The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. ...Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.
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•Phosphatidylserine is exposed prior to loss of cell integrity during necroptosis•ESCRT-III facilitates the shedding of MLKL-damaged plasma membrane from intact cells•ESCRT-III supports cell survival and functions downstream of active MLKL•ESCRT-III allows necroptotic cells to signal surrounding cells
Cells undergoing necroptosis are not always headed towards death; ESCRT-III helps preserve the plasma membrane in these cells, contributing to survival.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing ...crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by (i) pharmacologic inhibition of RIPK1 or (ii) enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.
Das soziale Entschädigungsrecht ist auf viele und oft wenig bekannte Einzelgesetze verteilt. Es bewegt nur einen sehr kleinen Teil des Sozialbudgets. Schon deshalb ist es kein Lieblingskind von ...Journalisten, Politikern und Wissenschaftlern. Licht fällt auf es nur am Rand, wenn Flutkatastrophen und Straßenkrawalle kurzzeitig für Aufsehen sorgen.Tatsächlich aber wirft das soziale Entschädigungsrecht ganz grundlegende Fragen einer staatlichen Verantwortungsübernahme auf, die im Zusammenhang mit dem privaten und öffentlich-rechtlichen Haftungsrecht stehen. Was unterscheidet es vom gemeinhin eigenständig behandelten Staatshaftungsrecht? Wieso übernimmt der Staat die Aufgabe, für einen Schadensausgleich zu sorgen? Warum wird bis heute auf Katastrophen und Krawalle nur mit Einzelgesetzen ad hoc reagiert?Die Beantwortung erfolgt in drei Schritten: erstens durch eine Bestandsaufnahme, die Randbereiche und internationale Vorgaben auch in historischer und vergleichender Perspektive einbezieht; zweitens durch eine Systematisierung, die normative Grundvorstellungen über die Verpflichtung zum Schadensausgleich aufnimmt; und drittens durch Überlegungen, wie bestehende Entschädigungstatbestände zu ordnen, neue anzuerkennen und alle diese im Wege einer Kodifikation zusammenzufassen sind.
Purpose
Among juvenile apophyseal avulsion injuries of the pelvis in adolescents, fractures of the ischial tuberosity are rare but sustainably debilitating. Also because informations on surgical ...repair options are very sparse and so far limited to general reviews, reports of individual cases or heterogeous small case series, practitioners, patients and their parental environment still feel a comprehensible hesitation regarding operative treatment. Therefore we intended to investigate patient related outcome measurements and return to sports rates after different types of surgical intervention in an own case series, so far unprecendented in its size.
Methods
Patient data of adolescents that underwent surgical intervention for a displaced apophyseal avulsion fracture of the ischial tuberosity between 01/2015 and 12/2019 in our institution were gathered. Patients were then evaluated using the hamstring injury specific Perth Hamstring Assessment Tool (PHAT). Furthermore the return to sports level in comparison to the particular pre-injury level was rated.
Results
Eleven adolescents with an acute or chronic mean fragment dislocation of 3.3 cm (SD ± 1.7) underwent surgical intervention in the assigned period. The mean post-operative PHAT score was 86.9 (0–100, SD ± 11.9) and thus good to excellent. The majority of adolescents (10/11) was able to return to their pre-injury sports, whereas 63.6% achieved full or nearly full level.
Conclusions
Surgical refixation or restoration of aphoyseal avulsion fractures of the ischial tuberosity result in good to excellent outcomes and return to sport rates, irrespective of the type of intervention. Here prompt diagnosis with a timely intervention seems more promising than delayed interventions in chronic cases. Beyond 1.5 cm of fragment displacement affected patients should be counselled for surgical intervention.
Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas ...the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4
) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.
Social insurance thrives, among other things, on the involvement of employers. This cooperation has remained important to the present day. In fact, in some Western European countries, employers are ...duty bound more than before, for example in cases of work accidents or continued payments of wages in the event of sickness. In the USSR, “employers“ were in a different position from the outset: their companies were state-owned and therefore, administrative state duties in the field of social security could be delegated to them at any time. The purpose of these conference proceedings is to investigate how the role of the Russian employer in the social security system has changed compared to the situation during the USSR era. Which legal liability is ascribed to employers today? Does the enforcement of employees’ entitlements to social benefits depend on the fulfilment of employers’ obligations in the fields of social insurance and occupational safety law? The answer to these questions contributes fundamentally to the understanding of Russian social security law. An analysis of the main aspects of the topic is given from a Russian point of view and subsequently summarised and expanded upon from a German point of view.
Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and ...the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.
Evidence suggests an increasing demand for culturally and linguistically responsive disease prevention programs and health interventions. It is important to understand how individuals seek health ...information to address the potential needs of the health care system.
Latent classes of health information-seeking behaviors in a linguistically mixed region of Italy were explored through a population-based telephone survey of ten health information sources. Data were collected in August and September 2014 from 504 adults in South Tyrol, Italy (primary language German, 68%; Italian, 28%), and analyzed using latent class analysis and latent class multinomial logistic regression models.
Three classes of health information-seeking behaviors emerged: "multidimensional" (23.3%), "interpersonal" (38.6%) and "technical/online" (38.1%). Compared to the "technical/online" class, "interpersonal" class members were older, had lower education than high school, and were less likely to be of Italian ethnicity. "Multidimensional" class members were more likely to be female, older, and of German ethnicity than those in the "technical/online" class.
Linguistic ethnicity explains membership in classes on health information-seeking behavior. Policymakers and healthcare providers should consider the health information-seeking behaviors of population subgroups to promote health and medical care in linguistic minority groups.
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