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Background: Health-related and disease-specific quality of life (HRQoL) has been increasingly valued as relevant clinical parameter in cystic fibrosis (CF) clinical care and clinical trials. HRQoL measures should assess – among other domains – daily functioning from a patient’s perspective. However, validation studies for the most frequently used HRQoL questionnaire in CF, the Cystic Fibrosis Questionnaire (CFQ), have not included measures of physical activity or fitness. The objective of this study was, therefore, to determine the cross-sectional and longitudinal relationships between HRQoL, physical activity and fitness in patients with CF.
Methods: Baseline (n = 76) and 6-month follow-up data (n = 70) from patients with CF (age ≥12 years, FEV1 ≥35%) were analysed. Patients participated in two multi-centre exercise intervention studies with identical assessment methodology. Outcome variables included HRQoL (German revised multi-dimensional disease-specific CFQ (CFQ-R)), body composition, pulmonary function, physical activity, short-term muscle power, and aerobic fitness by peak oxygen uptake and aerobic power.
Results: Peak oxygen uptake was positively related to 7 of 13 HRQoL scales cross-sectionally (r = 0.30-0.46). Muscle power (r = 0.25-0.32) and peak aerobic power (r = 0.24-0.35) were positively related to 4 scales each, and reported physical activity to 1 scale (r = 0.29). Changes in HRQoL-scores were directly and significantly related to changes in reported activity (r = 0.35-0.39), peak aerobic power (r = 0.31-0.34), and peak oxygen uptake (r = 0.26-0.37) in 3 scales each. Established associates of HRQoL such as FEV1 or body mass index correlated positively with fewer scales (all 0.24 < r < 0.55).
Conclusions: HRQoL was associated with physical fitness, especially aerobic fitness, and to a lesser extent with reported physical activity. These findings underline the importance of physical fitness for HRQoL in CF and provide an additional rationale for exercise testing in this population.
Trial registration: ClinicalTrials.gov, NCT00231686
Background: Despite improvements in liver surgery over the past decades, hemostasis during hepatic resections remains challenging. This multicenter randomized study compares the hemostatic effect of a collagen hemostat vs. a carrier-bound fibrin sealant after hepatic resection.
Methods: Patients scheduled for elective liver resection were randomized intraoperatively to receive either the collagen hemostat (COLL) or the carrier-bound fibrin sealant (CBFS) for secondary hemostasis. The primary endpoint was the proportion of patients with hemostasis after 3 min. Secondary parameters were the proportions of patients with hemostasis after 5 and 10 min, the total time to hemostasis, and the complication rates during a 3 months follow-up period.
Results: A total of 128 patients were included. In the COLL group, 53 out of 61 patients (86.9 %) achieved complete hemostasis within 3 min after application of the hemostat compared to 52 out of 65 patients (80.0 %) in the CBFS group. The 95 % confidence interval for this difference [−6.0 %, 19.8 %] does not include the lower noninferiority margin (−10 %). Thus, the COLL treatment can be regarded as noninferior to the comparator. The proportions of patients with hemostasis after 3, 5, and 10 min were not significantly different between the two study arms. Postoperative mortality and morbidity were similar in both treatment groups.
Conclusion: The collagen hemostat is as effective as the carrier-bound fibrin sealant in obtaining secondary hemostasis during liver resection with a comparable complication rate.
Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.
Introduction: Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated.
Methods: Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively.
Results: MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability.
Conclusions: These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
Inhibitors of the mammalian target of rapamycin (mTOR) have improved the treatment of renal cell carcinoma (RCC). However, chronic drug exposure may trigger resistance, limiting the utility of these agents. The metastatic behavior of RCC cells, susceptible (RCC(par)) or resistant (RCC(res)) to the mTOR inhibitor temsirolimus, was investigated. Adhesion to vascular endothelium or immobilized collagen and fibronectin was quantified. Chemotactic motility was evaluated with a modified Boyden chamber assay. Integrin α and β subtype receptors were analyzed by flow cytometry and Western blot analysis. The physiological relevance of the integrins was then determined by blocking studies and small interfering RNA knockdown. Adhesion to endothelial cells and to fibronectin (not to collagen) and chemotaxis were enhanced in RCC(res) compared to RCC(par). RCC(res) detached from fibronectin and motile activity further increased under retreatment with low-dosed temsirolimus. α5 integrin was diminished inside the cell and at the cell surface, whereas the β3 subtype was reduced intracellularly but elevated at the plasma membrane. In RCC(par), blocking α5 surface receptors enhanced RCC-collagen but reduced RCC-fibronectin interaction, whereas the opposite was true for RCC(res). Chemotaxis of RCC(par) but not of RCC(res) was strongly diminished by the α5 antibody. Blocking β3 significantly lowered chemotaxis with stronger effects on RCC(res), compared to RCC(par). Importantly, β3 knockdown reduced chemotaxis of RCC(par) but upregulated the motile behavior of RCC(res). Temsirolimus resistance is characterized by quantitative alterations of integrin α5 and β3 expression, coupled to functional changes of the integrin molecules, and forces a switch from RCC adhesion to RCC migration.
Background. Depression is the most common type of mental disorder in Germany. It is associated with a high level of suffering for individuals and imposes a significant burden on society. The aim of this study was to estimate the depression related costs in Germany taking a societal perspective.
Materials and Methods. Data were collected from the primary care monitoring for depressive patients trial (PRoMPT) of patients with major depressive disorder who were treated in a primary care setting. Resource utilisation and days of sick leave were observed and analysed over a 1-year period.
Results. Average depression related costs of €3813 were calculated. Significant differences in total costs due to sex were demonstrated. Male patients had considerable higher total costs than female patients, whereas single cost categories did not differ significantly. Further, differences in costs according to severity of disease and age were observed. The economic burden to society was estimated at €15.6 billion per year.
Conclusion. The study results show that depression poses a significant economic burden to society. There is a high potential for prevention, treatment, and patient management innovations to identify and treat patients at an early stage.
Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.
Einleitung: Im Rahmen dieser retrospektiven Studie wurde die Auswirkung der frühen reduzierten Belastung auf Festigkeit der Implantatverankerung untersucht. Zusätzlich wurde geprüft, welchen Einfluss die Faktoren Implantatlänge, Knochenqualität, Augmentationsart und Implantatlokalisation auf die Festigkeit der Implantatverankerung nach der frühen reduzierten Belastung haben.
Material und Methoden: In die Studie wurden Patienten einbezogen, die sich einer Implantationstherapie in Poliklinik für Zahnärztliche Chirurgie und Implantologie in ZZMK (Carolinum) der J. W. Goethe-Universität in dem Zeitraum von Januar 2001 bis Februar 2010 unterzogen haben. Alle teilnehmenden Patienten wurden von einem Behandler betreut. Es wurden ausschließlich Ankylos Implantate (Dentsply, Mannheim, Deutschland) verwendet. Die Festigkeit der Implantatverankerung wurde mit Periotets gemessen. Die Implantationstherapie lief grundsätzlich nach den Rahmenbedingungen der frühen reduzierten Implantatbelastung ab. Nach einer mindestens sechswöchigen geschlossen Einheilung (statische Phase) wurden die Implantate freigelegt und mit Standardabutment versorgt, anschließend wurde der erste Periotestwert erhoben. Die statische Phase nach externem Sinuslift betrug im Schnitt 5 Monate. Für weitere vier bis acht Wochen (dynamische Phase) wurden die Implantate mit Provisorien in Infraokklusion versorgt, bei zahnlosen Patienten wurden die Implantate durch die provisorische Versorgung grundsätzlich verblockt. Patienten wurden unterwiesen, nur weiche Kost zu sich zu nehmen. Nach vier bis acht Wochen im Anschluss an die dynamische Phase wurde der zweite Periotestwert erhoben. Definitiver Zahnersatz mit korrekt eingestellter Okklusion wurde eingegliedert. Die Periotestwerte vor und nach der frühen reduzierten Implantatbelastung wurden zusammengetragen und statistisch ausgewertet.
Ergebnisse: Bei 247 Patienten wurden im Zeitraum von 01.01.2001 bis 01.03.2010 634 Ankylos Implantate inseriert. In der statischen Phase gingen sieben Implantate verloren, restliche 627 Implantate wurden früh reduziert belastet. Kein Implantat ging in der dynamischen Phase verloren. Innerhalb des ersten Jahres unter voller funktioneller Belastung ging kein Implantat aufgrund von knöcherner Überbelastung verloren. Lediglich ein Implantat musste aufgrund von Abutmentfraktur ein Jahr nach der Eingliederung des definitiven Zahnersatzes entfernt werden. Die Periotestwerte nahmen bei 556 Implantaten um mindestens eine Einheit der Periotestwertskala ab. Diese Veränderung der Periotestwerte war statistisch signifikant (p = 0,0001). Der Einfluss der Faktoren Implantatlänge, Knochenqualität, Implantatlokalisation, Augmentationsverfahren auf die Reduktion der Periotestwerte um eine Einheit war statistisch nicht signifikant. Die Reduktion der Periotestwerte um mindestens zwei Einheiten trat bei 409 von insgesamt 627 Implantaten auf und war statistisch signifikant in den Gruppen „weiche Knochenqualität“, „Implantatlänge 8mm, 9,5mm“, „externer Sinuslift“, „Oberkiefer“ (p = 0,001). In zwei Gruppen, nämlich „11mm und 14mm“ sowie „Standardverfahren, laterale Augmentation, interner Sinuslift“ trat eine Abnahme der Periotestwerte statistisch signifikant seltener auf (p = 0,045 bei „11 und 14 mm“ und p = 0,033 bei „Standardverfahren, laterale Augmentation und interner Sinuslift“).
Schlussfolgerung:Die frühe reduzierte Implantatbelastung hat keinen negativen Einfluss auf den Implantaterfolg. Beim Vorliegen von ungünstigen Voraussetzungen, wie unzureichendem Knochenangebot und Knochenqualität sowie Implantation im Oberkiefer, verbessert sich die Festigkeit der Implantatverankerung besonders deutlich. Das Konzept zeichnet sich durch das breite Indikationsspektrum und die hohe Überlebensrate trotz der verkürzten Therapiezeit aus.
Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.
Programele computerizate au un rol indiscutabil în atingerea unor standarde ridicate în procesul educațional. Pe de altă parte acestea sunt instrumente eficiente în identificarea particularităților cazurilor clinice, evaluarea acestora în conformitate cu indicii clinico-biologici specifici. În timpul procesului didactic, simularea are un rol esenţial, ca o prefaţă la procedurile practice care formează abilităţile practice pe fiecare entitate clinică în medicina dentară.
Die kutane Larva migrans ist eine in ihrem klinischen Bild typische Hautinfektion, die durch aktives Eindringen und anschließende epidermale Wanderung von Nematodenlarven hervorgerufen wird. Dieses typische klinische Bild wird durch Larven von Hakenwürmern, meist Ancylostoma braziliense, selten andere bei Kaniden und Feliden vorkommende Hakenwurmarten, verursacht.
Ziele der Leitlinie sind die Verbesserung der Versorgung der Patienten durch Optimierung von Diagnostik und Therapie bei Infektionen mit Larva migrans cutanea sowie die Verbesserung der Kenntnisse von Ärztinnen und Ärzte über aktuelle Therapieoptionen.
Treating large bone defects represents a major challenge in traumatic and orthopedic surgery. Bone tissue engineering provides a promising therapeutic option to improve the local bone healing response. In the present study tissue biocompatibility, systemic toxicity and tumorigenicity of a newly developed composite material consisting of polylactic acid (PLA) and 20% or 40% bioglass (BG20 and BG40), respectively, were analyzed. These materials were seeded with mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) and tested in a rat calvarial critical size defect model for 3 months and compared to a scaffold consisting only of PLA. Serum was analyzed for organ damage markers such as GOT and creatinine. Leukocyte count, temperature and free radical indicators were measured to determine the degree of systemic inflammation. Possible tumor occurrence was assessed macroscopically and histologically in slides of liver, kidney and spleen. Furthermore, the concentrations of serum malondialdehyde (MDA) and sodium oxide dismutase (SOD) were assessed as indicators of tumor progression. Qualitative tissue response towards the implants and new bone mass formation was histologically investigated. BG20 and BG40, with or without progenitor cells, did not cause organ damage, long-term systemic inflammatory reactions or tumor formation. BG20 and BG40 supported bone formation, which was further enhanced in the presence of EPCs and MSCs.
This investigation reflects good biocompatibility of the biomaterials BG20 and BG40 and provides evidence that additionally seeding EPCs and MSCs onto the scaffold does not induce tumor formation.
Selection of higher order regression models in the analysis of multi-factorial transcription data
(2014)
Introduction: Many studies examine gene expression data that has been obtained under the influence of multiple factors, such as genetic background, environmental conditions, or exposure to diseases. The interplay of multiple factors may lead to effect modification and confounding. Higher order linear regression models can account for these effects. We present a new methodology for linear model selection and apply it to microarray data of bone marrow-derived macrophages. This experiment investigates the influence of three variable factors: the genetic background of the mice from which the macrophages were obtained, Yersinia enterocolitica infection (two strains, and a mock control), and treatment/non-treatment with interferon-γ.
Results: We set up four different linear regression models in a hierarchical order. We introduce the eruption plot as a new practical tool for model selection complementary to global testing. It visually compares the size and significance of effect estimates between two nested models. Using this methodology we were able to select the most appropriate model by keeping only relevant factors showing additional explanatory power. Application to experimental data allowed us to qualify the interaction of factors as either neutral (no interaction), alleviating (co-occurring effects are weaker than expected from the single effects), or aggravating (stronger than expected). We find a biologically meaningful gene cluster of putative C2TA target genes that appear to be co-regulated with MHC class II genes.
Conclusions: We introduced the eruption plot as a tool for visual model comparison to identify relevant higher order interactions in the analysis of expression data obtained under the influence of multiple factors. We conclude that model selection in higher order linear regression models should generally be performed for the analysis of multi-factorial microarray data.
Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133-expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. Here, we present CD133-LV, a lentiviral vector presenting a single chain antibody against CD133 on its envelope, as a vehicle for the selective transduction of CD133-expressing GSCs. We show that CD133-LV selectively transduces CD133+ human GSCs in dose-dependent manner and that transduced cells maintain their stem-like properties. The transduction efficiency of CD133-LV is reduced by an antibody that recognizes the same epitope on CD133 as the viral envelope and by shRNA-mediated knockdown of CD133. Conversely, the rate of transduction by CD133-LV is augmented by overexpression of CD133 in primary human GBM cultures. CD133-LV selectively transduces CD133-expressing cells in intracranial human GBM xenografts in NOD.SCID mice, but spares normal mouse brain tissue, neurons derived from human embryonic stem cells and primary human astrocytes. Our findings indicate that CD133-LV represents a novel tool for the selective genetic manipulation of CD133-expressing GSCs, and can be used to answer important questions about how these cells contribute to tumor biology and therapy resistance.
Considering the review by Puspitasari and colleagues, an additional discussion of the endpoints of the Se supplementation studies described would be helpful. In our view, selenium can safely be given to selenium-deficient cancer patients prior to and during radiotherapy. Therefore, in order to help the radiation oncologist in decision making, we strongly advocate to determine the selenium status prior to and during a potential adjuvant selenium supplementation, e.g. when trying to ease the side-effects of radiation treatment or in the aftercare situation when the selenium status may become insufficient.
Background: With increasing life expectancy the number of people affected by multimorbidity rises. Knowledge of factors associated with health-related quality of life in multimorbid people is scarce. We aimed to identify the factors that are associated with self-rated health (SRH) in aged multimorbid primary care patients.
Methods: Cross-sectional study with 3,189 multimorbid primary care patients aged from 65 to 85 years recruited in 158 general practices in 8 study centers in Germany. Information about morbidity, risk factors, resources, functional status and socio-economic data were collected in face-to-face interviews. Factors associated with SRH were identified by multivariable regression analyses.
Results: Depression, somatization, pain, limitations of instrumental activities (iADL), age, distress and Body Mass Index (BMI) were inversely related with SRH. Higher levels of physical activity, income and self-efficacy expectation had a positive association with SRH. The only chronic diseases remaining in the final model were Parkinson's disease and neuropathies. The final model accounted for 35% variance of SRH. Separate analyses for men and women detected some similarities; however, gender specific variation existed for several factors.
Conclusion: In multimorbid patients symptoms and consequences of diseases such as pain and activity limitations, as well as depression, seem to be far stronger associated with SRH than the diseases themselves. High income and self-efficacy expectation are independently associated with better SRH and high BMI and age with low SRH.
Background: Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.
Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.
Results: 270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).
Conclusion: Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.
Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes.
Silicosis : geographic changes in research ; an analysis employing density-equalizing mapping
(2014)
Background: A critical evaluation of scientific efforts is needed in times of modified evaluation criteria for academic personnel and institutions.
Methods: Using scientometric benchmark procedures and density-equalizing mapping, we analysed the global scientific efforts on "silicosis" of the last 92 years focusing on geographical changes within the last 30 years, specifying the most productive authors, institutions, countries and the most successful cooperations.
Results: The USA as the most productive supplier have established their position as center of international cooperation, followed in considerable distance by the United Kingdom, Germany and China. Asian countries, particularly China, catch up and are expected to excel the USA still in this decade.
Conclusion: The combination of scientometric procedures with density-equalizing mapping reveals a distinct global pattern of research productivity and citation activity. Modified h-index, citationrate and impact factor have to be discussed critically due to distortion by bias of self-citation, language and co-authorship.
Background & Aims: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy.
Methods: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group).
Results: Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6–53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir.
Conclusions: In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.
The neuroanatomical connectivity of cortical circuits is believed to follow certain rules, the exact origins of which are still poorly understood. In particular, numerous nonrandom features, such as common neighbor clustering, overrepresentation of reciprocal connectivity, and overrepresentation of certain triadic graph motifs have been experimentally observed in cortical slice data. Some of these data, particularly regarding bidirectional connectivity are seemingly contradictory, and the reasons for this are unclear. Here we present a simple static geometric network model with distance-dependent connectivity on a realistic scale that naturally gives rise to certain elements of these observed behaviors, and may provide plausible explanations for some of the conflicting findings. Specifically, investigation of the model shows that experimentally measured nonrandom effects, especially bidirectional connectivity, may depend sensitively on experimental parameters such as slice thickness and sampling area, suggesting potential explanations for the seemingly conflicting experimental results.
Background: Influenza vaccination of healthcare workers (HCWs) is recommended to prevent the transmission of influenza to vulnerable patients. Nevertheless, vaccination coverage rates of HCWs in European countries have been low.
Aim: To investigate the relative and combined strength of sociocognitive variables, from past research, theory and a qualitative study, in explaining the motivation of HCWs to receive the influenza vaccine.
Methods: An anonymous, online questionnaire was distributed among HCWs in hospital settings in Belgium, Germany and the Netherlands between February and April 2013.
Findings: Attitude and past vaccination uptake explained a considerable amount of variance in the intention of HCWs to receive the influenza vaccine. Moreover, low perceived social norms, omission bias, low moral norms, being older, having no patient contact, and being Belgian or Dutch (compared with German) increased the probability of having no intention to receive the influenza vaccine compared with being undecided about vaccination. High intention to receive the influenza vaccine was shown to be more likely than being undecided about vaccination when HCWs had high perceived susceptibility of contracting influenza, low naturalistic views, and lower motivation to receive the vaccine solely for self-protection.
Conclusion: Country-specific interventions and a focus on different sociocognitive variables depending on the intention/lack of intention of HCWs to receive the influenza vaccine may be beneficial to promote vaccination uptake.
Background: Hereditary angioedema (HAE) due to C1 inhibitor deficiency is a rare but serious and potentially life-threatening disease marked by spontaneous, recurrent attacks of swelling. The study objective was to characterize direct and indirect resource utilization associated with HAE from the patient perspective in Europe.
Methods: The study was conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE via a cross-sectional survey of HAE patients, including direct and indirect resource utilization during and between attacks for patients and their caregivers over the past 6 months. A regression model examined predictors of medical resource utilization.
Results: Overall, 164 patients had an attack in the past 6 months and were included in the analysis. The most significant predictor of medical resource utilization was the severity of the last attack (OR 2.6; p < 0.001). Among patients who sought medical care during the last attack (23%), more than half utilized the emergency department. The last attack prevented patients from their normal activities an average of 4-12 hours. Patient and caregiver absenteeism increased with attack severity and frequency. Among patients who were working or in school (n = 120), 72 provided work/school absenteeism data, resulting in an estimated 20 days missing from work/school on average per year; 51% (n = 84) indicated that HAE has hindered their career/educational advancement.
Conclusion: HAE poses a considerable burden on patients and their families in terms of direct medical costs and indirect costs related to lost productivity. This burden is substantial at the time of attacks and in between attacks.
Pattern recognition applied to whole-brain neuroimaging data, such as functional Magnetic Resonance Imaging (fMRI), has proved successful at discriminating psychiatric patients from healthy participants. However, predictive patterns obtained from whole-brain voxel-based features are difficult to interpret in terms of the underlying neurobiology. Many psychiatric disorders, such as depression and schizophrenia, are thought to be brain connectivity disorders. Therefore, pattern recognition based on network models might provide deeper insights and potentially more powerful predictions than whole-brain voxel-based approaches. Here, we build a novel sparse network-based discriminative modeling framework, based on Gaussian graphical models and L1-norm regularized linear Support Vector Machines (SVM). In addition, the proposed framework is optimized in terms of both predictive power and reproducibility/stability of the patterns. Our approach aims to provide better pattern interpretation than voxel-based whole-brain approaches by yielding stable brain connectivity patterns that underlie discriminative changes in brain function between the groups. We illustrate our technique by classifying patients with major depressive disorder (MDD) and healthy participants, in two (event- and block-related) fMRI datasets acquired while participants performed a gender discrimination and emotional task, respectively, during the visualization of emotional valent faces.
Background: Rapidly increasing temperatures in the mountain region of Nepal and recent reports of dengue fever and lymphatic filariasis cases from mountainous areas of central Nepal prompted us to study the spatio-temporal distribution of the vectors of these two diseases along an altitudinal transect in central Nepal.
Methodology/Principal Findings: We conducted a longitudinal study in four distinct physiographical regions of central Nepal from September 2011 to February 2012. We used BG-Sentinel and CDC light traps to capture adult mosquitoes. We found the geographical distribution of the dengue virus vectors Aedes aegypti and Aedes albopictus along our study transect to extend up to 1,310 m altitude in the Middle Mountain region (Kathmandu). The distribution of the lymphatic filariasis vector Culex quinquefasciatus extended up to at least 2,100 m in the High Mountain region (Dhunche). Statistical analysis showed a significant effect of the physiographical region and month of collection on the abundance of A. aegypti and C. quinquefasciatus only. BG-Sentinel traps captured significantly higher numbers of A. aegypti than CDC light traps. The meteorological factors temperature, rainfall and relative humidity had significant effects on the mean number of A. aegypti per BG-Sentinel trap. Temperature and relative humidity were significant predictors of the number of C. quinquefasciatus per CDC light trap. Dengue fever and lymphatic filariasis cases had previously been reported from all vector positive areas except Dhunche which was free of known lymphatic filariasis cases.
Conclusions/Significance: We conclude that dengue virus vectors have already established stable populations up to the Middle Mountains of Nepal, supporting previous studies, and report for the first time the distribution of lymphatic filariasis vectors up to the High Mountain region of this country. The findings of our study should contribute to a better planning and scaling-up of mosquito-borne disease control programmes in the mountainous areas of Nepal.
Dendritic cells (DCs) are the cutting edge in innate and adaptive immunity. The major functions of these antigen-presenting cells are the capture, endosomal processing and presentation of antigens, providing them an exclusive ability to provoke adaptive immune responses and to induce and control tolerance. Immature DCs capture and process antigens, migrate towards secondary lymphoid organs where they present antigens to naive T cells in a well-synchronized sequence of procedures referred to as maturation. Indeed, recent research indicated that sphingolipids are modulators of essential steps in DC homeostasis. It has been recognized that sphingolipids not only modulate the development of DC subtypes from precursor cells but also influence functional activities of DCs such as antigen capture, and cytokine profiling. Thus, it is not astonishing that sphingolipids and sphingolipid metabolism play a substantial role in inflammatory diseases that are modulated by DCs. Here we highlight the function of sphingosine 1-phosphate (S1P) on DC homeostasis and the role of S1P and S1P metabolism in inflammatory diseases.
In self-organized critical (SOC) systems avalanche size distributions follow power-laws. Power-laws have also been observed for neural activity, and so it has been proposed that SOC underlies brain organization as well. Surprisingly, for spiking activity in vivo, evidence for SOC is still lacking. Therefore, we analyzed highly parallel spike recordings from awake rats and monkeys, anesthetized cats, and also local field potentials from humans. We compared these to spiking activity from two established critical models: the Bak-Tang-Wiesenfeld model, and a stochastic branching model. We found fundamental differences between the neural and the model activity. These differences could be overcome for both models through a combination of three modifications: (1) subsampling, (2) increasing the input to the model (this way eliminating the separation of time scales, which is fundamental to SOC and its avalanche definition), and (3) making the model slightly sub-critical. The match between the neural activity and the modified models held not only for the classical avalanche size distributions and estimated branching parameters, but also for two novel measures (mean avalanche size, and frequency of single spikes), and for the dependence of all these measures on the temporal bin size. Our results suggest that neural activity in vivo shows a mélange of avalanches, and not temporally separated ones, and that their global activity propagation can be approximated by the principle that one spike on average triggers a little less than one spike in the next step. This implies that neural activity does not reflect a SOC state but a slightly sub-critical regime without a separation of time scales. Potential advantages of this regime may be faster information processing, and a safety margin from super-criticality, which has been linked to epilepsy.
Acute myeloid leukemia (AML) is characterized by an aberrant self-renewal of hematopoietic stem cells (HSC) and a block in differentiation. The major therapeutic challenge is the characterization of the leukemic stem cell as a target for the eradication of the disease. Until now the biology of AML-associated fusion proteins (AAFPs), such as the t(15;17)-PML/RARα, t(8;21)-RUNX1/RUNX1T1 and t(6;9)-DEK/NUP214, all able to induce AML in mice, was investigated in different models and genetic backgrounds, not directly comparable to each other. To avoid the bias of different techniques and models we expressed these three AML-inducing oncogenes in an identical genetic background and compared their influence on the HSC compartment in vitro and in vivo.
These AAFPs exerted differential effects on HSCs and PML/RARα, similar to DEK/NUP214, induced a leukemic phenotype from a small subpopulation of HSCs with a surface marker pattern of long-term HSC and characterized by activated STAT3 and 5. In contrast the established AML occurred from mature populations in the bone marrow. The activation of STAT5 by PML/RARα and DEK/NUP214 was confirmed in t(15;17)(PML/RARα) and t(6;9)(DEK/NUP214)-positive patients as compared to normal CD34+ cells. The activation of STAT5 was reduced upon the exposure to Arsenic which was accompanied by apoptosis in both PML/RARα- and DEK/NUP214-positive leukemic cells. These findings indicate that in AML the activation of STATs plays a decisive role in the biology of the leukemic stem cell. Furthermore we establish exposure to arsenic as a novel concept for the treatment of this high risk t(6;9)-positive AML.
Hintergrund: Das Monitoring von unfraktioniertem Heparin (UFH) bei extrakorporaler Zirkulation (EKZ) erfolgt standardmäßig mit Phospholipid-abhängigen Gerinnungstests wie „Activated Clotting Time“ [ACT, (sec)] bzw. „aktivierte partielle Prothrombinzeit“ [aPTT, (sec)]. Durch die im Rahmen von Autoimmunerkrankungen wie dem Antiphospholipid-Syndrom (APLS) auftretenden Antiphospholipid-Antikörper (aPL) ist die Aussagekraft dieser Tests bei solchen Patienten durch eine Verlängerung der Gerinnungszeit deutlich eingeschränkt. Die Wirkung von UFH kann auch mit der photometrischen Messung der aXa-Aktivität bestimmt werden. Ziel der vorliegenden Studie war es zu erfassen, ob die aXa-Aktivitiät mit der ACT korreliert und ob es Cut-off-Werte gibt, die bei der Steuerung der Antikoagulation von kardiochirurgischen Patienten z.B. mit Antiphospholipid-Antikörpern während EKZ hilfreich sein können.
Methodik: Nach einem positiven Ethikvotum wurden in diese prospektive Studie Patienten eingeschlossen, die sich einem erstmaligen elektiv geplanten kardiochirurgischen Eingriff unterzogen. Ausschlusskriterien waren Alter < 18 Jahren, bekanntes Antiphospholipidsyndrom, bekannte Heparin-induzierte Thrombozytopenie und Schwangerschaft. Die ACT-gesteuerte Antikoagulation mit UFH (ACT > 400 sec während EKZ) und dessen Reversierung mit Protamin (ACT ≤ 100 sec) wurden auf der Grundlage klinikinterner Standards durchgeführt. Für jeden perioperativ analysierten ACT-Wert (prä-, intra- und postoperativ) wurde die korrespondierende aXa-Aktivität erfasst. Abhängig von EKZ-Dauer ergaben sich bis zu 14 Messzeitpunkte mit insgesamt 144 Messungen. Die statistische Auswertung umfasste u.a. Spearman Rangkorrelation und die Receiver Operative Characteristic (ROC)-Kurve.
Ergebnisse: Es wurden die Daten von n = 15 Patienten in dieser Studie ausgewertet. Das Hauptergebnis zeigte eine hochsignifikante lineare Korrelation (r = 0.771, p < 0.0001) zwischen den Ergebnissen der ACT und der jeweils korrespondierenden aXa-Aktivität. Der optimale Cut-off-Wert der aXa-Aktivität zur Indikation einer ACT > 400 sec betrug 1.135 IU/ml (Fehlklassifikationsrate: 9.4%). Die Fläche unter der ROC betrug 0.899. Es wurde ein optimaler Cut-off-Wert von 0.55 IU/ml (Fehlerklassifikation: 13.3%, AUC: 0.867) analysiert, der eine ACT von ≤ 100 sec vor der Gabe von UFH und nach der Gabe von Protamin indiziert.
Zusammenfassung: Die aXa-Aktivität korreliert mit der ACT und kann für das Monitoring der Antikoagulation mit UFH während EKZ geeignet sein. Die im Rahmen dieser Studie ermittelten aXa-Cut-off-Werte können dazu beitragen, die Antikoagulation mittels UFH zu steuern, wenn die Messwerte von aPTT und ACT nicht aussagekräftig sind
Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.
We present an approach for combining high resolution MRI-based myelin mapping with functional information from electroencephalography (EEG) or magnetoencephalography (MEG). The main contribution to the primary currents detectable with EEG and MEG comes from ionic currents in the apical dendrites of cortical pyramidal cells, aligned perpendicularly to the local cortical surface. We provide evidence from an in-vivo experiment that the variation in MRI-based myeloarchitecture measures across the cortex predicts the variation of the current density over individuals and thus is of functional relevance. Equivalent current dipole locations and moments due to pitch onset evoked response fields (ERFs) were estimated by means of a variational Bayesian algorithm. The myeloarchitecture was estimated indirectly from individual high resolution quantitative multi-parameter maps (MPMs) acquired at 800 μm isotropic resolution. Myelin estimates across cortical areas correlated positively with dipole magnitude. This correlation was spatially specific: regions of interest in the auditory cortex provided significantly better models than those covering whole hemispheres. Based on the MPM data we identified the auditory cortical area TE1.2 as the most likely origin of the pitch ERFs measured by MEG. We can now proceed to exploit the higher spatial resolution of quantitative MPMs to identify the cortical origin of M/EEG signals, inform M/EEG source reconstruction and explore structure–function relationships at a fine structural level in the living human brain.
Aufgrund von § 44 Abs. 1 Nr. 1 des Hessischen Hochschulgesetzes vom 14. Dezember 2009 (GVBl. I S. 666), zuletzt geändert durch Gesetz vom 27. Mai 2013 (GVBl. S. 218), hat der Fachbereichsrat des Fachbereichs Medizin der Johann Wolfgang Goethe-Universität Frankfurt am Main am 3. Juli 2014 die nachstehende Ordnung erlassen:...
he aim of this study was to evaluate the effect of controlled intraoral grinding and polishing on the roughness of full-contour zirconia compared to classical veneered zirconia. Thirty bar-shaped zirconia specimens were fabricated and divided into two groups (n=15). Fifteen specimens (group 1) were glazed and 15 specimens (group 2) were veneered with feldspathic ceramic and then glazed. Prior to grinding, maximum roughness depth (Rmax) values were measured using a profilometer, 5 times per specimen. Simulated clinical grinding and polishing were performed on the specimens under water coolant for 15 s and 2 N pressure. For grinding, NTI diamonds burs with grain sizes of 20 µm, 10 µm, and 7.5 µm were used sequentially. The ground surfaces were polished using NTI kits with coarse, medium and fine polishers. After each step, Rmax values were determined. Differences between groups were examined using one-way analysis of variance (ANOVA). The roughness of group 1 was significantly lower than that of group 2. The roughness increased significantly after coarse grinding in both groups. The results after glazing were similar to those obtained after fine grinding for non-veneered zirconia. However, fine-ground veneered zirconia had significantly higher roughness than venerred, glazed zirconia. No significant difference was found between fine-polished and glazed zirconia, but after the fine polishing of veneered zirconia, the roughness was significantly higher than after glazing. It can be concluded that for full-contour zirconia, fewer defects and lower roughness values resulted after grinding and polishing compared to veneered zirconia. After polishing zirconia, lower roughness values were achieved compared to glazing; more interesting was that the grinding of glazed zirconia using the NTI three-step system could deliver smooth surfaces comparable to untreated glazed zirconia surfaces.
Survival according to BRAF-V600 tumor mutations : an analysis of 437 patients with primary melanoma
(2014)
The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.
The pharmacokinetic properties and tolerability of a triamcinolone acetonide poloxamer 407 hydrogel for intratympanic application were investigated in a guinea pig model. Evaluation of in vivo release kinetics showed very high initial perilymph drug levels, with clinically relevant levels present for a minimum of 10 days. Assessment of auditory brainstem response thresholds showed a minimal, delayed and transient threshold shift, which was apparent on day 3 and resolved by day 10. No relevant histological changes of the middle and inner ear structures were noted, and hair cell counts showed no significant differences between treated and untreated ears. Thus, the triamcinolone-acetonide-loaded poloxamer 407 hydrogel is an effective vehicle for sustained high-dose inner ear glucocorticoid delivery.
Background: Dysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. The contribution of different forms of renovascular hypertension and the mechanisms contributing to autonomic dysfunction in hypertension are incompletely understood. Here, murine models of renovascular hypertension with preserved (2-kidneys-1 clip, 2K1C) and reduced (1-kidney-1 clip, 1K1C) kidney mass were studied with regard to autonomic nervous system regulation (sympathetic tone: power-spectral analysis of systolic blood pressure; parasympathetic tone: power-spectral analysis of heart rate) and baroreflex sensitivity of heart rate by spontaneous, concomitant changes of systolic blood pressure and pulse interval. Involvement of the renin-angiotensin system and the rho-kinase pathway were determined by application of inhibitors.
Results: C57BL6N mice (6 to 11) with reduced kidney mass (1K1C) or with preserved kidney mass (2K1C) developed a similar degree of hypertension. In comparison to control mice, both models presented with a significantly increased sympathetic tone and lower baroreflex sensitivity of heart rate. However, only 2K1C animals had a lower parasympathetic tone, whereas urinary norepinephrine excretion was reduced in the 1K1C model. Rho kinase inhibition given to a subset of 1K1C and 2K1C animals improved baroreflex sensitivity of heart rate selectively in the 1K1C model. Rho kinase inhibition had no additional effects on autonomic nervous system in either model of renovascular hypertension and did not change the blood pressure. Blockade of AT1 receptors (in 2K1C animals) normalized the sympathetic tone, decreased resting heart rate, improved baroreflex sensitivity of heart rate and parasympathetic tone.
Conclusions: Regardless of residual renal mass, blood pressure and sympathetic tone are increased, whereas baroreflex sensitivity is depressed in murine models of renovascular hypertension. Reduced norepinephrine excretion and/or degradation might contribute to sympathoactivation in renovascular hypertension with reduced renal mass (1K1C). Overall, the study helps to direct research to optimize medical therapy of hypertension.
MicroRNAs are key modulators at molecular level in different biological processes, including determination of cell fate and differentiation. Herein, microRNA expression profiling experiments were performed on syngeneic cardiac (CStC) and bone marrow (BMStC) mesenchymal stromal cells cultured in standard growth medium and then in vitro exposed to adipogenic, osteogenic, cardiomyogenic and endothelial differentiation media. Analysis identified a tissue-specific microRNA signature composed of 16 microRNAs that univocally discriminated cell type of origin and that were completely unaffected by in vitro differentiation media: 4 microRNAs were over-expressed in cardiac stromal cells, and 12 were overexpressed or present only in bone marrow stromal cells. Further, results revealed microRNA subsets specifically modulated by each differentiation medium, irrespective of the cell type of origin, and a subset of 7 microRNAs that were down-regulated by all media with respect to growth medium. Finally, we identified 16 microRNAs that were differentially modulated by the media when comparing the two tissues of origin. The existence of a tissue-specific microRNA signature surviving to any differentiation stimuli, strongly support the role if microRNAs determining cell identity related to tissue origin. Moreover, we identified microRNA subsets modulated by different culture conditions in a tissue-specific manner, pointing out their importance during differentiation processes.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.
Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues. Multiple functions in different subcellular compartments have been assigned. It participates in the control of cell division, apoptosis, the cellular stress response, and also in the regulation of cell migration and metastasis. Survivin expression has been recognized as a biomarker: high expression indicates an unfavorable prognosis and resistance to chemotherapeutic agents and radiation treatment. Survivin is an unconventional drug target and several indirect approaches have been exploited to affect its function and the phenotype of survivin-expressing cells. Interference with the expression of the survivin gene, the utilization of its messenger RNA, the intracellular localization, the interaction with binding partners, the stability of the survivin protein, and the induction of survivin-specific immune responses have been taken into consideration. A direct strategy to inhibit survivin has been based on the identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand–survivin complex. Technology is being developed that might allow the derivation of small molecular-weight, drug-like compounds that are functionally equivalent to the peptide ligand.
Tumor cell plasticity is an event that has been observed in several malignancies. In fact, most of the solid tumors are characterized by cellular heterogeneity and undergo constant changes as the tumor develops. The increased plasticity displayed by these cells allows them to acquire additional properties, enabling epithelial-mesenchymal transitions, dedifferentiation and the acquisition of stem cell-like properties. Here we discuss the particular importance of an inflammatory microenvironment for the bidirectional control of cellular plasticity and the potential for therapeutic intervention.
Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient’s conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient's preferences – his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.
Background: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
Methods: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Results: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
Conclusions: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
The compulsive habit of cars
(2014)
The car dependence of people living in contemporary cities is a major concern for policy makers, who often find it difficult to persuade people into more sustainable transport modes. By contrast, recent insights from neuroscience have shown that a broad spectrum of behaviors can become habitual and, thus, resistant to change. Here, we outline the potential of collaboration between neuroscience and human geography aiming at a better understanding of habits that determine everyday commuting routines.
Escherichia coli α-hemolysin (HlyA) is a pore-forming protein of 110 kDa belonging to the family of RTX toxins. A hydrophobic region between the amino acid residues 238 and 410 in the N-terminal half of HlyA has previously been suggested to form hydrophobic and/or amphipathic α-helices and has been shown to be important for hemolytic activity and pore formation in biological and artificial membranes. The structure of the HlyA transmembrane channel is, however, largely unknown. For further investigation of the channel structure, we deleted in HlyA different stretches of amino acids that could form amphipathic β-strands according to secondary structure predictions (residues 71–110, 158–167, 180–203, and 264–286). These deletions resulted in HlyA mutants with strongly reduced hemolytic activity. Lipid bilayer measurements demonstrated that HlyAΔ71–110 and HlyAΔ264–286 formed channels with much smaller single-channel conductance than wildtype HlyA, whereas their channel-forming activity was virtually as high as that of the wildtype toxin. HlyAΔ158–167 and HlyAΔ180–203 were unable to form defined channels in lipid bilayers. Calculations based on the single-channel data indicated that the channels generated by HlyAΔ71–110 and HlyAΔ264–286 had a smaller size (diameter about 1.4 to 1.8 nm) than wildtype HlyA channels (diameter about 2.0 to 2.6 nm), suggesting that in these mutants part of the channel-forming domain was removed. Osmotic protection experiments with erythrocytes confirmed that HlyA, HlyAΔ71–110, and HlyAΔ264–286 form defined transmembrane pores and suggested channel diameters that largely agreed with those estimated from the single-channel data. Taken together, these results suggest that the channel-forming domain of HlyA might contain β-strands, possibly in addition to α-helical structures.
Acute kidney injury (AKI) is one of the most important complications in hospitalized patients and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of AKI following ischemia and reperfusion (IR). Male adult C57Bl6 wild-type (wt) mice and TLR-3 knock-out (-/-) mice were subjected to 30 minutes bilateral selective clamping of the renal artery followed by reperfusion for 30 min 2.5h and 23.5 hours or subjected to sham procedures. TLR-3 down-stream signaling was activated already within 3 h of ischemia and reperfusion in post-ischemic kidneys of wt mice lead to impaired blood perfusion followed by a strong pro-inflammatory response with significant neutrophil invasion. In contrast, this effect was absent in TLR-3-/- mice. Moreover, the quick TLR-3 activation resulted in kidney damage that was histomorphologically associated with significantly increased apoptosis and necrosis rates in renal tubules of wt mice. This finding was confirmed by increased kidney injury marker NGAL in wt mice and a better preserved renal perfusion after IR in TLR-3-/- mice than wt mice. Overall, the absence of TLR-3 is associated with lower cumulative kidney damage and maintained renal blood perfusion within the first 24 hours of reperfusion. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of early acute kidney injury.
Background: In an earlier study we demonstrated the feasibility to create tissue engineered venous scaffolds in vitro and in vivo. In this study we investigated the use of tissue engineered constructs for ureteral replacement in a long term orthotopic minipig model. In many different projects well functional ureretal tissue was established using tissue engineering in animals with short-time follow up (12 weeks). Therefore urothelial cells were harvested from the bladder, cultured, expanded in vitro, labelled with fluorescence and seeded onto the autologous veins, which were harvested from animals during a second surgery. Three days after cell seeding the right ureter was replaced with the cell-seeded matrices in six animals, while further 6 animals received an unseeded vein for ureteral replacement. The animals were sacrificed 12, 24, and 48 weeks after implantation. Gross examination, intravenous pyelogram (IVP), H&E staining, Trichrome Masson's Staining, and immunohistochemistry with pancytokeratin AE1/AE3, smooth muscle alpha actin, and von Willebrand factor were performed in retrieved specimens.
Results: The IVP and gross examination demonstrated that no animals with tissue engineered ureters and all animals of the control group presented with hydronephrosis after 12 weeks. In the 24-week group, one tissue engineered and one unseeded vein revealed hydronephrosis. After 48 weeks all tissue engineered animals and none of the control group showed hydronephrosis on the treated side. Histochemistry and immunohistochemistry revealed a multilayer of urothelial cells attached to the seeded venous grafts.
Comclusions: Venous grafts may be a potential source for ureteral reconstruction. The results of so far published ureteral tissue engineering projects reveal data up to 12 weeks after implantation. Even if the animal numbers of this study are small, there is an increasing rate of hydronephrosis revealing failure of ureteral tissue engineering with autologous matrices in time points longer than 3 months after implantation. Further investigations have to prove adequate clinical outcome and appropriate functional long-term results.
This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-α general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients.
Plexins are widely expressed transmembrane proteins that mediate the cellular effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still poorly understood. Here we show that signalling via B-family plexins leading to the activation of the small GTPase RhoA requires activation of the IκB kinase (IKK)-complex. In contrast, plexin-B-dependent regulation of R-Ras activity is not affected by IKK activity. This regulation of plexin signalling depends on the kinase activity of the IKK-complex, but is independent of NF-κB activation. We confirm that the IKK-complex is active in tumour cells and osteoblasts, and we demonstrate that plexin-B-dependent tumour cell invasiveness and regulation of osteoblast differentiation require an active IKK-complex. This study identifies a novel, NF-κB-independent function of the IKK-complex and shows that IKK directs plexin-B signalling to the activation of RhoA.
The role of RNA interference in the developmental separation of blood and lymphatic vasculature
(2014)
Background: Dicer is an RNase III enzyme that cleaves double stranded RNA and generates functional interfering RNAs that act as important regulators of gene and protein expression. Dicer plays an essential role during mouse development because the deletion of the dicer gene leads to embryonic death. In addition, dicer-dependent interfering RNAs regulate postnatal angiogenesis. However, the role of dicer is not yet fully elucidated during vascular development.
Methods: In order to explore the functional roles of the RNA interference in vascular biology, we developed a new constitutive Cre/loxP-mediated inactivation of dicer in tie2 expressing cells.
Results: We show that cell-specific inactivation of dicer in Tie2 expressing cells does not perturb early blood vessel development and patterning. Tie2-Cre; dicerfl/fl mutant embryos do not show any blood vascular defects until embryonic day (E)12.5, a time at which hemorrhages and edema appear. Then, midgestational lethality occurs at E14.5 in mutant embryos. The developing lymphatic vessels of dicer-mutant embryos are filled with circulating red blood cells, revealing an impaired separation of blood and lymphatic vasculature.
Conclusion: Thus, these results show that RNA interference perturbs neither vasculogenesis and developmental angiogenesis, nor lymphatic specification from venous endothelial cells but actually provides evidence for an epigenetic control of separation of blood and lymphatic vasculature.
Disruption of the renal endothelial integrity is pivotal for the development of a vascular leak, tissue edema and consequently acute kidney injury. Kidney ischemia amplifies endothelial activation and up-regulation of pro-inflammatory mechanisms. After restoring a sufficient blood flow, the kidney is damaged through complex pathomechanisms that are classically referred to as ischemia and reperfusion injury, where the disruption of the inter-endothelial connections seems to be a crucial step in this pathomechanism. Focusing on the molecular cell-cell interaction, the fibrinopeptide Bβ15–42 prevents vascular leakage by stabilizing these inter-endothelial junctions. The peptide associates with vascular endothelial-cadherin, thus preventing early kidney dysfunction by preserving blood perfusion efficacy, edema formation and thus organ dysfunction. We intended to demonstrate the early therapeutic benefit of intravenously administered Bβ15–42 in a mouse model of renal ischemia and reperfusion. After 30 minutes of ischemia, the fibrinopeptide Bβ15–42 was administered intravenously before reperfusion was commenced for 1 and 3 hours. We show that Bβ15–42 alleviates early functional and morphological kidney damage as soon as 1 h and 3 h after ischemia and reperfusion. Mice treated with Bβ15–42 displayed a significantly reduced loss of VE-cadherin, indicating a conserved endothelial barrier leading to less neutrophil infiltration which in turn resulted in significantly reduced structural renal damage. The significant reduction in tissue and serum neutrophil gelatinase-associated lipocalin levels reinforced our findings. Moreover, renal perfusion analysis by color duplex sonography revealed that Bβ15–42 treatment preserved resistive indices and even improved blood velocity. Our data demonstrate the efficacy of early therapeutic intervention using the fibrinopeptide Bβ15–42 in the treatment of acute kidney injury resulting from ischemia and reperfusion. In this context Bβ15–42 may act as a potent renoprotective agent by preserving the endothelial and vascular integrity.
Background: HER2 status assessment is a prerequisite for the establishment of an appropriate treatment strategy in gastric cancer. Gastric cancers are very heterogeneous and separate evaluations of gene amplification and protein expression lead to uncertainties in localizing distinct clones and are time consuming. This study evaluates the equivalence of the novel method combining both gene and protein platforms on one slide.
Methods: Immunohistochemistry (IHC) and HER2 dual-colour silver in situ hybridization (SISH) as single methods (IHC/SISH) and gene-protein platform combining both methods on one slide (gene/protein) were performed in randomly collected 100 cases of gastric adenocarcinoma. Results of IHC/SISH were compared with gene/protein staining.
Results: 96 of 100 samples were assessable. In the gene/protein staining, pathologists were able to assess gene amplification and consequent protein expression at the single cell level. In comparison trials, gene amplification was observed in 14.6% by both, conventional SISH and gene/protein platform (agreement 100%; Kappa-coefficient κ = 1.0). Protein expression scores by IHC were 70.8% (0), 10.4% (1+), 9.4% (2+), and 9.4% (3+). Protein expression by gene/protein method were: 70.8% (0), 11.5% (1+), 7.3% (2+) and 10.4% (3+) of patients. There were complete concordances in IHC assessment of cases with score 0 (100.0%; κ = 1). High concordances are shown in score 1+ (98.96%; κ = 0.947) and 3+ (96.88%; κ = 0.825) cases and good concordances in 2+ cases (95.83%; κ = 0.728).
Conclusions: This novel combined platform has the advantage of being able to evaluate both gene and the protein status in the same cancer cell and may be of particular interest for research and patient's care.
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10–30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Background: Diabetes mellitus and thyroid diseases frequently coexist. In order to evaluate how thyroid disorders interfere with glycemic control, we analysed insulin-treated type 2 diabetes patients with thyroid disease.
Methods: Diabetes patients (n = 1.957) were retrospectively investigated. We focused on type 2 diabetes patients who had been admitted for insulin-treatment and diagnosed thyroid diseases (n = 328). Patients were divided into three groups according to thyroid disease manifestation in relation to diabetes onset: prior to (group 1), same year (group 2) and thyroid disease following diabetes (group 3).
Results: Out of all diabetes patients 27.3% had a thyroid disorder with more women (62.2%) being affected (p < 0.001). Thyroid disease was predominantly diagnosed after diabetes onset. Patients with type 2 diabetes and prior appearance of thyroid disease required insulin therapy significantly earlier (median insulin-free period: 2.5 yrs; Q1 = 0.0, Q3 = 8.25) compared to patients who had thyroid dysfunction after diabetes onset (median insulin-free period: 8.0 yrs; Q1 = 3.0, Q3 = 12.0; p < 0.001). Age at diabetes onset correlated with insulin-free period (p < 0.001).
Conclusions: Thyroid disease may be a marker of a distinct metabolic trait in type 2 diabetes potentially requiring earlier insulin treatment.
The question of whether most gliomas are infected with human cytomegalovirus (HCMV) has been under dispute for more than 10 years. We recently reported our failure to detect HCMV in gliomas in Neuro-Oncology.1 Our article was accompanied by 2 related editorials,2,3 one of which boldly criticized our approach.3 Instead of fighting a petty, ivory tower dispute, we would like to lobby for a serious collaborative approach to providing conclusive evidence on the presence of HCMV in glioma (and other cancers). Since we developed the concept of oncomodulation (ie, that HCMV …
Moderate physical activity improves various cognitive functions, particularly when it is applied simultaneously to the cognitive task. In two psychoneuroendocrinological within-subject experiments, we investigated whether very low-intensity motor activity, i.e. walking, during foreign-language vocabulary encoding improves subsequent recall compared to encoding during physical rest. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum and salivary cortisol. Previous research has associated both substances with memory performance.In both experiments, subjects performed better when they were motorically active during encoding compared to being sedentary. BDNF in serum was unrelated to memory performance. In contrast we found a positive correlation between salivary cortisol concentration and the number of correctly recalled items. In summary, even very light physical activity during encoding is beneficial for subsequent recall.
Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10–20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.
Background: Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV.
Methods: A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population.
Results: One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57–85) and median overall survival (mOS) was 335 days (95% CI 210–604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3–4 treatment-emergent drug-related adverse events occurred in 9% of patients.
Conclusion: These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents.
A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.
Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9) is mainly considered to be a co-stimulatory activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in primary central nervous system (CNS) tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with a prominent tropism to the CNS.
Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number of tumor spots, and BRAF V600E expression status.
Results: Tumor necrosis factor receptor superfamily member 9 was frequently expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells with increasing distance from blood vessels, an observation that might be linked to hypoxia-driven TNFRSF9 expression in tumor cells.
Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic pool, and therefore further careful (re-) assessment of potential TNFRSF9 functions in cell types other than hematopoietic cells is needed. Furthermore, the hypothesis of hypoxia-driven TNFRSF9 expression in brain metastasis melanoma cells requires further functional testing.
Cross-frequency coupling (CFC) has been proposed to coordinate neural dynamics across spatial and temporal scales. Despite its potential relevance for understanding healthy and pathological brain function, the standard CFC analysis and physiological interpretation come with fundamental problems. For example, apparent CFC can appear because of spectral correlations due to common non-stationarities that may arise in the total absence of interactions between neural frequency components. To provide a road map towards an improved mechanistic understanding of CFC, we organize the available and potential novel statistical/modeling approaches according to their biophysical interpretability. While we do not provide solutions for all the problems described, we provide a list of practical recommendations to avoid common errors and to enhance the interpretability of CFC analysis.
Neben ihrer Rolle in der DNA Mismatch Reparatur wird eine Beteiligung von MMR Proteinen an der Apoptoseinduktion, der Antikörperbildung sowie an der Mitose und Meiose beschrieben. Untersuchungen zu Partnerproteinen des MMR Proteins MLH1 zeigten darüber hinaus eine Interaktion von MLH1 zu einigen Zytoskelett-assoziierten Proteinen. In der vorliegenden Arbeit sollte der Zusammenhang von MLH1 und nicht-erythroidem Spectrin alpha II (SPTAN1) auf Proteinebene untersucht und eine mögliche Beteiligung von SPTAN1 am DNA Mismatch Reparaturprozess mittels eines in vitro MMR-Assays analysiert werden. Die vergleichenden in vitro Analysen der MLH1 und SPTAN1 Expression erfolgten in fünf verschiedenen MLH1-profizienten und zwei MLH1-defizienten Zelllinien. Zudem wurde in vivo die Expression von MLH1 und SPTAN1 exemplarisch am Beispiel eines sporadischen sowie eines MLH1-defizienten Kolonkarzinomgewebes und des jeweils zugehörigen Normalgewebes durchgeführt. Im MMR-Assay wurden Kernextrakte aus HEK293T Zellen eingesetzte, in denen MLH1 und PMS2 bzw. MLH1, PMS2 sowie SPTAN1 überexprimiert wurde oder solche in denen die SPTAN1 Menge durch siRNA Behandlung zuvor reduziert worden war. Während die Untersuchungen hinsichtlich einer Beteiligung von SPTAN1 an der DNA Mismatch Reparatur keine eindeutigen Ergebnisse erbrachten, zeigten die Analysen der Expression von MLH1 und SPTAN1 interessanterweise sowohl in vitro als auch in vivo, dass die Proteinkonzentration von SPTAN1 bei MLH1-Profizienz deutlich höher war, als bei MLH1-Defizienz. Da SPTAN1 ein überaus wichtiges, filamentöses Gerüstprotein darstellt, an der Aktin-Vernetzung und der Stabilisierung der Plasmamembran beteiligt und mitverantwortlich für Organisation der intrazellulären Organellen ist, könnten die Expressions-unterschiede in MLH1-defizienten und MLH1-profizienten Zellen für die Progression und das Metastasierungsverhalten entsprechender Kolontumore eine wichtige Rolle spielen. Weiterführende Untersuchungen, die im Anschluss an diese Arbeit hinsichtlich des Einflusses der SPTAN1 Menge auf das Migrationsverhalten entsprechender Zellen durchgeführt wurden, zeigen, dass MLH1-defiziente Zellen SPTAN1 abhängig weniger stark migrieren, als die MLH1-profizienten Vergleichszellen. Möglicherweise ist die MLH1 abhängige Expression von SPTAN1 Grund dafür, dass Kolontumoren mit MLH1-Defizienz signifikant weniger zur Metastasierung neigen, als sporadische Kolonkarzinome, die MLH1 exprimieren. Ob dies wirklich zutrifft muss allerdings durch weitere nachfolgende Experimente noch weiter untersucht werden.
Vorhofflimmern ist die am weitesten verbreitete Herzrhythmusstörung. Die bisherige antiarrhythmische Therapie ist durch erhebliche kardiale und extrakardiale Nebenwirkungen nur wenig zufriedenstellend. Die Erforschung neuer antiarrhythmischer Substanzen ist aufgrund begrenzt zur Verfügung stehenden menschlichen Probematerials erschwert. Vorhofgewebe wird z.B. bei Herzoperationen gewonnen und kann dann für Forschungszwecke eingesetzt werden. Die Herzzellen sind allerdings sehr empfindlich, weswegen sie meist bereits nach einigen Stunden nicht mehr für weitere Untersuchungen zu gebrauchen sind. Man ist daher auf das Tiermodell angewiesen. Da das Schweineherz dem des Menschen sehr ähnlich ist, stellt es hier ein ideales Testsystem für neue Antiarrhythmika dar. In neuesten Studien wurde in Schweineherzen der IK,PO als ein vielversprechenden Angriffspunkt vorhofselektiver Antiarrhythmika beschrieben. Die diesem Strom zugrundeliegenden Kanaleinheiten sind jedoch zum jetzigen Zeitpunkt nicht genau erforscht.
Ziel der Arbeit war, ein stabiles Modell der Zellkultur mit atrialen Kardiomyozyten zu etablieren. An den kultivierten Herzzellen sollten elektrophysiologische aber auch molekular- und proteinbiologische Methoden angewandt werden. Das Modell sollte mit Zellen aus Schweineherzen erprobt werden und dazu dienen Untersuchungen an Zellen aus einer Gewebepräparation über mehrere Tage durchzuführen. Darüber hinaus sollte die Zellkultur dazu dienen einen Gen-„Knockdown“ anwenden zu können. Der IK,PO und dem diesem Strom möglicherweise zugrundeliegenden Kanaluntereinheiten Kv1.5, Kv4.3, KChIP2 und TASK-1 sollten hierbei charakterisiert werden.
Atriumzellen aus Schweineherzen wurden isoliert und direkt nach Zellisolation sowie unter dem Einfluss der Zellkultur nach bis zu 48 Stunden untersucht. Es kamen die Patch-Clamp-Technik, Real-time-PCR- und Western-Blot-Analysen zum Einsatz. Die Wirkung verschiedener Substanzen auf den IK,PO wurde getestet. Das Kv1.5-Protein wurde dargestellt und mRNA-Analysen für Kv1.5, Kv4.3, KChIP2 und TASK-1 durchgeführt.
Ein Teil der Zellen wurde mit einer gegen Kv1.5 gerichteten siRNA behandelt und anschließend mRNA-Analysen durchgeführt sowie der IK,PO–Strom gemessen.
Die atrialen Kardiomyozyten des Schweines in Kultur zeigten bis zu 48 Stunden vitale Eigenschaften und zeigten sich für die Patch-Clamp-Technik, Real-time-PCR und Western-Blot-Analysen als geeignet. Im Vergleich zu den frisch präparierten Zellen war eine signifikante Zunahme der Stromdichte für den IK,PO zu messen. Die Kinetik des IK,PO-Stroms sowie das Verhalten gegenüber den Substanzen AV0118, Heteropodatoxin und PAP-1 blieben im Vergleich zu den frisch präparierten Zellen unverändert. In Western-Blot-Analysen war im Vergleich zu frisch isolierten Zellen eine Zunahme des Kv1.5-Proteins zu sehen. Die mRNA-Expression des Kv1.5 war dagegen auf ca. ein Sechstel verringert. Eine Abnahme der mRNA-Expression auf ein Zehntel konnte für die Kanaleinheit KChIP2 gesehen werden. Kv4.3 wurde hingegen bis fast auf ein Zweieinhalbfaches vermehrt exprimiert, während die RNA-Expression für TASK-1 konstant blieb. Ein „Knockdown“ des Kv1.5 mit siRNA zeigte eine weitere Reduktion der Kv1.5 mRNA ohne eine messbare zusätzliche Veränderung des IK,PO.
Die Arbeit hat gezeigt, dass primäre Kulturen atrialer Kardiomyozyten des Schweines für elektrophysiologische sowie molekularbiologische Versuche geeignet sind. Der im Interesse stehende Strom IK,PO hat sich unter Kulturbedingungen zwar vergrößert, jedoch blieben Kinetik und vor allem die Eigenschaft auf verschiedene Substanzen zu reagieren unverändert. Es ist somit möglich neue Substanzen in der Entwicklung von Antiarrhythmika an kultivierten Herzzellen zu testen und somit die Anzahl der für die Experimente benötigten Tiere zu verringern. Die Ergebnisse deuten darauf hin, dass neben dem Kv1.5 die Kanaleinheiten der Kv4.3 und KChIP2 wesentlich zum IK,PO betragen. Die vorliegenden Ergebnisse deuten darauf, dass Kv1.5 den Grundstrom des IK,PO bildet und Kv4.3 vornehmlich den Spitzenstrom des IK,PO ausmacht. Kv1.5 wird dabei vermutlich wesentlich durch KChIP2 gehemmt. KChIP2 spielt eine nachweisliche Rolle in der Pathogenese von Herzrhythmusstörungen und zeigt im Vergleich zu Kv1.5 und Kv4.3 eine höhere Gewebespezifität. KChIP2-Blocker könnten in der Entwicklung vorhofselektiver Antiarrhythmika vielversprechende Ergebnisse liefern.
Die Wahrnehmung von Schmerzen ermöglicht es dem Organismus, auf noxische Reize zu reagieren. Der akute nozizeptive Schmerz hat somit eine natürliche Warnfunktion. Bei länger anhaltenden bzw. chronischen Schmerzen oder Nervenschädigungen kann es jedoch zu pathophysiologischen Veränderungen im Nervensystem kommen, die zur Verselbständigung des Schmerzes führen können. Unter diesen Umständen gilt der Schmerz nicht mehr als Warnsignal, sondern als eigenes Krankheitsbild. Die „International Association for the Study of Pain (IASP)“ definiert Schmerz als „ein unangenehmes Sinnes- und Gefühlserlebnis, das mit aktueller oder potenzieller Gewebsschädigung verknüpft ist oder mit Begriffen einer solchen Schädigung beschrieben wird“. Da bisher verfügbare Arzneimittel chronische Schmerzen in vielen Fällen nicht ausreichend reduzieren können und teilweise zu schwerwiegenden Nebenwirkungen führen, ist es unverzichtbar, an der Entwicklung neuer und noch spezifischer wirkenden Analgetika festzuhalten. Um Pharmaka zu entwickeln, die gezielt in den Mechanismus der Schmerzverarbeitung eingreifen können, ist es notwendig, diesen auf molekularer Ebene zu kennen und zu verstehen.
The disintegrin and metalloproteinases ADAM10 and ADAM17 are regarded as the most important α-secretases involved in the physiological processing of amyloid precursor protein (APP) in brain. Since it has been suggested that processing of APP by α-secretases could be involved in the reorganization of the brain following injury, we studied mRNA expression of the two α-secretases Adam10 and Adam17, the ß-secretase Bace1, and the App-gene family (App, Aplp1, Aplp2) in the dentate gyrus of the mouse following entorhinal denervation. Using laser microdissection, tissue was harvested from the outer molecular layer and the granule cell layer of the denervated dentate gyrus. Expression levels of candidate genes were assessed using Affymetrix GeneChip Mouse Gene 1.0 ST arrays and reverse transcription-quantitative PCR, revealing an upregulation of Adam10 mRNA and Adam17 mRNA in the denervated outer molecular layer and an upregulation of Adam10 mRNA and App mRNA in the dentate granule cell layer. Immunolabeling for ADAM10 or ADAM17 in combination with markers for astro- and microglia revealed an increased labeling of ADAM10 and ADAM17 in the denervated outer molecular layer that was associated with reactive astrocytes but not with microglia. Collectively, these data show that denervation affects the expression level of APP and its two most important α-secretases. This suggests that APP-processing could be shifted towards the non-amyloidogenic pathway in denervated areas of the brain and, thus, towards the formation of neuroprotective APP cleavage products, such as APPsα.
Use of drug-eluting balloon coronary intervention prior to living donor kidney transplantation
(2014)
Background: Kidney transplantation is the gold standard of therapy in patients with terminal renal insufficiency. Living donor transplantation is a well-established option in this field. Enlarging the donor's pool implicates the acceptance of an increased rate of comorbidities. Among them, coronary artery disease is a growing problem. An increasing number of patients, undergoing living donation, receive antiplatelet therapies due to coronary disease.
Case presentation: Here we report about the perioperative treatment with a drug-eluting balloon in a patient with major cardiac risk factors who underwent kidney transplantation.
Conclusion: At the current time no recommendation can be given for the routine use of drug-eluting balloons.
Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by problems in social behaviour, which are sometimes similar to some symptoms of autism-spectrum disorders (ASD). However, neuronal mechanisms of ASD-like deficits in ADHD have rarely been studied. The processing of biological motion–recently discussed as a marker of social cognition–was found to be disrupted in ASD in several studies. Thus in the present study we tested if biological motion processing is disrupted in ADHD. We used 64-channel EEG and spatio-temporal source analysis to assess event-related potentials associated with human motion processing in 21 children and adolescents with ADHD and 21 matched typically developing controls. On the behavioural level, all subjects were able to differentiate between human and scrambled motion. But in response to both scrambled and biological motion, the N200 amplitude was decreased in subjects with ADHD. After a spatio-temporal dipole analysis, a human motion specific activation was observable in occipital-temporal regions with a reduced and more diffuse activation in ADHD subjects. These results point towards neuronal determined alterations in the processing of biological motion in ADHD.
Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
Wassergefiltertes Infrarot A (wIRA) als spezielle Form der Wärmestrahlung mit hohem Eindringvermögen in das Gewebe bei geringer thermischer Oberflächenbelastung fördert die Heilung akuter und chronischer Wunden sowohl über thermische und temperaturabhängige als auch über nichtthermische und temperaturunabhängige Effekte. Wassergefiltertes Infrarot A steigert die Temperatur (+2,7°C in einer Gewebetiefe von 2 cm) und den Sauerstoffpartialdruck im Gewebe (+32% in einer Gewebetiefe von 2 cm) und die Gewebedurchblutung. Diese 3 Faktoren sind entscheidend für eine ausreichende Versorgung des Gewebes mit Energie und Sauerstoff und deshalb auch für Wundheilung und Infektionsabwehr. Wassergefiltertes Infrarot A hilft sowohl bei der normalen als auch bei der gestörten Wundheilung, indem es Entzündungsreaktionen und erhöhte Wundsekretion mindert, Infektionsabwehr und Regeneration fördert und Wundschmerzen lindern helfen kann. Die genannten Effekte wurden in insgesamt 7 prospektiven Studien (davon 6 randomisierten kontrollierten Studien) belegt, die meisten mit einem Evidenzgrad von Ia bzw. Ib. Die hier zusätzlich dargestellten Fallbeispiele komplizierter Wundheilungsverläufe illustrieren die belegten Wirkungen von wIRA. Nicht nur in den hier gezeigten 6 Fällen wendeten die Bestrahlungen mit wIRA komplizierte Wundheilungsverläufe zum Besseren und ermöglichten nach ganz unterschiedlich langen Gesamtdauern der Bestrahlungen (in den 6 Fällen: von 51–550 h) und nach verschieden langen Gesamtdauern der Wundpflege, meist nach Transplantation von Spalthautgittern, die Heilung der Wunden. Bei komplizierten Wundheilungsverläufen ersetzt wIRA nicht den Rat und ggf. auch die Behandlung eines erfahrenen plastischen Chirurgen und eines Chirurgen mit der Spezialisierung in septischer Chirurgie. Mit dieser Einschränkung kann wIRA als wertvolle Ergänzung der Behandlung von akuten und chronischen Wunden empfohlen werden.
The administration of intravenous fluid to critically ill patients is one of the most common but also one of the most fiercely debated interventions in intensive care medicine. During the past decade, a number of important studies have been published which provide clinicians with improved knowledge regarding the timing, the type and the amount of fluid they should give to their critically ill patients. However, despite the fact that many thousands of patients have been enrolled in these trials of alternative fluid strategies, consensus remains elusive and practice is widely variable. Early adequate resuscitation of patients in shock followed by a restrictive strategy may be associated with better outcomes. Colloids such as modern hydroxyethyl starch are more effective than crystalloids in early resuscitation of patients in shock, and are safe when administered during surgery. However, these colloids may not be beneficial later in the course of intensive care treatment and should best be avoided in intensive care patients who have a high risk of developing acute kidney injury. Albumin has no clear benefit over saline and is associated with increased mortality in neurotrauma patients. Balanced fluids reduce the risk of hyperchloraemic acidosis and possibly kidney injury. The use of hypertonic fluids in patients with sepsis and acute lung injury warrants further investigation and should be considered experimental at this stage. Fluid therapy impacts relevant patient-related outcomes. Clinicians should adopt an individualized strategy based on the clinical scenario and best available evidence. One size does not fit all.
Hintergrund: Es ist unbekannt bzw. umstritten, ob die in Deutschland eingeführten Umweltzonen (UWZ) die Feinstaubbelastung nachweisbar reduzieren.
Methode: PM10-Konzentrationen von den Messstationen innerhalb und außerhalb der UWZ in 19 deutschen Städten wurden analysiert (Augsburg, Berlin, Dortmund, Duisburg, Düsseldorf, Essen, Frankfurt a. M., Hannover, Herrenberg, Ilsfeld, Karlsruhe, Köln, Ludwigsburg, Mannheim, München, Reutlingen, Stuttgart, Tübingen, Wuppertal), um die Wirksamkeit der Fahrverbote (Stufe 1) für Fahrzeuge der Schadstoffgruppe 1 (ohne Plakette) auf die Schadstoffkonzentration zu untersuchen. Kontinuierliche Halbstundenmesswerte und gravimetrische Tagesmittelwerte wurden für den Zeitraum von ca. 2005 bis Ende 2009 übernommen. Die Analyse beruht auf vier einander paarweise zugeordneten Messwerten als gematchte Quadrupel aus zwei Index- und zwei Referenzwerten (Indexstationen liegen innerhalb, Referenzstationen messen außerhalb der UWZ). Ein Indexwert und der simultan gemessene Referenzwert wurden während der aktiven Phase der UWZ gemessen, das andere Wertepaar wurde vor Einführung der UWZ erhoben. Die Wertepaare haben eine Zeitdifferenz von 364 Tagen oder von einem Vielfachen von 364 Tagen, wodurch die Jahreszeit, der Wochentag und die Tageszeit im Quadrupel konstant gehalten werden. Differenzen der Indexwerte wurden regressionstechnisch mit den Differenzen der Referenzwerte korrigiert, wobei meteorologische Parameter (Mischungsschichthöhe, Niederschlagsmenge, Windgeschwindigkeit), Schulferienzeiten, Phase der Umweltprämie, LKW-Fahrverbotszeiten und Ausgangswerte an den Index- und Referenzstationen als Kovariablen in sog. „fixed effects“ Regressionsanalysen der Quadrupel berücksichtigt wurden (Differenzwertmethode im Zwei-Perioden-Fall). Dieser statistische Ansatz wurde vor der eigentlichen Datenanalyse an simulierten Messdaten der FU Berlin erfolgreich erprobt.
Ergebnisse: 2 110 803 Quadrupel kontinuierlicher PM10-Messungen und 15 735 gravimetrische Quadrupel wurden aus den verfügbaren Daten der Messstationen identifiziert, aus denen 61 169 Quadrupel zu Tagesmittelwerten aufgebaut wurden. Die Analysen für die erste Stufe ergaben als beste Effektschätzer (an allen Indexstationen) eine Feinstaubreduktion von ≤ 0,2 μg/m3 (bzw. relative PM10-Reduktionen ≤ 1 %). Der beste Effektschätzer an allen Verkehrsstationen (also ohne städtische Hintergrund- und Industrieindexstationen) lag unterhalb von 1 μg/m3 (bzw. weniger als 5 %).
Schlussfolgerungen: Alle Analysewerte liegen damit unter den vor Einführung von UWZ prognostizierten Feinstaubreduktionen. Diese Studie untersuchte als erste übergreifend die Wirksamkeit von UWZ der Stufe 1 in Deutschland auf die Feinstaubkonzentrationen von PM10 nach einem einheitlichen Datensammlungs- und Analyseplan und unter Berücksichtigung möglichst vieler Störeinflüsse.