Role of FGFRL1 and other FGF signaling proteins in early kidney development

The mammalian kidney develops from the ureteric bud and the metanephric mesenchyme. In mice, the ureteric bud invades the metanephric mesenchyme at day E10.5 and begins to branch. The tips of the ureteric bud induce the metanephric mesenchyme to condense and form the cap mesenchyme. Some cells of this cap mesenchyme undergo a mesenchymal-to-epithelial transition and differentiate into renal vesicles, which further develop into nephrons. The developing kidney expresses Fibroblast growth factor (Fgf)1, 7, 8, 9, 10, 12 and 20 and Fgf receptors Fgfr1 and Fgfr2. Fgf7 and Fgf10, mainly secreted by the metanephric mesenchyme, bind to Fgfr2b of the ureteric bud and induce branching. Fgfr1 and Fgfr2c are required for formation of the metanephric mesenchyme, however the two receptors can substitute for one another. Fgf8, secreted by renal vesicles, binds to Fgfr1 and supports survival of cells in the nascent nephrons. Fgf9 and Fgf20, expressed in the metanephric mesenchyme, are necessary to maintain survival of progenitor cells in the cortical region of the kidney. FgfrL1 is a novel member of the Fgfr family that lacks the intracellular tyrosine kinase domain. It is expressed in the ureteric bud and all nephrogenic structures. Targeted deletion of FgfrL1 leads to severe kidney dysgenesis due to the lack of renal vesicles. FgfrL1 is known to interact mainly with Fgf8. It is therefore conceivable that FgfrL1 restricts signaling of Fgf8 to the precise location of the nascent nephrons. It might also promote tight adhesion of cells in the condensed metanephric mesenchyme as required for the mesenchymal-to-epithelial transitio

Im Spannungsfeld zwischen Tun und Lassen – ein medizinphilosophischer Beitrag

Die Medizin ist im Wandel und ebenso unser Verständnis von Gesundheit und Krankheit. Die unaufhaltsame Technisierung unserer Lebenswelt verändert auch das Denken und Handeln in der Medizin. Immer mehr wird machbar, immer weniger scheint unmöglich. Die Medizin breitet sich aus und sie beansprucht im Leben jedes Einzelnen und in der Gesellschaft zunehmend mehr Platz. Hier gilt es, innezuhalten und sich über diese Entwicklung Gedanken zu machen. Dazu sind Klärungen zu drei wesentlichen und oft gebrauchten Begriffen der Medizin hilfreich: Es geht um das Begriffspaar Gesundheit und Krankheit, um den Begriff der Medikalisierung und um den der Macht in der Medizin. Die Geschichte der Medizin ist eine Erfolgsgeschichte – darüber besteht kein Zweifel. Stets aber regt sie zum Handeln, zum korrektiven Intervenieren an. Entsprechend ist das Tun das Übliche, das Unterlassen dagegen die Ausnahme. Dies gilt es zu beachten und zu hinterfragen – denn Unterlassen gilt in der Medizin als heikel, es ist gegebenenfalls einklagbar und entspricht so gar nicht unserem aktivistischen Denken und Handeln. Es gibt aber Situationen, in denen das Nichthandeln für den betroffenen Patienten die klar bessere Option ist. Um dieses situative Nicht(s)tun in der Medizin geht es in diesem Beitrag. Es braucht eine ausgewogene und paritätische Praxis des Handelns und des Nichthandelns, welche immer das Optimale für den Patienten im Visier hat. Keiner der beiden Optionen, weder dem Tun noch dem Nicht(s)tun, steht ein Primat zu, denn beide Handlungsweisen sind in ihrer Dignität ebenbürtig

Antibiotic Therapy of Infections Due to Pseudomonas aeruginosa in Normal and Granulocytopenic Mice: Comparison of Murine and Human Pharmacokinetics

An effort was made to elucidate the limits of drug-activity tests in small animals. Human plasma kinetics of gentamicin, netilmicin, ticarcillin, ceftazidime, and ceftriaxone were approximated in normal and in granulocytopenic mice infected with various strains of Pseudomonas aeruginosa in the thigh muscle or intraperitoneally. The effect of such dosing on bacterial time-kill curves and on survival was compared with the effect of identical amounts of drug given as a single-bolus injection. With β-lactams, a highly significant superiority of fractionated dosing (simulated human kinetics) over bolus injections (murine plasma kinetics) was demonstrated, whereas with aminoglycosides it was a single-bolus injection that tended to be more active. Thus, when tested in conventional small-animal models, aminoglycoside activity may be overestimated, whereas β-lactam activity may be underestimated in respect to humans. These differences found in vivo most probably reflect the different pharmacodynamics between aminoglycosides and β-lactam drugs (time-kill curves, dose-response curves, and postantibiotic effect) similar to those previously observed in vitr

Nicht Aufgeben bei seltenen Erkrankungen

Der Patient in unserem Fallbericht stellte sich erstmals 2004 aufgrund belastungsabhängiger Muskelschmerzen bei seinem Hausarzt vor. Es folgten über die Jahre viele Untersuchungen und diagnostische Irrwege bis die tatsächliche Ursache dank der Beharrlichkeit des Patienten und seines Hausarztes gefunden wurd

Coincident Pre- and Postsynaptic Activation Induces Dendritic Filopodia via Neurotrypsin-Dependent Agrin Cleavage

SummaryThe synaptic serine protease neurotrypsin is essential for cognitive function, as its deficiency in humans results in severe mental retardation. Recently, we demonstrated the activity-dependent release of neurotrypsin from presynaptic terminals and proteolytical cleavage of agrin at the synapse. Here we show that the activity-dependent formation of dendritic filopodia is abolished in hippocampal neurons from neurotrypsin-deficient mice. Administration of the neurotrypsin-dependent 22 kDa fragment of agrin rescues the filopodial response. Detailed analyses indicated that presynaptic action potential firing is necessary for the release of neurotrypsin, whereas postsynaptic NMDA receptor activation is necessary for the neurotrypsin-dependent cleavage of agrin. This contingency characterizes the neurotrypsin-agrin system as a coincidence detector of pre- and postsynaptic activation. As the resulting dendritic filopodia are thought to represent precursors of synapses, the neurotrypsin-dependent cleavage of agrin at the synapse may be instrumental for a Hebbian organization and remodeling of synaptic circuits in the CNS

Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry

AIMS OF THE STUDY: Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005–2014 and prospectively from 2015 onwards. METHODS: Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. RESULTS: Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33–4.87); it was 4.87 years (95% CI 3.14–7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48–3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4–95.3%), 68.5% (95% CI 57.4–81.7%) and 66.0% (95% CI 54.6–79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2–99.8%), 77.0% (95% CI 63.4–93.7%) and 50.6% (95% CI 31.8–80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). CONCLUSION: During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented. Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly

Comparison of the Gene Expression Profiles from Normal and Fgfrl1 Deficient Mouse Kidneys Reveals Downstream Targets of Fgfrl1 Signaling

Fgfrl1 (fibroblast growth factor receptor-like 1) is a transmembrane receptor that is essential for the development of the metanephric kidney. It is expressed in all nascent nephrogenic structures and in the ureteric bud. Fgfrl1 null mice fail to develop the metanephric kidneys. Mutant kidney rudiments show a dramatic reduction of ureteric branching and a lack of mesenchymal-to-epithelial transition. Here, we compared the expression profiles of wildtype and Fgfrl1 mutant kidneys to identify genes that act downstream of Fgfrl1 signaling during the early steps of nephron formation. We detected 56 differentially expressed transcripts with 2-fold or greater reduction, among them many genes involved in Fgf, Wnt, Bmp, Notch, and Six/Eya/Dach signaling. We validated the microarray data by qPCR and whole-mount in situ hybridization and showed the expression pattern of candidate genes in normal kidneys. Some of these genes might play an important role during early nephron formation. Our study should help to define the minimal set of genes that is required to form a functional nephron

Das Random-Walk-Modell des Wechselkurses als spezielle Form der Markteffizienzhypothese

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Der Zufallscharakter im Wechselkursverhalten

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