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Die Wirkungen von Acrylamid beschäftigen seit Jahrzehnten Mediziner, Toxikologen, Biologen und Analytiker. Zwar konnte eine kanzerogene Wirkung beim Tier eindeutig nachgewiesen werden, der Nachweis dieser Wirkung beim Menschen ist aber bis heute nicht erbracht. Bis 2000 wurde angenommen, dass Acrylamid ausschließlich technisch erzeugt vorkommt und der Mensch Acrylamid nur aus dieser Quelle aufnimmt. Hierauf beruhen Grenz- und Richtwerte auf nationaler und internationaler Ebene, sowohl am Arbeitsplatz als auch für Trinkwasser und Verpackungsmaterialien. Neben dem Acrylamidgehalt in technischen Produkten, Wasser und Luft gelang der Nachweis der aufgenommenen Acrylamidmenge über Acrylamid-Hämoglobin-Addukte im Blut erst 1995, nachdem der Acrylamid-Metabolismus aufgeklärt worden war und die analytischen Methoden verfeinert waren. Die Annahme, dass Acrylamid ausschließlich in technischen Prozessen gebildet wird, war jedoch nicht vereinbar mit Erkenntnissen, dass auch Probanden einen erhöhten Acrylamidspiegel im Blut aufzeigten, die nicht mit Acrylamid am Arbeitsplatz in Kontakt gekommen waren. Im Jahr 2002 gelang es eindeutig nachzuweisen, dass Acrylamid in vielen, meist alltäglich verzehrten Lebensmitteln abhängig von der Zubereitungsart zu finden ist. Mit Hilfe einer verbesserten Analytik konnten schließlich hohe Acrylamidmengen in zahlreichen, vor allem frittierten Lebensmitteln, belegt werden, die die Belastung aus technischen Quellen oft weit überschritten. Die Tatsache, dass die Nahrung der allgemeinen Bevölkerung deutlich Acrylamid-belastet ist, hat die Bewertung der Acrylamid-Toxizität und die Maßnahmen zum Gesundheitsschutz nachhaltig verändert. Durch den späten Nachweis der Acrylamid-Aufnahme mit Lebensmitteln sind viele frühere Annahmen für die Gesundheitsbewertung irrig, die hieraus gezogenen Schlußfolgerungen nicht haltbar. Seit 2002 ist die Reduktion der Lebensmittelbelastung in den Mittelpunkt gerückt, die Arbeitsplatzbelastung hat - mit Ausnahme der Schleimhautreizung - keine weitere Berücksichtigung erhalten. Die hohe Belastung von Lebensmitteln stellt bisherige Richtlinien und Expositionsauflagen in Frage, der fehlende bisherige epidemiologische Nachweis, der aus Tierversuchen eindeutig nachweisbaren Karzinogenität stellt für Acrylamid auch die bisherigen Modell-Annahmen der Krebsentstehung durch Umweltschadstoffe in der „one hit-Hypothese“ in Frage.
Protein turnover and quality control by the proteasome is of paramount importance for cell homeostasis. Dysfunction of the proteasome is associated with aging processes and human diseases such as neurodegeneration, cardiomyopathy, and cancer. The regulation, i.e. activation and inhibition of this fundamentally important protein degradation system, is still widely unexplored. We demonstrate here that the evolutionarily highly conserved type II triple-A ATPase VCP and the proteasome inhibitor PSMF1/PI31 interact directly, and antagonistically regulate proteasomal activity. Our data provide novel insights into the regulation of proteasomal activity.
Background The to date evidence for a dose-response relationship between physical workload and the development of lumbar disc diseases is limited. We therefore investigated the possible etiologic relevance of cumulative occupational lumbar load to lumbar disc diseases in a multi-center case-control study. Methods In four study regions in Germany (Frankfurt/Main, Freiburg, Halle/Saale, Regensburg), patients seeking medical care for pain associated with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were prospectively recruited. Population control subjects (453 males and 448 females) were drawn from the regional population registers. Cases and control subjects were between 25 and 70 years of age. In a structured personal interview, a complete occupational history was elicited to identify subjects with certain minimum workloads. On the basis of job task-specific supplementary surveys performed by technical experts, the situational lumbar load represented by the compressive force at the lumbosacral disc was determined via biomechanical model calculations for any working situation with object handling and load-intensive postures during the total working life. For this analysis, all manual handling of objects of about 5 kilograms or more and postures with trunk inclination of 20 degrees or more are included in the calculation of cumulative lumbar load. Confounder selection was based on biologic plausibility and on the change-in-estimate criterion. Odds ratios (OR) and 95% confidence intervals (CI) were calculated separately for men and women using unconditional logistic regression analysis, adjusted for age, region, and unemployment as major life event (in males) or psychosocial strain at work (in females), respectively. To further elucidate the contribution of past physical workload to the development of lumbar disc diseases, we performed lag-time analyses. Results We found a positive dose-response relationship between cumulative occupational lumbar load and lumbar disc herniation as well as lumbar disc narrowing among men and women. Even past lumbar load seems to contribute to the risk of lumbar disc disease. Conclusions According to our study, cumulative physical workload is related to lumbar disc diseases among men and women.
Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30–100 µM and 5–20-fold preference of AGMO relative to other BH4-dependent enzymes, i.e., phenylalanine-hydroxylase and nitric oxide synthase. The viability and metabolic activity of mouse 3T3-L1 fibroblasts, HepG2 human hepatocytes and mouse RAW264.7 macrophages were not affected up to 10-fold of the IC50. However, Cp6 reversibly inhibited the differentiation of 3T3-L1 cells towards adipocytes, in which AGMO expression was upregulated upon differentiation. Cp6 reduced the accumulation of lipid droplets in adipocytes upon differentiation and in HepG2 cells exposed to free fatty acids. Cp6 also inhibited IL-4-driven differentiation of RAW264.7 macrophages towards M2-like macrophages, which serve as adipocyte progenitors in adipose tissue. Collectively, the data suggest that pharmacologic AGMO inhibition may affect lipid storage.
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.
Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
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.
Fragment mass distributions for fission after full momentum transfer were measured in the reactions of 30Si,34,36 S,31P,40Ar + 238U at bombarding energies around the Coulomb barrier. Mass distributions change significantly as a function of incident beam energy. The asymmetric fission probability increases at sub-barrier energy. The phenomenon is interpreted as an enhanced quasifission probability owing to orientation effects on fusion and/or quasifission. The evaporation residue (ER) cross sections were measured in the reactions of 30Si + 238U and 34S + 238U to obtain information on fusion. In the latter reaction, significant suppression of fusion was implied. This suggests that fission events different from compound nucleus are included in the masssymmetric fragments. The results are supported by a model calculation based on a dynamical calculation using Langevin equation, in which the mass distribution for fusion-fission and quasifission fragments are separately determined.
Fission fragment mass distributions were measured in heavy-ion induced fissions using 238U target nucleus. The measured mass distributions changed drastically with incident energy. The results are explained by a change of the ratio between fusion and qasifission with nuclear orientation. A calculation based on a fluctuation dissipation model reproduced the mass distributions and their incident energy dependence. Fusion probability was determined in the analysis, and the values were consistent with those determined from the evaporation residue cross sections.