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Background: Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types.
Methods: Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition.
Results: VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5.
Conclusions: Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites. These patients may benefit from therapeutic VEGF inhibition.
Objective: Gestational diabetes mellitus (GDM) is associated with substantial morbidity for mothers and their offspring. While clinical and basic research activities on this important disease grow constantly, there is no concise analysis of global architecture of GDM research. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in relation to existing research networks and gender distribution of publishing authors.
Study design: On the basis of the New Quality and Quantity Indices in Science (NewQIS) platform, scientometric methods were combined with modern visualizing techniques such as density equalizing mapping, and the Web of Science database was used to assess GDM-related entries from 1900 to 2012.
Results: Twelve thousand five hundred four GDM-related publications were identified and analyzed. The USA (4295 publications) and the UK (1354 publications) dominated the field concerning research activity, overall citations and country-specific Hirsch-Index, which quantified the impact of a country’s published research on the scientific community. Semi-qualitative indices such as country-specific citation rates ranked New Zealand and the UK at top positions. Annual collaborative publications increased steeply between the years 1990 and 2012 (71 to 1157 respectively). Subject category analysis pointed to a minor interest of public health issues in GDM research. Gender analysis in terms of publication authorship revealed a clear dominance of the male gender until 2005; then a trend towards gender equity started and the activity of female scientists grew visibly in many countries. The country-specific gender analysis revealed large differences, i.e. female scientists dominated the scientific output in the USA, whereas the majority of research was published by male authors in countries such as Japan.
Conclusion: This study provides the first global sketch of GDM research architecture. While North-American and Western-European countries were dominating the GDM-related scientific landscape, a disparity exists in terms of research output between developed and low-resource countries. Since GDM is linked to considerable mortality and morbidity of mothers and their offspring and constitutes a tremendous burden for the healthcare systems in underserved countries, our findings emphasize the need to address disparities by fostering research endeavors, public health programs and collaborative efforts in these nations.
Mitochondrial complex I is a 1MDa membrane protein complex with a central role in aerobic energy metabolism. The bioenergetic core functions are executed by 14 central subunits that are conserved from bacteria to man. Despite recent progress in structure determination, our understanding of the function of the ~30 accessory subunits associated with the mitochondrial complex is still limited. We have investigated the structure of complex I from the aerobic yeast Yarrowia lipolytica by cryo-electron microscopy. Our density map at 7.9Å resolution closely matches the 3.6-3.9Å X-ray structure of the Yarrowia lipolytica complex. However, the cryo-EM map indicated an additional subunit on the side of the matrix arm above the membrane surface, pointing away from the membrane arm. The density, which is not present in any previously described complex I structure and occurs in about 20 % of the particles, was identified as the accessory sulfur transferase subunit ST1. The Yarrowia lipolytica complex I preparation is active in generating H2S from the cysteine derivative 3-mercaptopyruvate, catalyzed by ST1. We thus provide evidence for a link between respiratory complex I and mitochondrial sulfur metabolism.
Correlated activity of cortical neurons survives extensive removal of feedforward sensory input
(2016)
A fundamental property of brain function is that the spiking activity of cortical neurons is variable and that some of this variability is correlated between neurons. Correlated activity not due to the stimulus arises from shared input but the neuronal circuit mechanisms that result in these noise correlations are not fully understood. Here we tested in the visual system if correlated variability in mid-level area V4 of visual cortex is altered following extensive lesions of primary visual cortex (V1). To this end we recorded longitudinally the neuronal correlations in area V4 of two behaving macaque monkeys before and after a V1 lesion while the monkeys fixated a grey screen. We found that the correlations of neuronal activity survived the lesions in both monkeys. In one monkey, the correlation of multi-unit spiking signals was strongly increased in the first week post-lesion, while in the second monkey, correlated activity was slightly increased, but not greater than some week-by-week fluctuations observed. The typical drop-off of inter-neuronal correlations with cortical distance was preserved after the lesion. Therefore, as V4 noise correlations remain without feedforward input from V1, these results suggest instead that local and/or feedback input seem to be necessary for correlated activity.
Infections are an important cause for morbidity and mortality in pediatric acute myeloid leukemia (AML). We therefore characterized infectious complications in children treated according to the trial AML-BFM 2004. Patients with Down syndrome were excluded from the analysis. Data were gathered from the medical records in the hospital where the patients were treated. A total of 405 patients (203 girls; median age 8.4 years) experienced 1326 infections. Fever without identifiable source occurred in 56.1% of the patients and clinically and microbiologically documented infections in 17.5% and 32.4% of the patients, respectively. In all, 240 Gram-positive (112 viridans group streptococci) and 90 Gram-negative isolates were recovered from the bloodstream. Invasive fungal infection was diagnosed in 3% of the patients. Three children each died of Gram-negative bacteremia and invasive aspergillosis, respectively. As compared with the results of AML-BFM 93 with lower dose intensity, infection-related morbidity was slightly higher in AML-BFM 2004 (3.3. versus 2.8 infections per patient), whereas infection-related mortality significantly decreased (1.5% versus 5.4%; P=0.003). Specific anti-infective recommendations included in the treatment protocol, regular training courses for pediatric hematologists and increasing experience may be the reason for reduced infection-related mortality in children with AML. Further studies are needed to decrease infection-related morbidity.
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.
Background: Despite a recent statutory ruling stating the binding nature of advance directives (ADs), only a minority of the population has signed one. Yet, a majority deem it of utmost importance to ensure their wishes are followed through in case they are no longer able to decide. The reasons for this discrepancy have not yet been investigated sufficiently.
Patients and methods: This article is based on a survey of patients using a well-established structured questionnaire. First, patients were asked about their attitudes with respect to six therapeutic options at the end of life: intravenous fluids, artificial feeding, antibiotics, analgesia, chemotherapy/dialysis, and artificial ventilation; and second, they were asked about the negative effects related to the idea of ADs surveying their apprehensions: coercion to fulfill an AD, dictatorial reading of what had been laid down, and abuse of ADs.
Results: A total of 1,260 interviewees completed the questionnaires. A significant percentage of interviewees were indecisive with respect to therapeutic options, ranging from 25% (analgesia) to 45% (artificial feeding). There was no connection to health status. Apprehensions about unwanted effects of ADs were widespread, at 51%, 35%, and 43% for coercion, dictatorial reading, and abuse, respectively.
Conclusion: A significant percentage of interviewees were unable to anticipate decisions about treatment options at the end of life. Apprehensions about negative adverse effects of ADs are widespread.
"Toleranz kommt vor Glückseligkeit" : eine Zeitreise mit der Tugend des gegenseitigen Respekts
(2016)
Toleranz ist gerade da nötig, wo sie besonders schwerfällt. Das war schon vor gut 300 Jahren so, als Denker wie der französische Philosoph Pierre Bayle in Zeiten religiöser Auseinandersetzungen den Grundstein für ein fortschrittliches Toleranz-Verständnis legten. Warum der Begriff gerade heute wieder Konjunktur hat und wie umstritten er noch immer ist, erläutert der politische Philosoph Rainer Forst im Gespräch mit Bernd Frye.
Religion und Gesellschaft
(2016)
Sehnsucht nach absoluter Wissenschaft : die moderne Esoterik will nicht glauben, sondern wissen
(2016)
Esoterische Weltanschauungen versprechen "höhere", "ganzheitliche" Einsichten statt kalter, "materialistischer" Erkenntnis. Damit stellen sie sich in ein bewusstes, wenn auch aussichtsloses Konkurrenzverhältnis zu den akademischen Wissenschaften. Dennoch hat sich der esoterische Diskurs immer wieder gerade im Umfeld und im Schatten der gesellschaftlich anerkannten universitären Wissenschaften konstituiert, zumindest in reflexiver Abhängigkeit von ihren normativen Ansprüchen.
Gehört Religionsunterricht in den Fächerkanon einer staatlichen Schule? In Deutschland wird dies sogar im Grundgesetz bejaht. Während atheistische Kreise die Abschaffung dieses Grundrechts fordern, sehen Politik und Wissenschaft darin eine Chance, auch Kindern aus muslimischen Familien religiöses Wissen näherzubringen, sie auf diese Weise besser zu integrieren und vielleicht sogar gegen fundamentalistische Hasslehren zu wappnen. In Hessen erhalten Grundschüler seit dem Schuljahr 2013 / 2014 bekenntnisorientierten islamischen Religionsunterricht; die Justus-Liebig-Universität Gießen und künftig auch die Goethe-Universität bilden Lehrer aus.
Der Islam befindet sich in einer Phase fundamentaler Veränderungen, die neue progressive Spielarten, aber auch beunruhigende Formen religiösen Extremismus hervorbringt. In Deutschland diskutieren Muslime, ob es sinnvoll sei, einen spezifisch deutschen oder europäischen Islam zu entwickeln oder ob die herkunftsorientierte Religion der Moschee-Gemeinschaften beibehalten werden sollte.
Als Reaktion auf die von islamischen Extremisten begangenen Terroranschläge sowie auf das Wüten des IS in Syrien und im Irak werden diese Forderungen immer lauter: Muslime müssen selbstkritisch nach dem Zusammenhang von islamischer Religion und Gewalt fragen. Bloße Distanzierungen seien nicht ausreichend, so die Kritik von außen, aber zunehmend auch innerhalb der muslimischen Gemeinschaften. Wie setzt sich die islamische Theologie, wie sie u. a. in Frankfurt betrieben wird, damit auseinander?
In ihrem Gespräch beschäftigen sich Prof. Dr. Bekim Agai, geschäftsführender Direktor des Instituts für Studien der Kultur und Religion des Islam, und Ulrike Jaspers, Redakteurin von "Forschung Frankfurt", mit dem Wahrheitsanspruch der Religionen, der Debattenkultur in Deutschland, der jungen islamischen Theologie, den fundamentalistischen Strömungen und anderem mehr.
Die Geschichte der frühen Christenverfolgung wird in Hollywoodstreifen wesentlich dramatischer dargestellt, als sie in der jüngeren Forschung beurteilt wird. Auch andere Kulte wurden unterdrückt, denn es bestand kein Recht auf Religionsfreiheit. Die Gründe für solche Maßnahmen lagen nicht in Glaubensvorstellungen, sondern in Handlungen, die als gefährlich für das Gemeinwesen galten. So fürchtete man, dass die Weigerung der Christen, Opfer darzubringen, den Zorn der Götter heraufbeschwören könne oder ein Zeichen mangelnder Loyalität sei. Vor diesem Hintergrund forderten Christen Religionsfreiheit von den Heiden, doch wurde diese auch im später christlichen spätantiken Reich nicht praktiziert.
Seit seinen Anfängen ist das Christentum alles andere als einheitlich oder homogen. Mit dem Aufstieg zur Staatsreligion im Römischen Reich und dem Wunsch des Kaisertums, seine Herrschaft zu legitimieren, wuchs der Druck zur Vereinheitlichung. Diese Bemühungen ziehen sich wie ein roter Faden durch die mittelalterliche Geschichte. Doch die Alltags-, Gesellschafts- und Kulturgeschichte verweist in der mittelalterlichen Gesellschaft auf eine große Vielfalt der Ausprägungen des Christentums.
The CARIBIC (Civil Aircraft for the Regular Investigation of the Atmosphere Based on an Instrument Container) passenger aircraft observatory performed in situ measurements at 10–12 km altitude in the South Asian summer monsoon anticyclone between June and September 2008. These measurements enable us to investigate this atmospheric region (which so far has mostly been observed from satellites) using the broad suite of trace gases and aerosol particles measured by CARIBIC. Elevated levels of a variety of atmospheric pollutants (e.g. carbon monoxide, total reactive nitrogen oxides, aerosol particles, and several volatile organic compounds) were recorded. The measurements provide detailed information about the chemical composition of air in different parts of the monsoon anticyclone, particularly of ozone precursors. While covering a range of 3500 km inside the monsoon anticyclone, CARIBIC observations show remarkable consistency, i.e. with distinct latitudinal patterns of trace gases during the entire monsoon period.
Using the CARIBIC trace gas and aerosol particle measurements in combination with the Lagrangian particle dispersion model FLEXPART, we investigated the characteristics of monsoon outflow and the chemical evolution of air masses during transport. The trajectory calculations indicate that these air masses originated mainly from South Asia and mainland Southeast Asia. Estimated photochemical ages of the air were found to agree well with transport times from a source region east of 90–95° E. The photochemical ages of the air in the southern part of the monsoon anticyclone were systematically younger (less than 7 days) and the air masses were mostly in an ozone-forming chemical mode. In its northern part the air masses were older (up to 13 days) and had unclear ozone formation or destruction potential. Based on analysis of forward trajectories, several receptor regions were identified. In addition to predominantly westward transport, we found evidence for efficient transport (within 10 days) to the Pacific and North America, particularly during June and September, and also of cross-tropopause exchange, which was strongest during June and July. Westward transport to Africa and further to the Mediterranean was the main pathway during July.
We present an estimation of the uptake coefficient (γ) and yield of nitryl chloride (ClNO2) (f) for the heterogeneous processing of dinitrogen pentoxide (N2O5) using simultaneous measurements of particle and trace gas composition at a semi-rural, non-coastal, mountain site in the summer of 2011. The yield of ClNO2 varied between (0.035 ± 0.027) and (1.38 ± 0.60) with a campaign average of (0.49 ± 0.35). The large variability in f reflects the highly variable chloride content of particles at the site. Uptake coefficients were also highly variable with minimum, maximum and average γ values of 0.004, 0.11 and 0.028 ± 0.029, respectively, with no significant correlation with particle composition, but a weak dependence on relative humidity. The uptake coefficients obtained are compared to existing parameterisations based on laboratory datasets and with other values obtained by analysis of field data.
We present an estimation of the uptake coefficient (γ) and yield of nitryl chloride (ClNO2) (f) for the heterogeneous processing of dinitrogen pentoxide (N2O5) using simultaneous measurements of particle and trace gas composition at a semi-rural, non-coastal, mountain site in the summer of 2011. The yield of ClNO2 varied between (0.035 ± 0.027) and (1.38 ± 0.60) with a campaign average of (0.49 ± 0.35). The large variability in f reflects the highly variable chloride content of particles at the site. Uptake coefficients were also highly variable with minimum, maximum and average γ values of 0.004, 0.11 and 0.028 ± 0.029, respectively, with no significant correlation with particle composition, but a weak dependence on relative humidity. The uptake coefficients obtained are compared to existing parameterizations based on laboratory datasets and with other values obtained by analysis of field data.
BACKGROUND: Microvascular ischemia is one of the hallmarks of hypertrophic cardiomyopathy (HCM) and has been associated with poor outcome. However, myocardial fibrosis, seen on cardiovascular magnetic resonance (CMR) as late gadolinium enhancement (LGE), can be responsible for rest perfusion defects in up to 30% of patients with HCM, potentially leading to an overestimation of the ischemic burden. We investigated the effect of left ventricle (LV) scar on the total LV ischemic burden using novel high-resolution perfusion analysis techniques in conjunction with LGE quantification.
METHODS: 30 patients with HCM and unobstructed epicardial coronary arteries underwent CMR with Fermi constrained quantitative perfusion analysis on segmental and high-resolution data. The latter were corrected for the presence of fibrosis on a pixel-by-pixel basis.
RESULTS: High-resolution quantification proved more sensitive for the detection of microvascular ischemia in comparison to segmental analysis. Areas of LGE were associated with significant reduction of myocardial perfusion reserve (MPR) leading to an overestimation of the total ischemic burden on non-corrected perfusion maps. Using a threshold MPR of 1.5, the presence of LGE caused an overestimation of the ischemic burden of 28%. The ischemic burden was more severe in patients with fibrosis, also after correction of the perfusion maps, in keeping with more severe disease in this subgroup.
CONCLUSIONS: LGE is an important confounder in the assessment of the ischemic burden in patients with HCM. High-resolution quantitative analysis with LGE correction enables the independent evaluation of microvascular ischemia and fibrosis and should be used when evaluating patients with HCM.