“Зізнання авантюриста Фелікса Крулля” Томаса Манна як пародія на велику автобіографію

Статтю присвячено розгляду рецепції та відображення “Поезії і правди” Й.-В. Гете в романі Т. Манна “Зізнання авантюриста Фелікса Крулля”. Представлена розвідка продовжує ряд наукових досліджень, присвячених вивченню особливостей рецепції автобіографії Й.-В. Гете, зокрема в німецькомовному літературному просторі. При дослідженні особливостей наявного в аналізованому нами романі пародійного наслідування Й.-В. Гете основна увага зосереджується автором на його стилістичному та тематичному рівнях.Статья посвящена рассмотрению рецепции и отражения “Поэзии и правды” Й.-В. Гете в романе Т. Манна “Признания авантюриста Феликса Крулля”. Представленная статья продолжает ряд научных исследований, посвященных изучению особенностей рецепции автобиографии Й.-В. Гете в частности в немецкоязычном литературном пространстве. При изучении особенностей имеющихся в анализированном нами романе пародийного подражания Й.-В. Гете основное внимание автор сосредотачивает на его стилистическом и тематическом уровнях.The article focuses on the reception of Goethe’s “Poetry and Truth” and its reflection in T. Mann’s novel “The Confession of adventurer Felix Crool”. The given article extends the series of scientific investigations that deal with the peculiarities of Goethe’s reception in German literature. Studying the parody imitation peculiarities of Goethe in the analysed novel, the main attention is paid to the stylistic and theme levels

Transportomics: screening for substrates of ABC transporters in body fluids using vesicular transport assays

The ATP-binding cassette (ABC) genes encode the largest family of transmembrane proteins. ABC transporters translocate a wide variety of substrates across membranes, but their physiological function is often incompletely understood. We describe a new method to study the substrate spectrum of ABC transporters: We incubate extracts of mouse urine with membrane vesicles prepared from Spodoptera frugiperda Sf9 insect cells overproducing an ABC transporter and determine the compounds transported into the vesicles by LC/MS-based metabolomics. We illustrate the power of this simple “transportomics” approach using ABCC2, a protein present at sites of uptake and elimination. We identified many new substrates of ABCC2 in urine. These included glucuronides of plant-derived xenobiotics, a class of compounds to which humans are exposed on a daily basis. Moreover, we show that the excretion of these compounds in vivo depends on ABCC2: compared to wild-type mice, the urinary excretion of several glucuronides was increased up to 20-fold in Abcc2-/- mice. Transportomics has broad applicability, as it is not restricted to urine and can be applied to other ATP-dependent transport proteins as well.—Krumpochova, P., Sapthu, S., Brouwers, J. F., de Haas, M., de Vos, R., Borst, P., van de Wetering, K. Transportomics: screening for substrates of ABC transporters in body fluids using vesicular transport assay

Lipids Are the Preferred Substrate of the Protist Naegleria gruberi, Relative of a Human Brain Pathogen

Naegleria gruberi is a free-living non-pathogenic amoeboflagellate and relative of Naegleria fowleri, a deadly pathogen causing primary amoebic meningoencephalitis (PAM). A genomic analysis of N. gruberi exists, but physiological evidence for its core energy metabolism or in vivo growth substrates is lacking. Here, we show that N. gruberi trophozoites need oxygen for normal functioning and growth and that they shun both glucose and amino acids as growth substrates. Trophozoite growth depends mainly upon lipid oxidation via a mitochondrial branched respiratory chain, both ends of which require oxygen as final electron acceptor. Growing N. gruberi trophozoites thus have a strictly aerobic energy metabolism with a marked substrate preference for the oxidation of fatty acids. Analyses of N. fowleri genome data and comparison with those of N. gruberi indicate that N. fowleri has the same type of metabolism. Specialization to oxygen-dependent lipid breakdown represents an additional metabolic strategy in protists. Bexkens et al. show that N. gruberi amoebae live preferably on lipids, for which they need oxygen, a lifestyle largely unknown among protists. This challenges existing views about its energy metabolism, with implications for treatment of its pathogenic relative, N. fowleri, the brain-eating agent of primary amoebic me

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium

Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints

Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson's Disease

Contains fulltext : 225767.pdf (publisher's version ) (Open Access)22 p

Validation of the Dutch translation of the Cardiff wound impact schedule for evaluation of the health-related quality of life of patients with chronic wounds

The aim of this study was to validate a Dutch translation of the Cardiff wound impact schedule (CWIS), a disease-specific instrument to measure the health-related quality of life (HRQoL) in patients with chronic leg ulcers. To achieve this, the original instrument was translated. A total of 83 patients with chronic lower leg ulcers were included and completed the translated instrument and SF36 at baseline after assessment of their wound severity. Follow-up was performed 1 week after inclusion. The psychometric properties of the instrument were assessed. Construct validity was positively evaluated by an expert panel. Face validity was positively evaluated in a cognitive debriefing of a pilot group. Discriminant validity was assessed by correlating 1-year amputation risk according to the Wound, Ischaemia, foot Infection classification system with the instrument scores. Significant correlation could not be proven. Criterion validity was assessed by correlating domain scores of the instrument with domain scores of the gold standard: SF36. Moderate to high correlation was calculated for most domains of the instrument. Test-retest reliability and internal consistency were evaluated as acceptable. In conclusion, the Dutch translation of the CWIS is a valid and reliable disease-specific instrument to assess the HRQoL in patients with chronic lower leg ulcers.Vascular Surger

Imaging assessment of carotid artery stenosis varies in clinical practice

Vascular Surger

Imaging assessment of carotid artery stenosis varies in clinical practice

Cardiovascular Aspects of Radiolog

Using maximal systolic acceleration to diagnose and assess the severity of peripheral artery disease in a flow model study

Background: Because of the presence of medial calcific sclerosis, both ankle-branchial index and toe pressure measures can yield misleading results when attempting to diagnose peripheral artery disease (PAD). A new ultrasound parameter, maximal systolic acceleration (ACC(max)), can be an accurate tool for diagnosing PAD, including in diabetic patients. However, it has not been evaluated thoroughly. The aim of this study was to assess the feasibility of using ACC(max) to diagnose and assess the severity of PAD.Methods: The human circulatory system was simulated using an in vitro circulatory system driven by a pulsatile pneumatic pump. Arterial stenosis of various degrees (50%, 70%, 80%, and 90%) was simulated in order to investigate the change in several ultrasound parameters (including ACC(max)), as well as the intraluminal mean arterial pressure gradient. In a separate set of measurements, interobserver variability was measured using two investigators who were unaware of the degree of stenosis.Results: ACC(max) significantly decreased (P < .001), and the pressure gradient increased (P < .001) as the degree of stenosis increased. Moreover, we found a strong correlation between ACC(max) and the pressure gradient (R-2 = 0.937). Finally, interobserver variability with respect to ACC(max) was extremely low, with an intraclass correlation coefficient of 0.99.Conclusions: The results of this flow model study suggest that ACC(max) can be a valid, noninvasive tool for diagnosing PAD. Moreover, our finding that ACC(max) decreases as the severity of stenosis increases, together with the strong correlation between ACC(max) and the pressure gradient, suggests that ACC(max) may be useful as an alternative diagnostic tool for assessing the severity of PAD. These promising in vitro data warrant further study in a clinical setting.Vascular Surger