoire d’environ 14 000 livres spoliés et déposés dans une quarantaine de bibliothèques françaises entre 1950 et 1953, et leurs caractéristiques. https://presses.enssib.fr/catalogue/ou-sont-les-bibliotheques-francaises-spoliees-par-les-nazi

Impact of Increasing Dietary Calcium Levels on Calcium Excretion and Vitamin D Metabolites in the Blood of Healthy Adult Cats

Background Dietary calcium (Ca) concentrations might affect regulatory pathways within the Ca and vitamin D metabolism and consequently excretory mechanisms. Considering large variations in Ca concentrations of feline diets, the physiological impact on Ca homeostasis has not been evaluated to date. In the present study, diets with increasing concentrations of dicalcium phosphate were offered to ten healthy adult cats (Ca/phosphorus (P): 6.23/6.02, 7.77/7.56, 15.0/12.7, 19.0/17.3, 22.2/19.9, 24.3/21.6 g/kg dry matter). Each feeding period was divided into a 10-day adaptation and an 8-day sampling period in order to collect urine and faeces. On the last day of each feeding period, blood samples were taken. Results Urinary Ca concentrations remained unaffected, but faecal Ca concentrations increased (P < 0.001) with increasing dietary Ca levels. No effect on whole and intact parathyroid hormone levels, fibroblast growth factor 23 and calcitriol concentrations in the blood of the cats were observed. However, the calcitriol precursors 25(OH)D2 and 25(OH)D3, which are considered the most useful indicators for the vitamin D status, decreased with higher dietary Ca levels (P = 0.013 and P = 0.033). Increasing dietary levels of dicalcium phosphate revealed an acidifying effect on urinary fasting pH (6.02) and postprandial pH (6.01) (P < 0.001), possibly mediated by an increase of urinary phosphorus (P) concentrations (P < 0.001). Conclusions In conclusion, calcitriol precursors were linearly affected by increasing dietary Ca concentrations. The increase in faecal Ca excretion indicates that Ca homeostasis of cats is mainly regulated in the intestine and not by the kidneys. Long-term studies should investigate the physiological relevance of the acidifying effect observed when feeding diets high in Ca and P

ComPAIN—Communication of Pain in Patients with Headache

Primary headaches are a common debilitating health condition. Proper diagnosis and treatment depend on patients’ communication. We wanted to explore differences in pain communication with a special interest in potential sex differences. Patients visiting our headache unit for the first time filled in two different questionnaires (one before entering the consultation and one directly after finishing the consultation), through which we captured patients’ descriptions of their pain, its potential impact on daily lives, the well-being of our patients and the satisfaction with our consultation. We included a total of 35 patients (22 female, 13 male). Women reported experiencing a greater loss of socially active days during the last 3 months because of headaches compared to men. Furthermore, women were more satisfied with our consultation. In addition, we revealed migraineurs characterize their pain differently than stated in the International Classification of Headache Disorders (ICHD-3) criteria. The adjective “pressing” (drückend) was used significantly more often by migraineurs compared to patients with tension-type headaches. Nevertheless, in the physicians’ written report, the characterization more often contained the ICHD-3 corresponding adjective “pulsating” (pulsierend). Since the typification of headaches and subsequent therapy depends predominantly on the patients’ communication, consideration of the individual pain description and further research on headache characterization are indispensable

Health-related quality of life among patients with treated alcohol use disorders, schizophreniform disorders or affective disorders and the influence of flexible and integrative psychiatric care models in Germany (PsychCare)

IntroductionFlexible and integrated treatment options (FIT) have been established in German psychiatric hospitals to enhance continuous and patient-centered treatment for patients with mental disorders. We hypothesized that patients with experience in FIT treatment showed higher health-related quality of life (HRQoL) and comparable symptom severity compared with patients treated as usual (TAU). Further, we expected that some sub-dimensions of HRQoL determined HRQoL results clearer than others, while certain factors influenced HRQoL and symptom severity stronger in the FIT compared to the TAU group. In addition, we hypothesized that HRQoL is correlated with symptom severity.MethodsWe undertook a controlled, prospective, multicenter cohort study (PsychCare) conducted in 18 psychiatric hospitals in Germany, using the questionnaires Quality of Well Being Self-Administered (QWB-SA) (HRQoL) and Symptom-Checklist-K-9 (SCL-K-9) (symptom severity) at recruitment (measurement I) and 15 months later (measurement II). We assessed overall HRQoL (measured in health utility weights (HUW) and symptom severity score for patients from FIT and TAU treatment. We investigated the QWB-SA dimensions and separated the results by diagnosis. We used beta regressions to estimate the effect of multiple co-variates on both outcomes. To investigate the correlation between HRQoL and symptom severity, we used Pearson correlation.ResultsDuring measurement I, 1,150 patients were recruited; while 359 patients participated during measurement II. FIT patients reported higher HUWs at measurement I compared to TAU patients (0.530 vs. 0.481, p = 0.003) and comparable HUWs at measurement II (0.581 vs. 0.586, p = 0.584). Symptom severity was comparable between both groups (I: 21.4 vs. 21.1, p = 0.936; II: 18.8 vs. 19.8, p = 0.122). We found lowest HRQoL and highest symptom severity in participants with affective disorders. HRQoL increased and symptom severity decreased over time in both groups. The QWB-SA dimension acute and chronic symptoms was associated with highest detriments in HRQoL. We identified risk/protective factors that were associated with lower quality of life and higher symptom severity in both groups. We confirmed that HRQoL was negatively associated with symptom severity.DiscussionHealth-related quality of life (during hospital treatment) was higher among patients treated in FIT hospitals compared to patients in routine care, while symptom severity was comparable between both groups

TREM2 triggers microglial density and age‐related neuronal loss

The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 or TYROBP have been linked to inflammatory neurodegenerative diseases associated with aging. The typical aging process goes along with microglial changes and mild neuronal loss, but the exact contribution of TREM2 is still unclear. Aged TREM2 knock‐out mice showed decreased age‐related neuronal loss in the substantia nigra and the hippocampus. Transcriptomic analysis of the brains of 24 months old TREM2 knock‐out mice revealed 211 differentially expressed genes mostly downregulated and associated with complement activation and oxidative stress response pathways. Consistently, 24 months old TREM2 knock‐out mice showed lower transcription of microglial (Aif1 and Tmem119), oxidative stress markers (Inos, Cyba, and Cybb) and complement components (C1qa, C1qb, C1qc, C3, C4b, Itgam, and Itgb2), decreased microglial numbers and expression of the microglial activation marker Cd68, as well as accumulation of oxidized lipids. Cultured microglia of TREM2 knock‐out mice showed reduced phagocytosis and oxidative burst. Thus, microglial TREM2 contributes to age‐related microglial changes, phagocytic oxidative burst, and loss of neurons with possible detrimental effects during physiological aging

Long-term effects of treatment and response in patients with chronic hepatitis C on quality of life. An international, multicenter, randomized, controlled study

Background: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study). Methods: The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128). Results: At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL. Conclusions: Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females

So close, yet so far : discrepancies between uveal and other melanomas. A Position Paper from UM Cure 2020

Despite much progress in our understanding of uveal melanoma (UM) over the past decades, this rare tumour is still often misclassified. Although UM, like other melanomas, is very probably derived from melanocytes, it is drastically different from cutaneous melanoma and most other melanoma subtypes in terms of epidemiology, aetiology, biology and clinical features, including an intriguing metastatic hepatotropism. UM carries distinctive prognostic chromosome alterations, somatic mutations and gene expression profiles, allowing an active tailored surveillance strategy and dedicated adjuvant clinical trials. There is no standard systemic treatment for disseminated UM at present. In contrast to cutaneous melanoma, UMs are not BRAF-mutated, thus curtailing the use of B-Raf inhibitors. Although these tumours are characterised by some immune infiltrates, immune checkpoint inhibitors are rarely effective, possibly due to a low mutation burden. UM patients across the world not only face rare cancer-related issues (e.g., specific management strategies, access to information and to expert centres), but also specific UM problems, which can be exacerbated by the common misconception that it is a subtype of cutaneous melanoma. As a European Consortium dedicated to research on UM and awareness on the disease, “UM Cure 2020” participants urge medical oncologists, pharmaceutical companies, and regulatory agencies to acknowledge UM as a melanoma with specific issues, in order to accelerate the development of new therapies for patients

Effect of Particle Size and Pressure on the Transport Properties of the Fast Ion Conductor t‐Li₇SiPS₈

All‐solid‐state batteries promise higher energy and power densities as well as increased safety compared to lithium‐ion batteries by using non‐flammable solid electrolytes and metallic lithium as the anode. Ensuring permanent and close contact between the components and individual particles is crucial for long‐term operation of a solid‐state cell. This study investigates the particle size dependent compression mechanics and ionic conductivity of the mechanically soft thiophosphate solid electrolyte tetragonal Li₇SiPS₈ (t‐LiSiPS) under pressure. The effect of stack and pelletizing pressure is demonstrated as a powerful tool to influence the microstructure and, hence, ionic conductivity of t‐LiSiPS. Heckel analysis for granular powder compression reveals distinct pressure regimes, which differently impact the Li ion conductivity. The pelletizing process is simulated using the discrete element method followed by finite volume analysis to disentangle the effects of pressure‐dependent microstructure evolution from atomistic activation volume effects. Furthermore, it is found that the relative density of a tablet is a weaker descriptor for the sample's impedance compared to the particle size distribution. The multiscale experimental and theoretical study thus captures both atomistic and microstructural effects of pressure on the ionic conductivity, thus emphasizing the importance of microstructure, particle size distribution and pressure control in solid electrolytes