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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.
A thick Middle and Late Pleistocene loess/palaeosol sequence is exposed at the gravel quarry Gaul located east of Weilbach in the southern foreland of the Taunus Mountains. The loess/palaeosol sequence correlates to the last three glacial cycles. Seven samples were dated by luminescence methods using an elevated temperature IRSL (post-IR IRSL) protocol for polymineral fine-grains to determine the deposition age of the sediment and to set up a more reliable chronological framework for these deposits. The fading corrected IR50 and the pIRIR225 age estimates show a good agreement for almost all samples. The fading corrected IRSL ages range from 23.7 ± 1.6 ka to >350 ka indicating that the oldest loess was deposited during marine isotope stage (MIS) 10 or earlier and that the humic-rich horizon (Weilbacher Humuszone) was developed during the late phase of MIS 7. Loess taken above the fCc horizon most likely accumulated during MIS 6 indicating that the remains of the palaeosol are not belonging to the last interglacial soil. The two uppermost samples indicate that the youngest loess accumulated during MIS 2 (Upper Würmian). Age estimates for the loess-palaeosol sequence of the gravel quarry Gaul/Weilbach could be obtained up to ~350 ka using the pIRIR225 from feldspar. Keywords: loess, luminescence dating, IRSL, fading, Weilbach, chronostratigraphy
The design, construction, and commissioning of the ALICE Time-Projection Chamber (TPC) is described. It is the main device for pattern recognition, tracking, and identification of charged particles in the ALICE experiment at the CERN LHC. The TPC is cylindrical in shape with a volume close to 90 m3 and is operated in a 0.5 T solenoidal magnetic field parallel to its axis.
In this paper we describe in detail the design considerations for this detector for operation in the extreme multiplicity environment of central Pb–Pb collisions at LHC energy. The implementation of the resulting requirements into hardware (field cage, read-out chambers, electronics), infrastructure (gas and cooling system, laser-calibration system), and software led to many technical innovations which are described along with a presentation of all the major components of the detector, as currently realized. We also report on the performance achieved after completion of the first round of stand-alone calibration runs and demonstrate results close to those specified in the TPC Technical Design Report.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Methodik
(2002)
Die vegetationskundliche und strukturelle Zuordnung der Lebensraumtypen erfolgt nach der vorrangig von Braun-Blanquet entwickelten Vegetationsklassifizierung, einer hierarchischen Gliederung der Vegetationstypen (Syntaxonomie), die die Ebenen der Assoziation, des Verbandes, der Ordnung und der Klasse umfasst. Hierbei ist die Assoziation die grundlegende Einheit, in der die Pflanzengesellschaften zusammengefasst werden, die sich durch gleiche charakteristische Arten(gruppen)kombinationen auszeichnen. Der Verband vereinigt ähnliche Assoziationen. Das sind bereits umfassendere, jedoch standörtlich noch recht einheitliche Vegetationseinheiten. In Ordnungen werden ähnliche Verbände zusammengefasst. Die Klasse vereinigt ähnliche Ordnungen.
Background: The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC) could improve efficacy, but this combination was not examined in this context so far. Methods: Patients with stage II/IIIA EBC (four or more positive lymph nodes) received post-operative intensified dose-dense sequential epirubicin (150mg/m2 every 2 weeks) and paclitaxel (225mg/m2 every 2 weeks) with filgrastim and darbepoetin alfa, followed by capecitabine alone (dose levels 1 and 3) or with vinorelbine (dose levels 2 and 4). Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively). Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4). Results: Fifty-one patients were treated. There was one dose-limiting toxicity (DLT) at dose level 1. At dose level 2 (capecitabine and vinorelbine), five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy) was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively. Administration of capecitabine monotherapy after sequential dose-dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs. Trial registration: Current Controlled Trials ISRCTN38983527.
Early maternal care may counteract familial liability for psychopathology in the reward circuitry
(2018)
Reward processing is altered in various psychopathologies and has been shown to be susceptible to genetic and environmental influences. Here, we examined whether maternal care may buffer familial risk for psychiatric disorders in terms of reward processing. Functional magnetic resonance imaging during a monetary incentive delay task was acquired in participants of an epidemiological cohort study followed since birth (N = 172, 25 years). Early maternal stimulation was assessed during a standardized nursing/playing setting at the age of 3 months. Parental psychiatric disorders (familial risk) during childhood and the participants’ previous psychopathology were assessed by diagnostic interview. With high familial risk, higher maternal stimulation was related to increasing activation in the caudate head, the supplementary motor area, the cingulum and the middle frontal gyrus during reward anticipation, with the opposite pattern found in individuals with no familial risk. In contrast, higher maternal stimulation was associated with decreasing caudate head activity during reward delivery and reduced levels of attention deficit hyperactivity disorder (ADHD) in the high-risk group. Decreased caudate head activity during reward anticipation and increased activity during delivery were linked to ADHD. These findings provide evidence of a long-term association of early maternal stimulation on both adult neurobiological systems of reward underlying externalizing behavior and ADHD during development.
We investigate methods and tools for analysing translations between programming languages with respect to observational semantics. The behaviour of programs is observed in terms of may- and must-convergence in arbitrary contexts, and adequacy of translations, i.e., the reflection of program equivalence, is taken to be the fundamental correctness condition. For compositional translations we propose a notion of convergence equivalence as a means for proving adequacy. This technique avoids explicit reasoning about contexts, and is able to deal with the subtle role of typing in implementations of language extension.
We present a higher-order call-by-need lambda calculus enriched with constructors, case-expressions, recursive letrec-expressions, a seq-operator for sequential evaluation and a non-deterministic operator amb that is locally bottom-avoiding. We use a small-step operational semantics in form of a single-step rewriting system that defines a (nondeterministic) normal order reduction. This strategy can be made fair by adding resources for bookkeeping. As equational theory we use contextual equivalence, i.e. terms are equal if plugged into any program context their termination behaviour is the same, where we use a combination of may- as well as must-convergence, which is appropriate for non-deterministic computations. We show that we can drop the fairness condition for equational reasoning, since the valid equations w.r.t. normal order reduction are the same as for fair normal order reduction. We evolve different proof tools for proving correctness of program transformations, in particular, a context lemma for may- as well as mustconvergence is proved, which restricts the number of contexts that need to be examined for proving contextual equivalence. In combination with so-called complete sets of commuting and forking diagrams we show that all the deterministic reduction rules and also some additional transformations preserve contextual equivalence.We also prove a standardisation theorem for fair normal order reduction. The structure of the ordering <=c a is also analysed: Ω is not a least element, and <=c already implies contextual equivalence w.r.t. may-convergence.