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Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions.
Haematopoietic stem cells (HSCs) require the right composition of microRNAs (miR) for proper life-long balanced blood regeneration. Here we show a regulatory circuit that prevents excessive HSC self-renewal by upregulation of miR-193b upon self-renewal promoting thrombopoietin (TPO)-MPL-STAT5 signalling. In turn, miR-193b restricts cytokine signalling, by targeting the receptor tyrosine kinase c-KIT. We generated a miR-193b knockout mouse model to unravel the physiological function of miR-193b in haematopoiesis. MiR-193b−/− mice show a selective gradual enrichment of functional HSCs, which are fully competent in multilineage blood reconstitution upon transplantation. The absence of miR-193b causes an accelerated expansion of HSCs, without altering cell cycle or survival, but by decelerating differentiation. Conversely, ectopic miR-193b expression restricts long-term repopulating HSC expansion and blood reconstitution. MiR-193b-deficient haematopoietic stem and progenitor cells exhibit increased basal and cytokine-induced STAT5 and AKT signalling. This STAT5-induced microRNA provides a negative feedback for excessive signalling to restrict uncontrolled HSC expansion.
Zur quantitativen Plasmaproteinbestimmung sind die Immunnephelometrie und die Immunturbidimetrie häufig eingesetzte Bestimmungstechniken. Aufgrund der kürzeren Analysenzeit bei vergleichbarer oder besserer Präzision und Empfindlichkeit haben diese Techniken die radiale Immundiffusion in vielen Laboratorien ersetzt.
Die mechanisierte Plasmaproteinbestimmung erfolgt als Antigen-Antikörper-Reaktion entweder mit Proteinanalyzern oder mit klinisch-chemischen Analysensystemen, an denen normalerweise Enzyme und Substrate bestimmt werden.
Zwischen den verschiedenen Plasmaproteinen im Serum besteht ein bis zu 10.OOOfacher Konzentrationsunterschied und die biologische Varianz des einzelnen Plasmaproteins ist breit Damit die Plasmaproteine mit hoher analytischer Sensitivität über einen weiten Konzentrationsbereich, mit guter Präzision und der erforderlichen Richtigkeit mechanisiert bestimmt werden können, ist eine gute Adaption des Immunreagenzes auf das mechanisierte Analysensystem erforderlich. Diese Übersicht soll dazu Grundlagen vermitteln.
Die Entzündung ist eine Folge von Reaktionen mit der Zielsetzung, die Ausbreitung einer Gewebeschädigung, oder eines Infektionserregers einzudämmen. Zelluläre und humorale Mechanismen interagieren dabei in einem komplexen Netzwerk. In diesem Übersichtsbeitrag zeigen wir die wichtigsten Wege des inflammatorischen Reaktionsgeschehens auf und diskutieren die Bedeutung von Laboratoriumsuntersuchungen für die Diagnostik und das Monitoring von Entzündungen.
Wesentliche Schritte im Ablauf der Entzündungsreaktion sind
- die Synthese von Prostaglandinen aus Arachidonsäure, die durch Phospholipasen A2 (PLA2)-katalysierte Hydrolyse aus Membranphospholipiden gebildet wird;
- Interaktionen zwischen Gefäßendothel und Leukozyten, die Leukozytenextravasation und die Freisetzung freier Sauerstoffradikale und von Elastase im Gewebe;
- die Bildung inflammatorischer Cytokine, ihr Effekt auf Entzündungszellen und ihre systemische Wirkung auf Organe;
- die Synthese von Akute-Phase-Proteinen, deren Plasmakonzentration bei Entzündung als Antwort auf eine Vielfalt von Schädigungen ansteigt.
Zur Diagnostik und Verlaufsbeurteilung entzündlicher Krankheiten hat die Bestimmung des C-reaktiven Proteins den höchsten Stellenwert. Die Elastase hat nur eine begrenzte Bedeutung. Die Bestimmung von PLA2, der 'inflammatorischen Cytokine TNFa, IL-1, IL-6 und des s!L-2R als generelle Entzündungsmarker kann in der Routinediagnostik noch nicht empfohlen werden. Eingehende klinische Untersuchungen zur diagnostischen Bedeutung müssen noch abgewartet werden.
The tyrosine kinase inhibitor sunitinib is used as first‐line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed‐dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR‐2 and sVEGFR‐3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C‐II‐005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time‐to‐event (TTE) models. Baseline sVEGFR‐2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD‐guided strategies for the individualization of anti‐angiogenic therapies.
Poster presentation: Purpose of the study First-line HAART with tenofovir DF (TDF) and FTC in pivotal trials has been associated with high efficacy and good tolerability. However, real-life clinical practice often differs from clinical trials due to co-morbidities, co-infections, and less intensive clinical monitoring. To evaluate efficacy and safety of first-line HAART in a day-to-day setting, this Gilead-sponsored non-interventional cohort was established. Methods Between July 2005 and August 2006, 533 HIV-1 infected antiretroviral-naïve patients from 50 German centres enrolled in this non-interventional cohort. All patients were followed every 3 months for 3 years to monitor efficacy (viral load [VL], CD4), tolerability, renal safety, regimen changes and resistance profile. All patients received TDF+FTC as a single tablet (Truvada, TVD) in combination with either an NNRTI or PI/r as their first antiretroviral regimen. Summary of results As of June 2008, 2 years of therapy have been documented for 330/533 (62%) patients. At treatment initiation, 81% were male; median age was 39 years; clinical AIDS diagnosis was documented in 22%; 47% started therapy with CD4 <200 cells/mm3. TVD was combined with an NNRTI (43%) or a PI/r (57%). After 24 months, in an As-Treated (AT) analysis, 85% patients achieved a VL <50 copies/ml (VL <500 copies/ml: 97%), median CD4 count increased from 217 at baseline to 450 cells/mm3 (IQR: 325–608). Truvada showed a good safety profile; 76 adverse events (AEs) of any grade were reported in 66/533 patients (12%); six of these were judged serious. Fourteen (2.6%) patients discontinued TVD due to AEs. Renal abnormalities of any grade were reported in 10 patients (1.9%). Virological failure was documented in nine patients, of which eight were genotyped; M184V/I was detected in three, K65R in two patients. Conclusion During 2 years of follow-up, the overall safety of TVD was good; renal AEs of any grade were reported in 1.9% of patients. K65R was detected in two patients. First-line HAART with TVD plus an NNRTI or PI/r in clinical practice showed comparable efficacy to that observed in controlled clinical trials.
Wir haben einen kommerziell verfügbaren Test zur Bestimmung von Thyroxin (T4) am Analysensystem RA1000 auf seine Eignung in unserem Labor untersucht. Das Prinzip des Tests beruht auf einer immunturbidimetrischen Inhibitionstechnik, die besonders zur Messung niedriger T4-Konzentrationen geeignet ist Es wurde eine Präzision (in Serie, von Tag zu Tag) zwischen 2,6 und 4,6% (VK) ermittelt. Die Richtigkeit wurde untersucht an Patientenproben mit 2 Vergleichsmethoden und vergleichend zu den Sollwerten kommerziell verfügbarer Richtigkeitskontrollseren. Der Vergleich an Patientenproben ergab eine gute bis akzeptable Übereinstimmung, der Vergleich mit den Sollwerten von Richtigkeitskontrollseren zeigte in einigen Seren gewisse methodische Differenzen. Insgesamt ergaben unsere Untersuchungen, daß die immunturbidimetrische Inhibitionstechnik am HA-1000 eine schnelle und zuverlässige Bestimmung der T4-Konzentration ermöglicht.
A central motivation for the development of x-ray free-electron lasers has been the prospect of time-resolved single-molecule imaging with atomic resolution. Here, we show that x-ray photoelectron diffraction—where a photoelectron emitted after x-ray absorption illuminates the molecular structure from within—can be used to image the increase of the internuclear distance during the x-ray-induced fragmentation of an O2 molecule. By measuring the molecular-frame photoelectron emission patterns for a two-photon sequential K-shell ionization in coincidence with the fragment ions, and by sorting the data as a function of the measured kinetic energy release, we can resolve the elongation of the molecular bond by approximately 1.2 a.u. within the duration of the x-ray pulse. The experiment paves the road toward time-resolved pump-probe photoelectron diffraction imaging at high-repetition-rate x-ray free-electron lasers.
We present data on charged kaons (K±) and ϕ mesons in Au(1.23A GeV)+Au collisions. It is the first simultaneous measurement of K− and ϕ mesons in central heavy-ion collisions below a kinetic beam energy of 10A GeV. The ϕ/K− multiplicity ratio is found to be surprisingly high with a value of 0.52±0.16 and shows no dependence on the centrality of the collision. Consequently, the different slopes of the K+ and K− transverse-mass spectra can be explained solely by feed-down, which substantially softens the spectra of K− mesons. Hence, in contrast to the commonly adapted argumentation in literature, the different slopes do not necessarily imply diverging freeze-out temperatures of K+ and K− mesons caused by different couplings to baryons.
We present first data on sub-threshold production of Ks0 mesons and Λ hyperons in Au+Au collisions at sNN=2.4 GeV. We observe an universal 〈Apart〉 scaling of hadrons containing strangeness, independent of their corresponding production thresholds. Comparing the yields, their 〈Apart〉 scaling, and the shapes of the rapidity and the pt spectra to state-of-the-art transport model (UrQMD, HSD, IQMD) predictions, we find that none of them can simultaneously describe these observables with reasonable χ2 values.
We investigate identical pion HBT intensity interferometry in central Au+Au collisions at 1.23A GeV. High-statistics π−π− and π+π+ data are measured with HADES at SIS18/GSI. The radius parameters, derived from the correlation function depending on relative momenta in the longitudinally comoving system and parametrized as three-dimensional Gaussian distribution, are studied as function of transverse momentum. A substantial charge-sign difference of the source radii is found, particularly pronounced at low transverse momentum. The extracted source parameters agree well with a smooth extrapolation of the center-of-mass energy dependence established at higher energies, extending the corresponding excitation functions down towards a very low energy.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.