Ein dediziertes Beschleuniger-Massenspektrometer für mittelschwere Radionuklide am Kölner FN-Tandembeschleuniger

In dieser Arbeit wurde erfolgreich ein Beschleuniger-Massenspektrometer für mittelschwere Radionuklide am Kölner FN-Tandembeschleuniger berechnet, aufgebaut und getestet. Mit diesem AMS-System konnten (53Mn/55Mn)-Isotopenverhältnisse im Bereich von 1e-9 bis 1e-10 mit einem Detektionslimit von 7,2e-13 erstmalig an einem 10MV Tandembeschleuniger gemessen werden. Das aufgebaute AMS-System ist dediziert für den Nachweis von mittelschweren Radionukliden. Es verfügt über einen achromatischen Injektor mit Fast-Injection-System sowie ein Hochenergie-Massenspektrometer mit einem 90°-Analysiermagneten (rho=1,1 m), hinter dem die Ionenströme der stabilen Nuklide in Offset-Farady-Cups gemessen werden. Die Isobarenunterdrückung kann über eine mehrstufige isotopenspezifische Energieverlust-Messung mit Kombinationen aus Siliziumnitrid-Folien, einem 30° elektrostatischen Analysierer (rho=3,5 m), einem 4 m Time-of-Flight-System sowie einem Gasionisationsdetektor erfolgen. Zusätzlich wurde das AMS-System für die Erhöhung der Transmission bei Radionuklidmessungen wie 60Fe um einen 135°-Magneten (rho=0,9 m) für den gasgefüllten Modus erweitert. Entscheidend sind bei allen AMS-Messungen die erreichbare Sensitivität und das Detektionslimit. Die hier gegebene Definition der fehlernormalisierten Sensitivität ermöglicht den Vergleich der Ergebnisse der (53Mn/55Mn)-Isotopenverhältnismessungen mit den Werten etablierter Labore. Das erreichte Detektionslimit ist trotz der niedrigen Ionenenergien mit anderen Forschungseinrichtungen vergleichbar, die über Tandembeschleuniger mit höherer Terminalspannung verfügen. Das gesamte AMS-System wurde mit Messungen von stabilen Isotopen und Isotopenverhältnissen überprüft. Bei den Testmessungen zu (41Ca/40Ca)-Isotopenverhältnissen wurde ohne passive Absorber ein Detektionslimit von <5,32e-13 erreicht. Bei den (53Mn/55Mn)-Isotopenverhältnismessungen wurde der hohe 53Cr Isobarentrennungsfaktor mit Siliziumnitrid-Folien und elektrostatischem Analysierer durch die Verwendung der optimalen Siliziumnitrid-Foliendicke erreicht. Die Foliendicke wurde unter Berücksichtigung der Beiträge der 53Cr Nachbarladungszustände berechnet. Eine weitere Unterdrückung des Isobars ohne starke Reduktion des Radionuklids konnte mit Schlitzen in der dispersiven Ebene vor dem elektrostatischen Analysierer erreicht werden. Die erreichte Isobarenunterdrückung mit Siliziumnitrid-Folien und dem 4 m Time-of-Flight-System ist nur hoch, wenn die Kernladungszahl des Isobars höher als die des Radionuklids ist. Die Isobarentrennung in einem 2-Anoden-Gasionisationsdetektor wurde mit den verschiedenen Kombinationen der mehrstufigen Energieverlustmessungen bestimmt. Durch die Verwendung des Gasionisationsdetektors direkt hinter dem elektrostatischen Analysierer konnte die Sensitivität der 53Mn-Messung gesteigert werden. Des Weiteren wurde das Isobarentrennungsvermögen von 53Cr/53Mn und 60Ni/60Fe über die Messung der charakteristischen Projektil-Röntgenenergien bestimmt. Dabei zeichnete sich der Messaufbau durch die intrinsische Kalibration des Energiespektrums über die M_alpha, L_alpha und L_beta Linien des Goldtargets aus

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation

Differential prognostic utility of adiposity measures in chronic kidney disease

Objective Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD. Methods The German Chronic Kidney Disease (GCKD) study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate (eGFR): 30–60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC and BMI with all-cause death, major cardiovascular events (MACE: a composite of non-fatal stroke, non-fatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria (AIC) were calculated. Models included sex interactions with adiposity measures. Results A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (HR 1.080 per cm; 95% CI 1.009–1.155), but not in men. Irrespective of sex, WC was associated with all-cause death (HR 1.014 per cm; 95% CI 1.005–1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death including WC offered the best (lowest) AIC. Conclusion In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause, but BMI was not

Association of osteopontin with kidney function and kidney failure in chronic kidney disease patients: the GCKD study

Background: Osteopontin (OPN), synthesized in the thick ascending limb of Henle's loop and in the distal tubule, is involved in the pathogenesis of kidney fibrosis, a hallmark of kidney failure (KF). In a cohort of chronic kidney disease (CKD) patients, we evaluated OPN's association with kidney markers and KF. Methods: OPN was measured from baseline serum samples of German Chronic Kidney Disease study participants. Cross-sectional regression models for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) as well as Cox regression models for all-cause mortality and KF were evaluated to estimate the OPN effect. Additionally, predictive ability, of OPN and time-dependent population-attributable fraction were evaluated. Results: Over a median follow-up of 6.5 years, 471 KF events and 629 deaths occurred among 4,950 CKD patients. One-unit higher log(OPN) was associated with 5.5 mL/min/1.73m2 lower eGFR (95%CI: [-6.4,-4.6]) and 1% change in OPN with 0.7% higher UACR (estimated effect 0.7, 95%CI: [0.6,0.8]). Moreover, higher OPN levels were associated with a higher risk of KF (hazard ratio [HR] 1.4, 95%CI: [1.2,1.7]) and all-cause mortality (HR 1.5, 95%CI: [1.3,1.8]). After 6 years, 31% of the KF events could be attributed to higher OPN levels (95%CI: [3%,56%]). Conclusions: In this study, higher OPN levels were associated with kidney function markers worsening, and a higher risk for adverse outcomes. A larger proportion of KF could be attributed to higher OPN levels warranting further research on OPN with regards to its role in CKD progression and possible treatment options

Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study

Rationale & objective: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD). Study design: Prospective cohort study. Setting & participants: 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent). Exposure: Serum levels of H-FABP and hs-TNT were measured at study entry. Outcome: Noncardiovascular (non-CV) death, CV death, combined major adverse CV events (MACE), and hospitalization for congestive heart failure (CHF). Analytical approach: Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors. Results: During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]). Limitations: Single-point measurements of H-FABP and hs-TNT. Uncertain generalizability to non-European populations. Conclusions: In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies

Käytännön kosteikkosuunnittelu

Maatalouden vesiensuojelua edistetään monin tavoin. Ravinteita ja eroosioainesta sisältäviä valumavesiä pyritään puhdistamaan erilaisissa kosteikoissa. Tämä opas on kirjoitettu avuksi pienimuotoisten kosteikkojen perustamiseen. Oppaassa esitetään käytännönläheisesti kosteikon toteuttamisen eri vaiheet paikan valinnasta suunnitteluun ja rakentamiseen. Vuonna 2010 julkaistun painoksen tiedot on saatettu ajantasalle. Julkaisu on toteutettu osana Tehoa maatalouden vesiensuojeluun (TEHO) -hanketta ja päivitetty TEHO Plus -hankkeen toimesta. Oppaan toivotaan lisäävän kiinnostusta kosteikkojen suunnitteluun ja edelleen niiden rakentamiseen

Urine Metabolite Levels, Adverse Kidney Outcomes, and Mortality in CKD Patients: A Metabolome-wide Association Study

Rationale & objective: Mechanisms underlying the variable course of disease progression in patients with chronic kidney disease (CKD) are incompletely understood. The aim of this study was to identify novel biomarkers of adverse kidney outcomes and overall mortality, which may offer insights into pathophysiologic mechanisms. Study design: Metabolome-wide association study. Setting & participants: 5,087 patients with CKD enrolled in the observational German Chronic Kidney Disease Study. Exposures: Measurements of 1,487 metabolites in urine. Outcomes: End points of interest were time to kidney failure (KF), a combined end point of KF and acute kidney injury (KF+AKI), and overall mortality. Analytical approach: Statistical analysis was based on a discovery-replication design (ratio 2:1) and multivariable-adjusted Cox regression models. Results: After a median follow-up of 4 years, 362 patients died, 241 experienced KF, and 382 experienced KF+AKI. Overall, we identified 55 urine metabolites whose levels were significantly associated with adverse kidney outcomes and/or mortality. Higher levels of C-glycosyltryptophan were consistently associated with all 3 main end points (hazard ratios of 1.43 [95% CI, 1.27-1.61] for KF, 1.40 [95% CI, 1.27-1.55] for KF+AKI, and 1.47 [95% CI, 1.33-1.63] for death). Metabolites belonging to the phosphatidylcholine pathway showed significant enrichment. Members of this pathway contributed to the improvement of the prediction performance for KF observed when multiple metabolites were added to the well-established Kidney Failure Risk Equation. Limitations: Findings among patients of European ancestry with CKD may not be generalizable to the general population. Conclusions: Our comprehensive screen of the association between urine metabolite levels and adverse kidney outcomes and mortality identifies metabolites that predict KF and represents a valuable resource for future studies of biomarkers of CKD progression

Uromodulin and its association with urinary metabolites: the German Chronic Kidney Disease Study

Background. The progression of chronic kidney disease (CKD), a global public health burden, is accompanied by a declining number of functional nephrons. Estimation of remaining nephron mass may improve assessment of CKD progression. Uromodulin has been suggested as a marker of tubularmass.We aimed to identify metabolites associated with uromodulin concentrations in urine and serumto characterize pathophysiologic alterations of metabolic pathways to generate new hypotheses regarding CKD pathophysiology. Methods. We measured urinary and serum uromodulin levels (uUMOD, sUMOD) and 607 urinary metabolites and performed cross-sectional analyses within the German Chronic Kidney Disease study (N = 4628), a prospective observational study. Urinary metabolites significantly associated with uUMOD and sUMODwere used to buildweightedmetabolite scores for urine (uMS) and serum uromodulin (sMS) and evaluated for time to adverse kidney events over 6.5 years. Results. Metabolites cross-sectionally associated with uromodulin included amino acids of the tryptophan metabolism, lipids and nucleotides. Higher levels of the sMS [hazard ratio (HR) = 0.73 (95% confidence interval 0.64; 0.82), P = 7.45e-07] and sUMOD [HR = 0.74 (95% confidence interval 0.63;0.87), P=2.32e-04]were associated with a lower risk of adverse kidney events over time, whereas uUMOD and uMS showed the same direction of association but were not significant. Conclusions. We identified urinary metabolites associated with urinary and serum uromodulin. The sUMOD and the sMS were associated with lower risk of adverse kidney events among CKD patients. Higher levels of sUMOD and sMS may reflect a higher number of functional nephrons and therefore a reduced risk of adverse kidney outcomes