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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.
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.
The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction leading to reduced energy supply, impaired neuroplasticity, and finally cell death as one major pathomechanism underlying the continuum from brain aging over mild cognitive impairment to initial and advanced late onset Alzheimer's disease. Accordingly, improving mitochondrial function has become an important strategy to treat the early stages of this continuum. The metabolic enhancer piracetam has been proposed as possible prototype for those compounds by increasing impaired mitochondrial function and related aspects like mechanisms of neuroplasticity. We here report that piracetam at therapeutically relevant concentrations improves neuritogenesis in the human cell line SH-SY5Y over conditions mirroring the whole spectrum of age-associated cognitive decline. These effects go parallel with improvement of impaired mitochondrial dynamics shifting back fission and fusion balance to the energetically more favorable fusion site. Impaired fission and fusion balance can also be induced by a reduction of the mitochondrial permeability transition pore (mPTP) function as atractyloside which indicates the mPTP has similar effects on mitochondrial dynamics. These changes are also reduced by piracetam. These findings suggest the mPTP as an important target for the beneficial effects of piracetam on mitochondrial function.
CRISPR/Cas9-mediated knockout of p22phox leads to loss of Nox1 and Nox4, but not Nox5 activity
(2016)
The NADPH oxidases are important transmembrane proteins producing reactive oxygen species (ROS). Within the Nox family, different modes of activation can be discriminated. Nox1-3 are dependent on different cytosolic subunits, Nox4 seems to be constitutively active and Nox5 is directly activated by calcium. With the exception of Nox5, all Nox family members are thought to depend on the small transmembrane protein p22phox. With the discovery of the CRISPR/Cas9-system, a tool to alter genomic DNA sequences has become available. So far, this method has not been widely used in the redox community. On such basis, we decided to study the requirement of p22phox in the Nox complex using CRISPR/Cas9-mediated knockout. Knockout of the gene of p22phox, CYBA, led to an ablation of activity of Nox4 and Nox1 but not of Nox5. Production of hydrogen peroxide or superoxide after knockout could be rescued with either human or rat p22phox, but not with the DUOX-maturation factors DUOXA1/A2. Furthermore, different mutations of p22phox were studied regarding the influence on Nox4-dependent H2O2 production. P22phox Q130* and Y121H affected maturation and activity of Nox4. Hence, Nox5-dependent O2•- production is independent of p22phox, but native p22phox is needed for maturation of Nox4 and production of H2O2.
Recently, several magnetic resonance imaging contrast mechanisms have been shown to distinguish cortical substructure corresponding to selected cortical layers. Here, we investigate cortical layer and area differentiation by automatized unsupervised clustering of high-resolution diffusion MRI data. Several groups of adjacent layers could be distinguished in human primary motor and premotor cortex. We then used the signature of diffusion MRI signals along cortical depth as a criterion to detect area boundaries and find borders at which the signature changes abruptly. We validate our clustering results by histological analysis of the same tissue. These results confirm earlier studies which show that diffusion MRI can probe layer-specific intracortical fiber organization and, moreover, suggests that it contains enough information to automatically classify architecturally distinct cortical areas. We discuss the strengths and weaknesses of the automatic clustering approach and its appeal for MR-based cortical histology.
A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.
Hypercholesterolemia and elevated homocysteine concentrations are associated with cardiovascular risk. Previous studies have demonstrated a cholesterol-lowering effect of red yeast rice (RYR) supplements which contained 5 to 10 mg of monacolin K. We hypothesized that the intake of a low monacolin K dose may likewise reduce low-density lipoprotein-cholesterol (LDL-C) and other plasma lipids. In secondary analyses, we tested the homocysteine lowering effect of folic acid, which was also included in the study preparation. Therefore, we conducted a randomized, double-blind, and placebo-controlled intervention study. One hundred forty-two nonstatin-treated participants with hypercholesterolemia (LDL-C ≥ 4.14 ≤ 5.69 mmol/L) were randomized to the supplement group with RYR or the placebo group. Participants of the supplement group consumed 3 mg monacolin K and 200 μg folic acid per day. A significant (P < .001) reduction of LDL-C (-14.8%), total cholesterol (-11.2%), and homocysteine (-12.5%) was determined in the supplement group after 12 weeks. A total of 51% of the participants treated with RYR achieved the limit of LDL-C <4.14 mmol/L advised and 26% reached the threshold level of homocysteine <10 μmol/L. No significant changes were exhibited within the placebo group. Other parameters remained unchanged and no intolerances or serious adverse events were observed. In conclusion, we demonstrated that a low dose of daily 3 mg monacolin K from RYR reduces the concentration of LDL-C; a risk factor for cardiovascular diseases.
DNA methylation is a major regulatory process of gene transcription, and aberrant DNA methylation is associated with various diseases including cancer. Many compounds have been reported to modify DNA methylation states. Despite increasing interest in the clinical application of drugs with epigenetic effects, and the use of diagnostic markers for genome-wide hypomethylation in cancer, large-scale screening systems to measure the effects of drugs on DNA methylation are limited. In this study, we improved the previously established fluorescence polarization-based global DNA methylation assay so that it is more suitable for application to human genomic DNA. Our methyl-sensitive fluorescence polarization (MSFP) assay was highly repeatable (inter-assay coefficient of variation = 1.5%) and accurate (r2 = 0.99). According to signal linearity, only 50–80 ng human genomic DNA per reaction was necessary for the 384-well format. MSFP is a simple, rapid approach as all biochemical reactions and final detection can be performed in one well in a 384-well plate without purification steps in less than 3.5 hours. Furthermore, we demonstrated a significant correlation between MSFP and the LINE-1 pyrosequencing assay, a widely used global DNA methylation assay. MSFP can be applied for the pre-screening of compounds that influence global DNA methylation states and also for the diagnosis of certain types of cancer.
BACKGROUND: Platinum-based drugs are used as cancer chemotherapeutics for the last 40 years. However, drug resistance and nephrotoxicity are the major limitations of the use of platinum-based compounds in cancer therapy. Platinum (IV) complexes are believed to act as platinum prodrugs and are able to overcome some of platinum (II) limitations.
METHODS: A number of previously sensitized platinum (IV) complexes were evaluated for their anti-cancer activity by monitoring ability to affect proliferation, clonigenicity and apoptosis induction of Cisplatin sensitive and resistant cancer cells. In addition, the uptake of Cisplatin and the platinum (IV) derivatives to Cisplatin sensitive and resistant cancer cells was monitored.
RESULTS: The bis-octanoatoplatinum (IV) complex (RJY13), a Cisplatin derivative with octanoate as axial ligand, exhibited strong anti-proliferative effect on the Cisplatin resistant and sensitive ovarian cells, A2780cisR and A2780, respectively. Moreover, RJY13 exhibited good activity in inhibiting clonigenicity of both cells. Anti-proliferative activity of RJY13 was mediated by induction of apoptosis. Interestingly, a bis-lauratopaltinum (IV) complex (RJY6) was highly potent in inhibiting clonigenicity of both Cisplatin sensitive and Cisplatin resistant cells, however, exhibited reduced activity in assays that utilize cells growing in two dimensional (2D) conditions. The uptake of Cisplatin was reduced by 30% in A2780 in which the copper transporter-1 (Ctr1) was silenced. Moreover, uptake of RJY6 was marginally dependent on Ctr1, while uptake of RJY13 was Ctr1-independent.
CONCLUSIONS: Our data demonstrated the potential of platinum (IV) prodrugs in overcoming acquired and inherited drug resistance in cancer cell lines. Moreover, our data demonstrated that the uptake of Cisplatin is partially dependent on Ctr1 transporter, while uptake of RJY6 is marginally dependent on Ctr1 and RJY13 is Ctr1-independent. In addition, our data illustrated the therapeutic potential of platinum (IV) prodrugs in cancer therapy.
OBJECTIVE: To compare efficacy, safety, and tolerability of an oral enzyme combination (OEC) containing proteolytic enzymes and bioflavonoid vs diclofenac (DIC), a nonselective nonsteroidal anti-inflammatory drug in the treatment of osteoarthritis of the knee.
MATERIALS AND METHODS: This was an individual patient-level pooled reanalysis of patient-reported data from prospective, randomized, double-blind, parallel-group studies in adult patients with moderate-to-severe osteoarthritis of the knee treated for at least 3 weeks with OEC or DIC. Appropriate trials were identified with a systemic literature and database search. Data were extracted from the original case-report forms and reanalyzed by a blinded evaluation committee. The primary end point was the improvement of the Lequesne algofunctional index (LAFI) score at study end vs baseline. Secondary end points addressed LAFI response rates, treatment-related pain-intensity changes, adverse events, and laboratory parameters.
RESULTS: Six trials were identified that enrolled in total 774 patients, of whom 759 had post-baseline data for safety analysis, 697 (n=348/349 with OEC/DIC) for intent to treat, 524 for per protocol efficacy analysis, and 500 for laboratory evaluation. LAFI scores - the primary efficacy end point - decreased comparably with both treatments and improved with both treatments significantly vs baseline (OEC 12.6±2.4 to 9.1±3.9, DIC 12.7±2.4 to 9.1±4.2, effect size 0.9/0.88; P<0.001 for each). In parallel, movement-related 11-point numeric rating-scale pain intensity improved significantly (P<0.001) and comparably with both treatments from baseline (6.4±1.9/6.6±1.8) to study end (3.8±2.7/3.9±2.5). Overall, 55/81 OEC/DIC patients of the safety-analysis population (14.7%/21.1%, P=0.022) reported 90/133 treatment-emergent adverse events, followed by premature treatment discontinuations in 22/39 patients (5.9%/10.2%, P=0.030). Changes in laboratory parameters were significantly less with OEC vs DIC: on average 18.8% vs 86.3% of patients presented a decrease with respect to hemoglobin, hematocrit, or erythrocyte count (P<0.001), and 28.2% vs 72.6% showed an increase in AST, ALT, or GGT (P<0.001).
CONCLUSION: When compared with DIC, OEC showed comparable efficacy and a superior tolerability/safety profile associated with a significantly lower risk of treatment-emergent adverse events, related study discontinuations, and changes in laboratory parameters.
Introduction: Neuronal death and subsequent denervation of target areas are hallmarks of many neurological disorders. Denervated neurons lose part of their dendritic tree, and are considered "atrophic", i.e. pathologically altered and damaged. The functional consequences of this phenomenon are poorly understood.
Results: Using computational modelling of 3D-reconstructed granule cells we show that denervation-induced dendritic atrophy also subserves homeostatic functions: By shortening their dendritic tree, granule cells compensate for the loss of inputs by a precise adjustment of excitability. As a consequence, surviving afferents are able to activate the cells, thereby allowing information to flow again through the denervated area. In addition, action potentials backpropagating from the soma to the synapses are enhanced specifically in reorganized portions of the dendritic arbor, resulting in their increased synaptic plasticity. These two observations generalize to any given dendritic tree undergoing structural changes.
Conclusions: Structural homeostatic plasticity, i.e. homeostatic dendritic remodeling, is operating in long-term denervated neurons to achieve functional homeostasis.
The general assumption that brain size differences are an adequate proxy for subtler differences in brain organization turned neurobiologists toward the question why some groups of mammals such as primates, elephants, and whales have such remarkably large brains. In this meta-analysis, an extensive sample of eutherian mammals (115 species distributed in 14 orders) provided data about several different biological traits and measures of brain size such as absolute brain mass (AB), relative brain mass (RB; quotient from AB and body mass), and encephalization quotient (EQ). These data were analyzed by established multivariate statistics without taking specific phylogenetic information into account. Species with high AB tend to (1) feed on protein-rich nutrition, (2) have a long lifespan, (3) delayed sexual maturity, and (4) long and rare pregnancies with small litter sizes. Animals with high RB usually have (1) a short life span, (2) reach sexual maturity early, and (3) have short and frequent gestations. Moreover, males of species with high RB also have few potential sexual partners. In contrast, animals with high EQs have (1) a high number of potential sexual partners, (2) delayed sexual maturity, and (3) rare gestations with small litter sizes. Based on these correlations, we conclude that Eutheria with either high AB or high EQ occupy positions at the top of the network of food chains (high trophic levels). Eutheria of low trophic levels can develop a high RB only if they have small body masses.
There is a debate over the association between low testosterone levels in body fluids and the occurrence of chronic periodontitis (CP). The aim of the present systematic review was to assess whether low testosterone levels in body fluids reflect CP. In order to identify studies relevant to the focus question: “Is there a relationship between low testosterone levels in body fluids and CP?” an electronic search without time or language restrictions was conducted up to June 2016 in indexed databases using different keywords: periodontitis, chronic periodontitis, periodontal diseases, testosterone, and gonadal steroid hormones. A total of eight studies were included in the present systematic review. The number of study participants ranged from 24 to 1,838 male individuals with ages ranging from 15 to 95 years. Seven studies measured testosterone levels in serum, two studies in saliva, and one study in gingiva. Four studies reported a negative association between serum testosterone levels and CP. Two studies reported a positive association between decreased testosterone levels in serum and CP. Increased levels of salivary testosterone among patients with CP were reported in one study; whereas one study reported no significant difference in the concentration of salivary testosterone between patients with and without CP. One study identified significant increase in the metabolism of testosterone in the gingiva of patients with CP. Within the limits of the evidence available, the relationship between low testosterone levels and CP remains debatable and further longitudinal studies and control trials are needed.
Background: Community acquired viruses (CRVs) may cause severe disease in cancer patients. Thus, efforts should be made to diagnose CRV rapidly and manage CRV infections accordingly.
Methods: A panel of 18 clinicians from the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology have convened to assess the available literature and provide recommendations on the management of CRV infections including influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus and adenovirus.
Results: CRV infections in cancer patients may lead to pneumonia in approximately 30% of the cases, with an associated mortality of around 25%. For diagnosis of a CRV infection, combined nasal/throat swabs or washes/aspirates give the best results and nucleic acid amplification based-techniques (NAT) should be used to detect the pathogen. Hand hygiene, contact isolation and face masks have been shown to be of benefit as general infection management. Causal treatment can be given for influenza, using a neuraminidase inhibitor, and respiratory syncytial virus, using ribavirin in addition to intravenous immunoglobulins. Ribavirin has also been used to treat parainfluenza virus and human metapneumovirus, but data are inconclusive in this setting. Cidofovir is used to treat adenovirus pneumonitis.
Conclusions: CRV infections may pose a vital threat to patients with underlying malignancy. This guideline provides information on diagnosis and treatment to improve the outcome.
Der Nucleus suprachiasmaticus (SCN) ist ein Kerngebiet des Hypothalamus mit der Funktion des zentralen Taktgebers für die Generierung der circadianen Rhythmik. Zahlreiche petale Verbindungen zum SCN dienen der Synchronisierung der circadianen Uhr mit der tatsächlichen Tagesphase. Fugale Verbindungen des SCN dienen der Verteilung der Tageszeiteninformation über das Gehirn, insbesondere in vegetativen Zentren. So werden beispielsweise die physiologischen Vorgänge des Kreislaufsystems, Hormonausschüttung, der Schlaf-Wach-Zyklus etc. kontrolliert und mit Tag-Nacht-Wechsel synchronisiert. Obwohl viele dieser Verbindungen verstanden und beschrieben sind, sind die nahen Verbindungen in der unmittelbaren Nähe des SCN und des-sen intrinsische Verbindung nicht genau untersucht. Zur Darstellung dieser nahen Verbindungen wurden DiI-Tracer-Studien an Gehirnschnitten von Mäusen durchgeführt. Untersucht wurde parallel zu der DiI-Färbung das Neuropeptid Vasopressin innerhalb und außerhalb des SCN bei Mäusen von zwei verschiedenen Mäusestämmen (C3H und C57BL); C57BL ist defizient für das photoperiodische sezernierte Epiphysenhormon Melatonin, C3H-Mäuse er-blinden im frühen Lebensalter. Die immunzytochemische Untersuchung des Vasopressin-Systems belegte einen Unterschied in der Zytoarchitektur des SCN zwischen den C3H und C57BL Mäusen. Obwohl einige Elemente ähnliche Lokalisations- und Reaktivitätscharakteristika aufwiesen z.B. die dorsomediale Verteilung der Vasopressin-Perikaryen im Kerngebiet, so zeigte sich bei den C57BL-Mäusen eine deutlich schwächere Reaktivität des Neuropeptids AVP in diesem Bereich und ferner eine deutliche inhomogenere Verteilung der Vasopressin-Elemente im gesamten Kerngebiet. Die Tracing Untersuchung zeigte bei beiden Mäuse-Stämmen die gleichen Verbindungswege des SCN mit der nahen Periphere. Zum einen zeigen die Ergebnisse, dass der Hauptpassage des SCN im dorsomedialen, also im periventrikulären Bereich lokalisiert ist und das der SCN multiple Zugänge an seiner dorsalen und lateralen Grenze zur subparaventrikulären Zone besitzt. Ferner konnte auch gezeigt werden, dass beide bilateralen SCN-Kerne direkt über ausgeprägte Kommissurfaserverbindungen miteinander kommunizieren. Diese Kommissuren dürften dafür verantwortlich sein, den SCN einer Seite mit dem SCN der kontralateralen Seite zu synchronisieren. Obwohl in der vorliegenden Arbeit der Tracer nur einseitig appliziert wurde, ist dennoch von einer gekreuzten kontralateralen Verbindung auszugehen. Hier liegen Ansätze für weitere Un-tersuchungen. Ein weiterer Aspekt der Untersuchungen zeigen Faserverbin-dungen in die Area hypothalamica lateralis (AHL), die eine wichtige Rolle in der Kontrolle der zentralen Nahrungsaufnahme besitzt. Diese Faserverbin-dungen haben ihren Ursprung im SCN bzw. Nucl. paraventricularis und dem Nucl. arcuatus. Diese Verbindungen dienen am ehesten der Modulation der zentralen Regulation der Nahrungsaufnahme und spielen daher eine besondere Rolle in der Krankheitsentstehung wie Adipositas, Diabetes und Herz-Kreislauf-Erkrankung bei gestörter circadianen Rhythmik. Neu ist der Befund einer beachtlichen Anzahl von suprachiasmaticopetalen Fasern aus der sub-paraventrikulären Zone. Diese könnten die Einbindung des limbischen Systems in die Modulation der inneren Uhr erklären, die darüber hinaus ursächlich für zahlreiche Pathologien sein könnten.
Endometriosis and its global research architecture : an in-depth density-equalizing mapping analysis
(2016)
Background: Endometriosis is one of the most common gynecological diseases. It is still a chameleon in many aspects and urges intense research activities in the fields of diagnosis, therapy and prevention. Despite the need to foster research in this area, no in-depth analysis of the global architecture of endometriosis research exists yet.
Methods: We here used the NewQIS platform to conduct a density equalizing mapping study, using the Web of Science as database with endometriosis related entries between 1900 and 2009. Density equalizing maps of global endometriosis research encompassing country-specific publication activities, and semi-qualitative indices such as country specific citations, citation rates, h-Indices were created.
Results: In total, 11,056 entries related to endometriosis were found. The USA was leading the field with 3705 publications followed by the United Kingdom (952) and Japan (846). Concerning overall citations and country-specific h-Indices, the USA again was the leading nation with 74,592 citations and a modified h-Index of 103, followed by the UK with 15,175 citations (h-Index 57). Regarding the citation rate, Sweden and Belgium were at top positions with rates of 22.46 and 22.26, respectively. Concerning collaborative studies, there was a steep increase in numbers present; analysis of the chronological evolution indicated a strong increase in international collaborations in the past 10 years.
Conclusions: This study is the first analysis that illustrates the global endometriosis research architecture. It shows that endometriosis research is constantly gaining importance but also underlines the need for further efforts and investments to foster research and ultimately improve endometriosis management on a global scale.
Objectives: This study aimed to analyse and compare differences in occupational stress, depressive symptoms, work ability and working environment among residents working in various medical specialties.
Methods: 435 German hospital residents in medical training working in 6 different medical specialties participated in a cross-sectional survey study. Physicians were asked about their working conditions and aspects of mental health and work ability. The Copenhagen Psychosocial Questionnaire, the Work Ability Index, the ICD-10 Symptom Rating and the Perceived Stress Questionnaire were used to measure working conditions, mental health and work ability.
Results: Results show that up to 17% of the physicians reported high levels of occupational distress and 9% reported high levels of depressive symptoms. 11% of the hospital physicians scored low in work ability. Significant differences between medical specialties were demonstrated for occupational distress, depressive symptoms, work ability, job demands and job resources. Surgeons showed consistently the highest levels of perceived distress but also the highest levels of work ability and lowest scores for depression. Depressive symptoms were rated with the highest levels by anaesthesiologists. Significant associations between physicians’ working conditions, occupational distress and mental health-related aspects are illustrated.
Conclusions: Study results demonstrated significant differences in specific job stressors, demands and resources. Relevant relations between work factors and physicians' health and work ability are discussed. These findings should be reinvestigated in further studies, especially with a longitudinal study design. This work suggests that to ensure physicians' health, hospital management should plan and implement suitable mental health promotion strategies. In addition, operational efficiency through resource planning optimisation and work process improvements should be focused by hospital management.
Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.
Background: Clonidine effectively decreases perioperative mortality by reducing sympathetic tone. However, application of clonidine might also restrict anaemia tolerance due to impairment of compensatory mechanisms. Therefore, the influence of clonidine induced, short-term sympathicolysis on anaemia tolerance was assessed in anaesthetized pigs. We measured the effect of clonidine on anaemia tolerance and of the potential for macrohemodynamic alterations to constrain the acute anaemia compensatory mechanisms.
Methods: After governmental approval, 14 anaesthetized pigs of either gender (Deutsche Landrasse, weight (mean ± SD) 24.1 ± 2.4 kg) were randomly assigned to intravenous saline or clonidine treatment (bolus: 20 μg · kg−1, continuous infusion: 15 μg · kg−1 · h−1). Thereafter, the animals were hemodiluted by exchange of whole blood for 6 % hydroxyethyl starch (MW 130.000/0.4) until the individual critical haemoglobin concentration (Hbcrit) was reached. Primary outcome parameters were Hbcrit and the exchangeable blood volume (EBV) until Hbcrit was reached.
Results: Hbcrit did not differ between both groups (values are median [interquartile range]: saline: 2.2 (2.0–2.5) g · dL−1 vs. clonidine: 2.1 (2.1–2.4) g · dL−1; n.s.). Furthermore, there was no difference in exchangeable blood volume (EBV) between both groups (saline: 88 (76–106) mL · kg−1 vs. clonidine: 92 (85–95) mL · kg−1; n.s.).
Conclusion: Anaemia tolerance was not affected by clonidine induced sympathicolysis. Consequently, perioperative clonidine administration probably has not to be omitted in view of acute anaemia.
Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends.
Background: Although noise is one of the leading work-related health risk factors for teachers, many nursery schools lack sufficient noise reduction measures. Methods: This intervention study evaluated the noise exposure of nursery school teachers when dropping DUPLO toy bricks into storage cases. Sound analyses of the impact included assessment of the maximum sound pressure level (LAFmax) as well as frequency analyses with 1/3 octave band filter. For the purpose of standardization, a customized gadget was developed. Recordings were performed in 11 cases of different materials and designs to assess the impact on sound level reduction. Thereby, the acoustic effects of three damping materials (foam rubber, carpet, and PU-foam) were investigated. Results: The lowest LAFmax was measured in cases consisting of “metal grid” (90.71 dB) or of a woven willow “basket” (91.61 dB), whereas a case of “aluminium” (103.34 dB) generated the highest impact LAFmax. The frequency analyses determined especially low LAFmax in the frequency bands between 80 and 2500 Hz in cases designs “metal grid” and “basket”. The insertion of PU-foam achieved the most significant attenuation of LAFmax (−13.88 dB) and, in the frequency analyses, the best sound damping. Conclusion: The dropping of DUPLO bricks in cases contributes to the high noise level in nursery schools, but measured LAFmax show no evidence for the danger of acute hearing loss. However, continuous exposure may lead to functional impairment of the hair cells and trigger stress reactions. We recommend noise reduction by utilizing cases of woven “basket” with an insert of PU-foam.
Ziel. Lokoregionäre Rezidive sind der Hauptgrund für ein Therapieversagen nach primärer multimodaler Behandlung von Plattenepithelkarzinomen der Kopf-Hals-Region (SCCHN). Wir verglichen die Effektivität und Toxizität von Cisplatin oder Cetuximab simultan zur Re-Bestrahlung (ReRT) bei inoperablen SCCHN-Rezidiven. Ein prognostischer Score sollte auf Grundlage verschiedener klinischer und pathologischer Faktoren etabliert werden.
Patienten und Methoden. 66 Patienten mit in vorbestrahlten Regionen rezidivierten SCCHN wurden von 2007 bis 2014 simultan mit Cetuximab (n=33) oder cisplatin-basierter Chemotherapie (n=33) re-bestrahlt. Die Toxizität wurde wöchentlich sowie bei jedem Nachsorgetermin erfasst. Klinische Untersuchung, Endoskopie, CT- oder MRT-Untersuchungen wurden zur Beurteilung des Therapieansprechens und der Krankheitskontrolle eingesetzt.
Ergebnisse. Nach einer mittleren Nachbeobachtungszeit von 18,3 Monaten betrug das 1-Jahres-Überleben (OS) für ReRT mit Cetuximab 44,4% und mit cisplatin-basierter Chemotherapie 45,5% (p=0.352). Die lokalen Kontollraten nach einem Jahr waren jeweils 46,4% und 54,2% (p=0.625); die Raten an Metastasenfreiheit 73,6% und 81% (p=0.842). Hämatologische Toxizität ≥ Grad 3 kam in der Cisplatin-Gruppe häufiger vor (p<0.001), dagegen trat Schmerz ≥ Grad 3 in der Cetuximab-Gruppe häufiger auf (p=0.034). Ein physiologischer Hb-Wert und ein längeres Intervall zwischen primärer RT und ReRT erwiesen sich als signifikante prognostische Faktoren für das OS (multivariat: p=0.003 und p=0.002). Die Rezidivlokalisation sowie das GTV zeigten keinen signifikanten Einfluss auf das OS in der multivariaten Analyse (p=0.160 und p=0.167). Ein auf Grundlage dieser Variablen konstruierter Prognose-Score (0 bis 4 Punkte) zeigte signifikante Überlebensunterschiede: 1-Jahres-OS für 0/1/2/3/4 Prognosepunkte: 10%, 38%, 76%, 80% und 100% (p<0.001).
Schlussfolgerung. Sowohl Cetuximab- als auch Cisplatin-basierte ReRT für SCCHN-Rezidive sind gut durchführbare und effektive Behandlungsoptionen mit vergleichbaren Ergebnissen bezüglich Tumorkontrolle und Überleben. Die akuten Nebenwirkungen könnten gering variieren. Unser Prognose-Score könnte zur Identifizierung der für ReRT geeigneten Patienten sowie zur Stratifizierung in künftigen klinischen Studien dienen.
Shrew-1, also called AJAP1, is a transmembrane protein associated with E-cadherin-mediated adherence junctions and a putative tumor suppressor. Apart from its interaction with β-catenin and involvement in E-cadherin internalization, little structure or function information exists. Here we explored shrew-1 expression during postnatal differentiation of mammary gland as a model system. Immunohistological analyses with antibodies against either the extracellular or the cytoplasmic domains of shrew-1 consistently revealed the expression of full-length shrew-1 in myoepithelial cells, but only part of it in luminal cells. While shrew-1 localization remained unaltered in myoepithelial cells, nuclear localization occurred in luminal cells during lactation. Based on these observations, we identified two unknown shrew-1 transcript variants encoding N-terminally truncated proteins. The smallest shrew-1 protein lacks the extracellular domain and is most likely the only variant present in luminal cells. RNA analyses of human tissues confirmed that the novel transcript variants of shrew-1 exist in vivo and exhibit a differential tissue expression profile. We conclude that our findings are essential for the understanding and interpretation of future functional and interactome analyses of shrew-1 variants.
Background: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.
Methods: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.
Results: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1–10.1), CD4 cell count 297 cells/mm3 (98–639), and HIV-RNA 5.2 log10copies/mL (4.7–5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5–10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4–23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2–54.8) versus 19.4 % (15.9–23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82–0.95; P < 0.001).
Conclusions: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
Ataxin-2 (Atxn2)-knock-out mice show branched chain amino acids and fatty acids pathway alterations
(2016)
Human Ataxin-2 (ATXN2) gene locus variants have been associated with obesity, diabetes mellitus type 1,and hypertension in genome-wide association studies, whereas mouse studies showed the knock-out of Atxn2 to lead to obesity, insulin resistance, and dyslipidemia. Intriguingly, the deficiency of ATXN2 protein orthologs in yeast and flies rescues the neurodegeneration process triggered by TDP-43 and Ataxin-1 toxicity. To understand the molecular effects of ATXN2 deficiency by unbiased approaches, we quantified the global proteome and metabolome of Atxn2-knock-out mice with label-free mass spectrometry. In liver tissue, significant downregulations of the proteins ACADS, ALDH6A1, ALDH7A1, IVD, MCCC2, PCCA, OTC, together with bioinformatic enrichment of downregulated pathways for branched chain and other amino acid metabolism, fatty acids, and citric acid cycle were observed. Statistical trends in the cerebellar proteome and in the metabolomic profiles supported these findings. They are in good agreement with recent claims that PBP1, the yeast ortholog of ATXN2, sequestrates the nutrient sensor TORC1 in periods of cell stress. Overall, ATXN2 appears to modulate nutrition and metabolism, and its activity changes are determinants of growth excess or cell atrophy.
Sie hören Stimmen, vermuten Botschaften in bedeutungslosen Ereignissen oder fühlen sich ferngesteuert: Die Symptome von Menschen mit einer schizophrenen Störung galten bisher als »uneinfühlbar«, da für Außenstehende nicht nachvollziehbar. Aktuelle neurowissenschaftliche Modelle helfen, die Verwechslung von »eigen« und »fremd« aufzuklären.
The use of fetal bovine serum (FBS) as a cell culture supplement is discouraged by regulatory authorities to limit the risk of zoonoses and xenogeneic immune reactions in the transplanted host. Additionally, FBS production came under scrutiny due to animal welfare concerns. Platelet derivatives have been proposed as FBS substitutes for the ex-vivo expansion of mesenchymal stem/stromal cells (MSCs) since platelet-derived growth factors can promote MSC ex-vivo expansion. Platelet-derived growth factors are present in platelet lysate (PL) obtained after repeated freezing-thawing cycles of the platelet-rich plasma or by applying physiological stimuli such as thrombin or CaCl2.PL-expanded MSCs have been used already in the clinic, taking advantage of their faster proliferation compared with FBS-expanded preparations. Should PL be applied to other biopharmaceutical products, its demand is likely to increase dramatically. The use of fresh platelet units for the production of PL raises concerns due to limited availability of platelet donors. Expired units might represent an alternative, but further data are needed to define safety, including pathogen reduction, and functionality of the obtained PL. In addition, relevant questions concerning the definition of PL release criteria, including concentration ranges of specific growth factors in PL batches for various clinical indications, also need to be addressed. We are still far from a common definition of PL and standardized PL manufacture due to our limited knowledge of the mechanisms that mediate PL-promoting cell growth. Here, we concisely discuss aspects of PL as MSC culture supplement as a preliminary step towards an agreed definition of the required characteristics of PL for the requirements of manufacturers and users.
BACKGROUND: Local implantation of ex vivo concentrated, washed and filtrated human bone marrow-derived mononuclear cells (BMC) seeded onto β-tricalciumphosphate (TCP) significantly enhanced bone healing in a preclinical segmental defect model. Based on these results, we evaluated in a first clinical phase-I trial safety and feasibility of augmentation with preoperatively isolated autologous BMC seeded onto β-TCP in combination with angle stable plate fixation for the therapy of proximal humeral fractures as a potential alternative to autologous bone graft from the iliac crest.
METHODS: 10 patients were enrolled to assess whether cell therapy with 1.3 × 106 autologous BMC/ml/ml β-TCP, collected on the day preceding the definitive surgery, is safe and feasible when seeded onto β-TCP in patients with a proximal humeral fracture. 5 follow-up visits for clinical and radiological controls up to 12 weeks were performed.
RESULTS: β-tricalciumphosphate fortification with BMC was feasible and safe; specifically, neither morbidity at the harvest site nor at the surgical wound site were observed. Neither local nor systemic inflammation was noted. All fractures healed within the observation time without secondary dislocation. Three adverse events were reported: one case each of abdominal wall shingles, tendon loosening and initial screw perforation, none of which presumed related to the IND.
CONCLUSIONS: Cell therapy with autologous BMC for bone regeneration appeared to be safe and feasible with no drug-related adverse reactions being described to date. The impression of efficacy was given, although the study was not powered nor controlled to detect such. A clinical trial phase-II will be forthcoming in order to formally test the clinical benefit of BMC-laden β-TCP for PHF patients. Trial registration The study was registered in the European Clinical Trial Register as EudraCT No. 2012-004037-17. Date of registration 30th of August 2012. Informed consent was signed from all patients enrolled.
The Hepatitis C virus (HCV) infects more than 170 million individuals worldwide and causes challenging HCV-related diseases. Unfortunately, there is no vaccine available. Therefore, a better understanding of the HCV life cycle is urgently needed to develop more effective and better tolerated therapies.
It has been reported that the secretory pathway plays an essential role for the release of HCV, and the SNARE complexes are a central factor controlling intracellular vesicular trafficking. Recently, our group observed that α-taxilin that binds to free syntaxin 4 prevents the SNARE complex formation and exerts an inhibitory effect on the release of HCV particles. Therefore, it was analyzed whether the t-SNARE protein syntaxin 4 is involved in the HCV life cycle.
An increased intracellular amount of syntaxin 4 was found in HCV-positive cells, while the level of syntaxin 4-specific transcripts was decreased as observed in HCV-positive Huh7.5 cells and in HCV-infected primary human hepatocytes (PHH). Since in HCV-positive cells a significant longer half-life of syntaxin 4 was found, the decreased expression is overcompensated, leading to the elevated amount of syntaxin 4. Overexpression of syntaxin 4 increases the amount of secreted infectious viral particles, while silencing of syntaxin 4 expression decreases the number of released viral particles, which indicates that HCV could use the SNARE-dependent secretory pathway for viral release. Confocal immunofluorescence microscopy and co-immunoprecipitation experiments revealed that syntaxin 4 interacts with HCV core and NS5A. To identify the binding domain, various mutants of syntaxin 4 were generated. Based on these mutants, it was found that the H3 domain of syntaxin 4 interacts with core. These data show that the t-SNARE protein syntaxin 4 is an essential cellular factor for HCV morphogenesis and secretion.
HCV induces autophagy, and in HCV-infected cells a major fraction of the de novo synthesized viral particles is not released but intracellularly degraded. Syntaxin 17 is an autophagosomal SNARE required for the fusion of autophagosomes with lysosomes to form autolysosomes and thereby to deliver the enclosed contents for degradation. Therefore, we aim to investigate whether syntaxin 17 is a relevant factor for the HCV life cycle by regulating the fusion between autophagosomes and lysosomes. It was found that HCV-positive cells possess a decreased amount of syntaxin 17, and HCV reduces the intracellular level of syntaxin 17 by NS5A-mediated interruption of c-Raf signaling, which triggers the syntaxin 17 transcription, and by HCV-dependently induced autophagy. Overexpression of syntaxin 17 decreases the intracellular amount of viral particles and reduces the number of released infectious viral particles by favoring the formation of autolysosomes, in which HCV particles can be degraded. Vice versa, inhibition of syntaxin 17 expression by specific siRNAs results in an elevated amount of intracellular viral particles and increases the number of released viral particles by impaired autophagosome-lysosome fusion. Confocal immunofluorescence microscopy analyses show a fraction of core protein in autophagosomes as stained by lysotracker and the autophagy maker p62. These data identify syntaxin 17 as a novel factor controlling the release of HCV and reveal the autophagosome-autolysosome fusion as an essential step affecting the equilibrium between the release of infectious viral particles and lysosomal degradation of intracellular viral particles.
Taken together, these data identify the t-SNARE proteins syntaxin 4 and syntaxin 17 as essential cellular factors for HCV morphogenesis and secretion.
kurz und kn@pp news : Nr. 37
(2016)
kurz und kn@pp news : Nr. 38
(2016)
kurz und kn@pp news : Nr. 36
(2016)
Prognostische Faktoren und das Outcome von Patienten mit einem primären Glioblastom sind in der Fachliteratur gut beschrieben. Im Gegensatz dazu gibt es wenige vergleichbare Informationen zu Patienten mit einem sekundären Glioblastom. Das Ziel dieser Arbeit war es, das Outcome von Patienten mit einem sekundären Glioblastom zu beurteilen und prognostische Faktoren in Be-zug auf das Gesamtüberleben zu identifizieren.
Dazu wurde die interne Datenbank des Universitätsklinikums Frankfurt/Main von Patienten mit Hirntumoren retrospektiv nach klinischen Daten durchsucht. Alle Patienten hatten ein histologisch gesichertes WHO Grad II oder III Gliom und anschließend ein WHO Grad IV sekundäres Glioblastom. Paraffiniertes Hirntumorgewebe wurde auf Mutationen der Isocitrat Dehydrogenase-1 (IDH1) mittels einer immunhistochemischen Färbung mit einem R132H (clone H09) spezifischen Antikörper untersucht. Eine uni- und multivariate statistische Analyse wurde durchgeführt, um Faktoren zu ermitteln, die potentiell das Gesamt-überleben beeinflussen könnten.
Es wurden 45 Patienten mit einem histologisch gesicherten sekundären Glioblastom untersucht. Das mediane Alter betrug 41 Jahre. 14 Patienten unterzogen sich einer radiologisch kompletten Resektion des sekundären Glioblastoms, 31 Patienten wurden subtotal reseziert oder biopsiert. Initial ist bei 37 Patienten ein astrozytärer Tumor nachgewiesen worden und die restlichen Patienten litten an Oligodendrogliomen oder gemischten Gliomen; bei der initialen Diagnose wurden 17 WHO Grad II und 28 WHO Grad III Tumoren fest-gestellt. Die mediane Zeit zwischen Ursprungstumor und dem Auftreten des sekundären Glioblastoms betrug 158,9 Wochen. Das mediane Gesamtüberleben betrug 445 Tage nach der Diagnose eines sekundären Glioblastoms. Mutationen des IDH1 (R132H) Proteins wurden bei 24 Patienten festgestellt und fehlten bei 17 Patienten; bei 4 Patienten konnte keine IDH1 immunhistochemische Färbung durchgeführt werden.
In der univariaten Analyse konnte der Zeitraum zwischen initialer Läsion und dem Progress zu einem sekundären Glioblastom als statistisch signifikanter Einflussfaktor identifiziert werden- Patienten mit einem Zeitraum von mehr als 2 Jahren hatten ein besseres Gesamtüberleben (460 vs. 327 Tage, p = 0,011). Außerdem konnte bei Patienten, die eine kombinierte Radiochemotherapie bekamen, ein besseres Gesamtüberleben nachgewiesen werden als bei Patienten, welche ausschließlich eine Therapieform erhielten (611 vs. 380 Tage, p < 0,001). Weiterhin konnten ein WHO Grad II Ursprungstumor (472 vs. 421 Tage, p = 0,05) und eine Frontalllappenlokalisation des Glioblastoms (472 vs. 425 Ta-ge, p = 0,031) das Überleben steigern.
In der multivariaten Analyse konnte gezeigt werden, dass die Mutation des IDH1 (R132H) Proteins in statistisch signifikanter Weise mit einem längeren Gesamtüberleben assoziiert war (p = 0,012); statistische Signifikanz für ein län-geres Gesamtüberleben bei Patienten mit initial einem WHO Grad II (p = 0,047) und einer Frontallappenlokalisation des Glioblastoms (p = 0,042) stellte sich auch ein. In Bezug auf die Patienten spezifischen Daten wurden zwei Prognosegruppen erstellt; Patienten in der guten Prognosegruppe scheinen einen Benefit von einer totalen Tumorresektion zu haben (p = 0,02), während eine Resektion für die andere Prognosegruppe keine große Rolle spielte (p = 0,926).
Trotz des relativ geringen Erkrankungsalters haben sekundäre Glioblastom Patienten eine schlechte Prognose. Die Ergebnisse dieser Arbeit unterstreichen die Wichtigkeit und den prognostischen Wert der IDH1 Diagnostik, die Notwendigkeit einer kombinierten Radiochemotherapie und eine Risikostratifizierung für eine Prognoseabschätzung anhand der Patienten spezifischen Einflussfaktoren.
Dieser Artikel beschreibt die Inverted-Classroom-Methode(ICM) im Sinne einer Einführung in die Thematik und soll als Praxisleitleitfaden für diejenigen dienen, die diese Methode in der medizinischen Aus-, Fort- und Weiterbildung einsetzen möchten. Es handelt sich bei der ICM um einen Blended-Learning-Methode, bei dem eine Selbstlernphase (individuelle Phase) vor die Präsenzunterrichtsphase gesetzt wird. In der Online-Phase wird Faktenwissen vermittelt, das als Grundlage für die Präsenzphase dient. Die Präsenzphase soll anschließend dafür genutzt werden, das erlernte Wissen zu vertiefen und anzuwenden. Dem gegenüber stehen die traditionellen Kurskonzepte, in denen das Faktenwissen beispielsweise in Vorlesungen oder in anderen Präsenzunterricht-Formaten vermittelt wird und die Vertiefung dieses Wissens durch die Studierenden im Anschluss daran im Selbststudium stattfinden soll. Das Ziel der ICM ist die Verschiebung des passiven Lernens hin zum aktivierenden Lernen, um das Lernen auf kognitiv anspruchvollen Ebenen wie Analyse, Synthese und Evaluation zu unterstützen. Dabei haben die gestiegene Produktion und Nutzung von Screencasts und Lernvideos, die „Bewegung“ der „Open Educational Resources“ und die verbreitete Nutzung von „Massive Open Online Courses“ (MOOCs) zu einer gestiegenen Verbreitung der Inverted-Classroom-Methode beigetragen. Der Artikel soll als Einführung in die Thematik dienen und dabei eine kurze Übersicht über wichtige Projekte und Forschungsergebnisse in der medizinischen Ausbildung und in weiteren Gesundheitsberufen geben. Außerdem werden die Vor- und Nachteile der Methode und ihr potentieller Nutzen für die zukünftige medizinische Aus- und Weiterbildung dargestellt.
Background: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.
Methods: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).
Results: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.
Conclusions: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.
Trial registration: NCT01598129. Registered 19/04/2012
We assessed the prognostic value of hypoxia (carbonic anhydrase 9; CA9), vessel density (CD31), with macrophages (CD68) and B cells (CD20) that can interact and lead to immune suppression and disease progression using scanning and histological mapping of whole-mount FFPE pancreatectomy tissue sections from 141 primarily resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with surgery and adjuvant chemotherapy. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin). The median OS was 21 months after a mean follow-up of 20 months (range, 2–69 months). The median tumor surface area positive for CA9 and CD31 was 7.8% and 8.1%, respectively. Although total expression of these markers lacked prognostic value in the entire cohort, nevertheless, high tumor compartment CD68 expression correlated with worse PFS (p = 0.033) and DMFS (p = 0.047). Also, high CD31 expression predicted for worse OS (p = 0.004), PFS (p = 0.008), LPFS (p = 0.014) and DMFS (p = 0.004) in patients with moderate density stroma. High stromal and peripheral compartment CD68 expression predicted for significantly worse outcome in patients with loose and moderate stroma density, respectively. Altogether, in contrast to the current notion, hypoxia levels in PDAC appear to be comparable to other malignancies. CD31 and CD68 constitute prognostic markers in patient subgroups that vary according to tumor compartment and stromal density. Our study provides important insight on the pathophysiology of PDAC and should be exploited for future treatments.
A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior
(2016)
Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-d-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression.
Effect of M3 muscarinic acetylcholine receptor deficiency on collagen antibody-induced arthritis
(2016)
Background: There is increasing evidence that the non-neuronal cholinergic system might be of importance for the pathology of rheumatoid arthritis. The role of M3 muscarinic acetylcholine receptor (M3R) in this regard has, however, not been investigated to date. Thus, in the present study we analyzed if M3R deficiency might have a protective effect on experimentally induced arthritis.
Methods: Collagen antibody-induced arthritis (CAIA) was evoked in M3R-deficient (M3R −/− ) mice and wild-type (WT) littermates. Severity of arthritis was assessed by scoring of paw swelling. The joints of arthritic and nonarthritic animals were analyzed for histopathological changes regarding synovial tissue, cartilage degradation and bone destruction. Further, gene expression analysis of respective markers was performed. Systemic and local inflammatory response was determined by flow cytometry and immunohistochemistry for leukocytes as well as mRNA and protein measurements for pro-inflammatory cytokines and chemokines.
Results: In arthritic M3R −/− mice the number of leukocytes, specifically neutrophils, was enhanced even though clinical arthritis score was not significantly different between WT and M3R −/− mice with CAIA. In M3R −/− mice, levels of neutrophil chemoattractant chemokine C-X-C-motif ligand 2 (CXCL2) as well as the pro-inflammatory cytokine interleukin-6 were already strongly increased in mice with low arthritis score, whereas WT mice only showed prominent expression of these markers when reaching high arthritis scores. Furthermore, arthritic M3R −/− mice displayed a stronger degradation of collagen II in the articular cartilage and, most strikingly, histopathological evaluation revealed more severe bone destruction in arthritic mice with M3R deficiency compared to WT littermates. Moreover, in M3R −/− mice, gene expression of markers for bone degradation (matrix metalloproteinase 13, cathepsin K and receptor activator of nuclear factor-κB ligand) was already increased in mice with low arthritis score.
Conclusions: Taken together, the present study shows that while M3R −/− mice were not protected from CAIA, they had a tendency toward a higher inflammatory response after arthritis induction than WT mice. Further, arthritis-induced joint destruction was significantly stronger in mice with M3R deficiency, indicating that stimulation of M3R might have protective effects on arthritis.
Evading innate immunity is a prerequisite for pathogenic microorganisms in order to survive in their respective hosts. Concerning Lyme disease spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato group, a broad range of diverse vertebrates serve as reservoir or even as incidental hosts, including humans. The capability to infect multiple hosts implies that spirochetes have developed sophisticated means to counter the destructive effects of complement of humans and various animals. While the means by which spirochetes overcome the hosts immune defense are far from being completely understood, there is a growing body of evidence suggesting that binding of the key regulator of the alternative pathway, Factor H, plays a pivotal role for immune evasion and that Factor H is an important determinant of host specificity. This review covers (i) the contribution of complement in host-specificity and transmissibility of Lyme disease spirochetes; (ii) the involvement of borrelial-derived determinants to host specificity; (iii) the interplay of human and animal Factor H with complement-acquiring surface proteins of diverse borrelial species; and (iv) the potential role of additional animal complement proteins in the immune evasion of spirochetes.
Alle lebenden Organismen sind in der Lage, sich an den re-gelmäßigen Wechsel von Licht und Dunkelheit und den zeitli-che Veränderungen im Takt der Jahreszeiten anzupassen. Die-se Synchronisierung der Aktivitäts- und Ruhephasen, sowie von physiologischen Stoffwechselprozessen an die vorgegebe-nen tageszeitlichen und saisonalen Zyklen findet beim Säu-getier in der inneren Uhr im Nucleus Suprachiasmaticus (SCN) statt. Das Licht, als wichtigster Zeitgeber für die Synchronisation der inneren Uhr, findet Eingang zum SCN über die Retina und den retinohypothalamischen Trakt (RTH), der Glutamat als Neurotransmitter nutzt. Ist dieses System fehlerhaft, führt dies zu Störung der oben beschriebenen Anpassungsprozesse. Dies hat eine gestörte Homöostase des Organismus zu Folge, aus denen sich wiederum Veränderungen im Tag/Nacht- Rhythmus, Schlafstörungen und depressive Ver-stimmungen ergeben können. Die genannten Symptome decken sich mit den Frühsymptomen den neurodegenerativen Erkran-kung Morbus Parkinson.
Ziel der vorliegenden Arbeit war es, Störungen im photoneu-roendokrinen System, insbesondere Veränderungen in der Re-tina an den photosensitiven Ganglienzellen mit dem Photo-pigment Melanopsin und dem SCN bei transgene Mäuse mit dem humanen alpha-Synuclein zu untersuchen. Hierbei wurden transgene Mäuse mit dem gesunden humanen alpha-Synuclein (Wildtyp) und transgene Mäuse mit der für Parkinson spezi-fischen Mutation im alpha-Synuclein Ala53Thr (A53T) vergli-chen.
Die immunochemischen Untersuchungen an Retina und SCN zei-gen einen signifikanten Anstieg der alpha-Synuclein Immun-reaktion bei der A53T Maus im Vergleich zum Wildtyp.
Parallel dazu wurden Unterschiede in Bezug auf das Photo-pigment Melanopsin zwischen den beiden Gruppen untersucht. Melanopsin ist lichtsensitiv und trägt, durch Übermittlung der aktuellen Lichtverhältnisse über den retinohypothalami-schen Trakt zum SCN, zur Synchronisation der circadianen Rhythmik bei. Durch den in dieser Arbeit nachgewiesene Me-lanopsindefizit und des deutlich reduzierten Vglut2 im hy-pothalamischen Trakt der A53T Maus lässt sich die Hypothese ableiten, dass möglicherweise die Überexpression des mu-tierten alpha-Synuclein in der Retina einen Untergang von melanopsinhaltigen Ganglienzellen herbeiführt und dadurch die Synchronisation der inneren Uhr durch Licht gestört ist. Diese Hypothese wird durch die Aktivitätsprofile ge-stützt, die durch die Aufzeichnung der lokomotorischen Ak-tivität der Tiere erstellt wurden.
Da in beiden Gruppen unter Dauerdunkel (DD) ein endogener zirkadianer Rhythmus beobachtet werden konnte, lässt dies auf die Funktionstüchtigkeit der inneren Uhr im SCN schlie-ßen. Im anschließenden Versuch die endogene Rhythmik an exogenen Reize anzupassen, zeigte sich bei dem A53T Stamm eine fehlende Synchronisierung an vorgegebene Lichtverhält-nisse mit gesteigerter Tagaktivität und reduzierten Schlaf-phasen. Somit trägt der fehlerhaft verarbeitete Lichtreiz bei A53T Mutanten zur Destabilisierung des zirkadianen Rhythmus der Lokomotion bei. Trotz des gestörten glutama-tergen Signalweges im retinohypothalamischen Trakt konnten keine Unterschiede in der Expression der Homerproteine zwi-schen Wildtyp und A53T unter Standard-Photoperiode und nach Schlafdeprivation nachgewiesen werden.
Die vorliegenden Befunde liefern Erkenntnisse zur Entste-hung der Frühsymptome bei Morbus Parkinson. Dies könnte neue Ansatzpunkte für die Therapie und Linderung von Schlafstörungen sowie Veränderungen im Tag/Nachtrhythmus liefern.
Das idiopathische Parkinsonsyndrom (IPS) wurde durch James Parkinson im Jahr 18171 vornehmlich als neurologische Bewegungsstörung beschrieben. Durch die Verdienste umfassender Forschung und klinischer Diagnostik der letzten Jahrzehnte wird das IPS heute als Syndrom aufgefasst, das neben motorischen auch durch neuropsychiatrische, vegetative und sensible Symptome charakterisiert ist. Eines dieser sogenannten „nicht-motorischen Symptome“ bildet die (milde) kognitive Beeinträchtigung, die jeden vierten nicht-dementen Parkinsonpatienten betrifft2 und die im oft langjährigen Krankheitsverlauf in eine Parkinsondemenz münden kann, an der 8 Jahre nach Krankheitsbeginn bis zu 78% der Parkinsonpatienten leiden.3 Durch die steigende Lebenserwartung der Patienten und die besseren Therapieoptionen der motorischen Komponente eines IPS finden derzeit gerade die nicht-motorischen Symptome sowohl in der Forschung als auch der Klinik zunehmend stärkere Beachtung.
Die motorische Symptomatik des IPS wird vorrangig durch die Degeneration dopaminerger Neuronen in bestimmten Strukturen des Hirnstamms hervorgerufen.4 Die Entwicklung kognitiver Symptome ist komplexer und umfasst vermutlich neben der (genannten) dopaminergen Degeneration die Beeinträchtigung weiterer Neurotransmitter sowie degenerative Prozesse an anderer Stelle des ZNS.5 Insbesondere die Atrophie von frontalem, parietalem und (medio-) temporalem Cortex scheint mit der Parkinsondemenz assoziiert.6–8 Auch gleichzeitig auftretende histopathologische Prozesse, die für die Alzheimer-Demenz charakteristisch sind, werden diskutiert.9
Der Hippocampus, eine Struktur des Mediotemporallappens, leistet einen bedeutenden Beitrag zum deklarativen räumlichen Gedächtnis und zum Arbeitsgedächtnis sowie zur Verarbeitung von Emotionen, sodass er beim normalen Altern, aber auch vielen Erkrankungen, eine wichtige Rolle einnimmt.10–12 Vor allem bei der Alzheimer-Demenz ist der Hippocampus eine sehr früh von der Atrophie betroffene Struktur.13 In den letzten Jahren mehren sich die Hinweise, dass dies auch bei der Parkinsondemenz der Fall ist.14–16 Aus diesem Grund wird im Folgenden ein besonderes Augenmerk auf diese Struktur gelegt.
Die vorliegende Studie setzt sich mit der Fragestellung auseinander, ob und inwiefern sich Parkinsonpatienten mit unterschiedlich ausgeprägten kognitiven Einschränkungen in den Volumina ausgewählter Hirnstrukturen – darunter die corticale graue und weiße 8 Substanz, der Hippocampus und die Hirnventrikel – sowie in den neuropsychologischen Domänen Gedächtnis, Exekutivfunktionen und Aufmerksamkeit, Sprache und visuell-räumliche Funktionen unterscheiden. Außerdem wird untersucht, ob zwischen den Hirnvolumina und dem Grad der kognitiven Einschränkung ein Zusammenhang besteht. Hierzu werden Parkinsonpatienten ohne Demenz (PD), Parkinsonpatienten mit milder kognitiver Beeinträchtigung (PD-MCI) und Patienten mit Parkinsondemenz (PDD) neuropsychologisch untersucht und magnetresonanztomographische Aufnahmen des Gehirns erstellt. Die mit einem automatisierten Messprogramm ermittelten Hirnvolumina werden in Korrelation zu Testungen des Gedächtnisses, der Exekutive und Aufmerksamkeit, der Sprache und visuell-räumlicher Funktionen gesetzt.
Die Arbeit gliedert sich wie folgt: Zum besseren Verständnis der kognitiven Symptomatik werden im ersten Kapitel die nicht-kognitiven Symptome des IPS charakterisiert sowie der aktuelle Wissensstand über Kognition beim IPS wiedergegeben. Anschließend werden die technischen Grundlagen der Magnetresonanztomographie und Methoden zur Auswertung struktureller MRT-Bilder erläutert. Darauf aufbauend wird die Fragestellung konkretisiert, bevor im zweiten Teil der Arbeit die Vorstellung des Studiendesigns, die Präsentation der Ergebnisse und im letzten Teil die Diskussion erfolgen.
Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia
(2016)
Objective: To evaluate the influence of the soluble fms-like tyrosine kinase 1/placental growth factor ratio in physicians’ decision making in pregnant women with signs and symptoms of preeclampsia in routine clinical practice.
Methods: A multicenter, prospective, open, non-interventional study enrolled pregnant women presenting with preeclampsia signs and symptoms in several European perinatal care centers. Before the soluble fms-like tyrosine kinase 1/placental growth factor ratio result was known, physicians documented intended clinical procedures using an iPad® application (data locked/time stamped). After the result was available, clinical decisions were confirmed or revised and documented. An independent adjudication committee evaluated the appropriateness of decisions based on maternal/fetal outcomes. Clinician decision making with regard to hospitalization was the primary outcome.
Results: In 16.9% of mothers (20/118) the hospitalization decision was changed after knowledge of the ratio. In 13 women (11.0%), the initial decision to hospitalize was changed to no hospitalization. In seven women (5.9%) the revised decision was hospitalization. All revised decisions were considered appropriate by the panel of adjudicators (McNemar test; p < 0.0001).
Conclusions: The use of the soluble fms-like tyrosine kinase 1/placental growth factor test influenced clinical decision making towards appropriate hospitalization in a considerable proportion of women with suspected preeclampsia. This is the first study to demonstrate the impact of angiogenic biomarkers on decision making in a routine clinical practice.
BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases.
METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity.
RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954-0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2.
CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.
Hintergrund: Die Delegation ärztlicher Leistungen an nichtärztliches medizinisches Fachpersonal wird in Deutschland vor dem Hintergrund eines absehbaren Hausärztemangels bei gleichzeitig wachsendem Bedarf an hausärztlichen Betreuungsleistungen seit einiger Zeit diskutiert. Inzwischen wurden unterschiedliche Qualifikationsmodelle für Medizinische Fachangestellte (MFA) (z.B. die Versorgungs-assistentin in der Hausarztpraxis, VERAH) konzipiert und implementiert, die für eine Delegation von Leistungen qualifizieren. VERAH sind v.a. in Baden-Württemberg in Hausarztpraxen tätig, da deren Einsatz dort im Rahmen der Hausarztzentrierten Versorgung (HzV) seit 2008 finanziell honoriert wird. Dabei ist es den Praxen freigestellt, wie sie das VERAH-Konzept und damit auch die Delegation umsetzen. Auch gesetzliche Vorgaben zur Delegation lassen erheblichen Spielraum bei der Umsetzung. Erschwerend kommt hinzu, dass weiterhin Unklarheit darüber besteht, welche Leistungsübertragung als „Delegation“ und welche eher als „Substitution“ zu verstehen ist.
Zielrichtung der Arbeit: Ziel dieser publikationsbasierten Dissertation ist eine Darstellung der Formen und Graduierungen von Delegation, d.h. der tatsächlichen Umsetzung von Leistungsübertragung in der Hausarztpraxis am Beispiel der VERAH in Baden-Württemberg. Es können Empfehlungen für das Gelingen der Delegation aus der Analyse von Ergebnissen auf Patienten-, Praxis- und Teamebene abgeleitet werden.
Resultate: Diese Dissertation basiert auf sechs Publikationen, die im Rahmen von zwei Projekten zur Evaluation des VERAH-Einsatzes in der HzV in Baden-Württemberg entstanden. Die Evaluationen basieren auf einem Mixed Methods-Design, d.h. auf der Analyse von querschnittlich erhobenen quantitativen Daten sowie qualitativen Daten zu verschiedenen Fragen des VERAH-Einsatzes.
Es existiert ein breites Spektrum an Formen und Graduierungen der Delegation in Hausarztpraxen, die am HzV-Modell teilnehmen. VERAH übernehmen einerseits supplementäre (zusätzliche) ärztliche Tätigkeiten, wie z.B. Geriatrisches Assessment oder Impfberatungen, aber auch komplementäre (ergänzende) Tätigkeiten wie z.B. die Beratung der Angehörigen zu Hilfeleistungen im Gesundheitssystem. Vor allem im Rahmen von Hausbesuchen üben VERAH auch substituierende (ersetzende) Funktionen
aus. Auf Patientenseite sind gerade ältere, multimorbide und pflegebedürftige Patienten Empfänger delegierter Leistungen. Sie erhalten eine umfassende Betreuung und werden beim Erhalt ihrer häuslichen Selbständigkeit unterstützt. Die Patienten sehen in der VERAH eine zusätzliche Vertrauensperson in der Praxis und akzeptieren sie als kompetente Ansprechpartnerin. Die Hausärzte profitieren durch die Delegation von Tätigkeiten an VERAH, indem sie entlastet werden und Zeit für wichtige medizinische Aufgaben gewinnen. Für VERAH stellt die Delegation eine Erweiterung ihrer Tätigkeits- und Kompetenzbereiche dar und kann insofern als ein Schritt zur Professionalisierung des nichtärztlichen Personals einer Hausarztpraxis gelten.
Viele Faktoren, die zum Gelingen einer Umsetzung der Delegation beitragen, können vom hausärztlichen Team selbst beeinflusst werden. Darunter fallen das Engagement der MFA, die Qualifikation, zeitliche Flexibilität, ausreichend Gestaltungsspielraum, Grad der Autonomie, Abgrenzung des Verantwortungsbereiches und auch adäquates Equipment. Entsprechend richten sich die hier formulierten Empfehlungen meist an die Praxis, aber auch an den Gesetzgeber.
Bedeutung für die übergeordnete Fragestellung: Die Ergebnisse dieser Arbeit zeigen, dass mit dem VERAH-Konzept erste Ansätze einer teambasierten Versorgung vorhanden sind, und dass sich die Analyse dieses Konzeptes eignet, um Desiderata für die Zukunft von Delegation (haus-)ärztlicher Leistungen an nichtärztliches Personal formulieren zu können. Teambasierte Ansätze bedürfen, wie auch internationale Beispiele verdeutlichen, einer Weiterentwicklung der bestehenden Delegationskonzepte in deutschen Hausarztpraxen. Idealerweise mündet eine mit Delegation einhergehende Aufgaben- und Rollenneuverteilung in einer Betreuungsform, in der alle Teammitglieder entsprechend ihrer Qualifikation an der Versorgung der Patienten in der Hausarztpraxis beteiligt sind. Daher kommt die Einbindung von Pflegekräften in die hausärztliche Versorgung genauso in Frage, wie auch speziell ausgebildete VERAH/MFA. In jedem Fall sollte über Schritte der Professionalisierung nichtärztlicher Berufsgruppen nachgedacht werden. Ob sich in Deutschland, wie in den USA und in Kanada, aus diesen Delegationskonzepten im Laufe der Zeit Substitution (im Sinne der Verantwortungsübertragung an nichtärztliche Berufsgruppen) entwickelt, bleibt abzuwarten. Die Ergebnisse der Dissertation zeigen, dass es mit der gegenwärtigen Umsetzung der Delegation an VERAH zu einer Erweiterung des Leistungsspektrums in den Hausarztpraxen kommen kann; eine Ausweitung der Delegation sollte jedoch zeitnah vorangetrieben werden.
Background: Due to the steadily increasing number of cancer patients worldwide the early diagnosis and treatment of cancer is a major field of research. The diagnosis of cancer is mostly performed by an experienced pathologist via the visual inspection of histo-pathological stained tissue sections. To save valuable time, low quality cryosections are frequently analyzed with diagnostic accuracies that are below those of high quality embedded tissue sections. Thus, alternative means have to be found that enable for fast and accurate diagnosis as the basis of following clinical decision making.
Methods: In this contribution we will show that the combination of the three label-free non-linear imaging modalities CARS (coherent anti-Stokes Raman-scattering), TPEF (two-photon excited autofluorescence) and SHG (second harmonic generation) yields information that can be translated into computational hematoxylin and eosin (HE) images by multivariate statistics. Thereby, a computational HE stain is generated resulting in pseudo-HE overview images that allow for identification of suspicious regions. The latter are analyzed further by Raman-spectroscopy retrieving the tissue’s molecular fingerprint.
Results: The results suggest that the combination of non-linear multimodal imaging and Raman-spectroscopy possesses the potential as a precise and fast tool in routine histopathology.
Conclusions: As the key advantage, both optical methods are non-invasive enabling for further pathological investigations of the same tissue section, e.g. a direct comparison with the current pathological gold-standard.
Background: The quantification of global DNA methylation has been established in epigenetic screening. As more practicable alternatives to the HPLC-based gold standard, the methylation analysis of CpG islands in repeatable elements (LINE-1) and the luminometric methylation assay (LUMA) of overall 5-methylcytosine content in “CCGG” recognition sites are most widely used. Both methods are applied as virtually equivalent, despite the hints that their results only partly agree. This triggered the present agreement assessments.
Results: Three different human cell types (cultured MCF7 and SHSY5Y cell lines treated with different chemical modulators of DNA methylation and whole blood drawn from pain patients and healthy volunteers) were submitted to the global DNA methylation assays employing LINE-1 or LUMA-based pyrosequencing measurements. The agreement between the two bioassays was assessed using generally accepted approaches to the statistics for laboratory method comparison studies. Although global DNA methylation levels measured by the two methods correlated, five different lines of statistical evidence consistently rejected the assumption of complete agreement. Specifically, a bias was observed between the two methods. In addition, both the magnitude and direction of bias were tissue-dependent. Interassay differences could be grouped based on Bayesian statistics, and these groups allowed in turn to re-identify the originating tissue.
Conclusions: Although providing partly correlated measurements of DNA methylation, interchangeability of the quantitative results obtained with LINE-1 and LUMA was jeopardized by a consistent bias between the results. Moreover, the present analyses strongly indicate a tissue specificity of the differences between the two methods.
Plus Puls : 2016, 1
(2016)
The aim of this preliminary prospective RCT was to histologically evaluate peri-implant soft tissues around titanium abutments treated using different cleaning methods. Sixteen patients were randomized into three groups: laboratory customized abutments underwent Plasma of Argon treatment (Plasma Group), laboratory customized abutments underwent cleaning by steam (Steam Group), and abutments were used as they came from industry (Control Group). Seven days after the second surgery, soft tissues around abutments were harvested. Samples were histologically analyzed. Soft tissues surrounding Plasma Group abutments predominantly showed diffuse chronic infiltrate, almost no acute infiltrate, with presence of few polymorphonuclear neutrophil granulocytes, and a diffuse presence of collagenization bands. Similarly, in Steam Group, the histological analysis showed a high variability of inflammatory expression factors. Tissues harvested from Control Group showed presence of few neutrophil granulocytes, moderate presence of lymphocytes, and diffuse collagenization bands in some sections, while they showed absence of acute infiltrate in 40% of sections. However, no statistical difference was found among the tested groups for each parameter (p > 0.05). Within the limit of the present study, results showed no statistically significant difference concerning inflammation and healing tendency between test and control groups.
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 02/2016
(2016)
We integrated recent improvements within the floating catchment area (FCA) method family into an integrated ‘iFCA`method. Within this method we focused on the distance decay function and its parameter. So far only distance decay functions with constant parameters have been applied. Therefore, we developed a variable distance decay function to be used within the FCA method. We were able to replace the impedance coefficient β by readily available distribution parameter (i.e. median and standard deviation (SD)) within a logistic based distance decay function. Hence, the function is shaped individually for every single population location by the median and SD of all population-to-provider distances within a global catchment size. Theoretical application of the variable distance decay function showed conceptually sound results. Furthermore, the existence of effective variable catchment sizes defined by the asymptotic approach to zero of the distance decay function was revealed, satisfying the need for variable catchment sizes. The application of the iFCA method within an urban case study in Berlin (Germany) confirmed the theoretical fit of the suggested method. In summary, we introduced for the first time, a variable distance decay function within an integrated FCA method. This function accounts for individual travel behaviors determined by the distribution of providers. Additionally, the function inherits effective variable catchment sizes and therefore obviates the need for determining variable catchment sizes separately.
Plus Puls : 2016, 2
(2016)
Plus Puls : 2016, 3
(2016)
Aims: To investigate real-world clinical and patient-related variables associated with initiating GLP-1 receptor agonist (GLP-1RA) treatment relative to initiation of other glucose-lowering therapies in type 2 diabetes (T2D) patients of primary care in Germany.
Methods: Data for 938 T2D patients who started therapy with a GLP-1RA within 823 practices of primary care throughout Germany were retrospectively analyzed (Disease Analyser: 01/2011–03/2014). 5,197 T2D patients who initiated other non-GLP-1RA antidiabetic therapies were selected as controls. Multivariate logistic regression analyses were applied to identify factors associated with GLP-1RA initiation in primary care.
Results: Mean age (SD) of GLP-1RA users was 57.8 (11.8) years (males: 55.5%) and the average BMI was 36.1 (6.7) kg/m2. 22.8% were in diabetologist care and 12.0% had private health insurance. In multivariate regression, choice of GLP-1RA therapy instead of a different glucose-lowering drug class was associated with obesity (odds ratio: 1.68; 95% CI: 1.34–2.10), private health insurance (2.42; 1.89–3.09), younger age (0.94; 0.93–0.95 per year), male sex (0.85; 0.73–0.99), diabetologist care (2.11; 1.73–2.57), and geographic practice location (East vs. West-Germany; 1.25; 1.05–1.49). Among co-medication, angiotensin II antagonists (increased) and non-steroidal antirheumatic agents (decreased) were related to GLP-1RA prescriptions (both p<0.001).
Conclusions: Consistent with German guidelines, GLP-1RA is mainly prescribed preferentially in T2D patients who are obese. GLP-1RA drugs were more frequently used than other options in privately health insured patients and in patients seeing a diabetologist.
In light of increasing division of labour in healthcare, the training and acquisition of both profession-specific and interprofessional competencies have been attributed growing significance, creating the need to test and establish specific teaching formats. Despite ever more complex and interconnected healthcare systems, an increase in patients’ active self-responsibility and innumerable pedagogical and technological innovations, educational systems have not reacted adequately to these new demands. Many authors, not lease the German Council of Science and Humanities, have therefore urged a rethinking of traditional medical education. Student-centred learning activities, such as problem-based and research-based learning, are becoming increasingly significant in view of the numbers of students achieving unsatisfactory levels of competence in critical thinking, communication and writing abilities and complex clinical decision making, for example. The Council of Science and Humanities arrived at a positive evaluation of the various model and reformed courses of study attempting to effectuate a comprehensive reorganisation of medical studies in content and structure as well as methods and didactics. The persistent pervasiveness of instructor-centred learning formats is not only to be found in medical education but in all of the health professions. Although alternative teaching and instruction formats have already been designed and their effectiveness deemed positive in empirical evaluation, the lecture remains the most practised means of transmitting knowledge. In its essence, however, learning is not a question of transmitting information but, moreover, a question of processing information. In traditional instruction units, referred to as “chalk and talk classes” by Becker and Watts, the teaching party presents material in the form of a lecture. As appropriate, questions may be permitted or short processing periods for the students may be integrated into the lecture. The knowledge-assimilating and most essential analysis of the lecture’s contents takes place in the subsequent self-instruction phase, in which the student works alone on concrete tasks. It is during the transfer of knowledge conveyed in the lectures, however, that most questions arise. Of further disadvantage in the traditional lecture is the low level of motivation among students to attend lectures as well as their often heterogeneous knowledge. The Inverted Classroom Model seems to be an eligible instrument for greater facilitation of student-centred and interprofessional learning.
Ubiquitination plays a critical role in the activation of host immune responses to infection and serves as a signal for pathogen delivery to phagophores along the xenophagy pathway. We recently performed systematic ubiquitination site profiling of epithelial cells infected with Salmonella Typhimurium. Our findings specifically highlight components of the NFKB, membrane trafficking pathways and RHO GTPase systems as ubiquitination hubs during infection. In addition, a broad spectrum of bacterial effectors and several outer membrane proteins are ubiquitinated in infected cells. This comprehensive resource of ubiquitinome dynamics during Salmonella infection enables further understanding of the complex host-pathogen interplay and may reveal novel targets for the inhibition of Salmonella invasion and inflammation.
Objectives: Patient safety is a crucial issue in medicine. Its main objective is to reduce the number of deaths and health damages that are caused by preventable medical errors. To achieve this, it needs better health systems that make mistakes less likely and their effects less detrimental without blaming health workers for failures. Until now, there is no in-depth scientometric analysis on this issue that encompasses the interval between 1963 and 2014. Therefore, the aim of this study is to sketch a landscape of the past global research output on patient safety including the gender distribution of the medical discipline of patient safety by interpreting scientometric parameters. Additionally, respective future trends are to be outlined.
Setting: The Core Collection of the scientific database Web of Science was searched for publications with the search term ‘Patient Safety’ as title word that was focused on the corresponding medical discipline. The resulting data set was analysed by using the methodology implemented by the platform NewQIS. To visualise the geographical landscape, state-of-the-art techniques including density-equalising map projections were applied.
Results: 4079 articles on patient safety were identified in the period from 1900 to 2014. Most articles were published in North America, the UK and Australia. In regard to the overall number of publications, the USA is the leading country, while the output ratio to the population of Switzerland was found to exhibit the best performance. With regard to the ratio of the number of publications to the Gross Domestic Product (GDP) per Capita, the USA remains the leading nation but countries like India and China with a low GDP and high population numbers are also profiting.
Conclusions: Though the topic is a global matter, the scientific output on patient safety is centred mainly in industrialised countries.
In etwa 40% der Fälle erleiden Patienten bei einem Polytrauma eine Verletzung des Thorax. Diese Patienten haben im Verlau ein erhöhtes Pneumonierisiko, eine längere Beatmungs-, Intensiv- und Krankenhausverweildauer sowie ein erhöhtes Letalitätsrisiko. Um eine optimierte Versorgung dieser Patienten zu erreichen wurde seit 2003 im Universitätsklinikum Frankfurt ein standardisiertes Behandlungsverfahren durchgeführt und über die Jahre weiterentwickelt. Grundlage dieses Konzepts ist die Behandlung des Patienten mittels kinetischer Therapie im Rotorest®Bett sowie den drei Kern-Maßnahmen: Beatmung mit einem PEEP von 15mbar, frühzeitige assistierte Spontanatmung und frühzeitige enterale Ernährung. Ziel der Arbeit war die Weiterentwicklung des Behandlungsstandards wissenschaftlich unter besonderem Fokus auf die Entwicklung einer Pneumonie aufzuarbeiten. Das Konzept sah 2003 eine Beatmung, mit einem an die Oxygenierung adaptierten PEEP vor. Die Dauer der Therapie im Rotorest®Bett wurde nach Klinik entschieden. 2006 wurde standardmäßig die Therapie im Rotorest®Bett für mindestens 72h mit einem PEEP von 15mbar durchgeführt. Eine assistierte Beatmungsform sollte zeitnah etabliert werden. Im Jahr 2009, wurde das Behandlungsschema verkürzt, die Therapiedauer mit einem PEEP von 15mbar wurde auf 40 bis 48 Stunden reduziert sowie der PEEP danach initial um 4mbar reduziert. Im Anschluss erfolgte alle 8 Stunden eine weitere Reduktion des PEEP um 2mbar. Weiterhin wurde in diesem Zeitraum auf eine Antiinfektivaprophylaxe verzichtet. 108 Patienten (61,7%; ISS 37±13 Punkte) konnten in diese retrospektive Studie eingeschlossen werden. 38,3% der Patienten mussten ausgeschlossen werden, einerseits auf Grund fehlender Krankenakten oder anderseits auf Grund des Beginns der Therapie im RotoRest®Bett erst nach >48h. Durch die Anpassung des Therapiestandards über die Jahre reduzierte sich die Beatmungszeit von 17±15 Tage auf 8±8 Tage (p<0,001), die Verweildauer auf ITS von 17±9 auf 10±9 Tage (p<0,001), während die Krankenhausverweildauer unverändert blieb. Dies war begleitet von einer Reduktion der Therapiedauer im Rotorest®Bett von im Median 5 auf 3 Tage (p=0,017) sowie einer Reduktion des Anteils an Patienten mit mandatorischer Beatmung in den ersten drei Behandlungstagen von 87% (95% CI 78-96%) im Jahr 2003 auf 38,6% (95% CI 29-49%) im Jahr 2009. Die Rate an Pneumonien konnte von 25% in 2003 über 37% in 2006 auf 17% in 2009 gesenkt werden, der Unterschied war jedoch nicht signifikant. Das Risiko zu versterben war bei Entwicklung einer Pneumonie signifikant erhöht (24% vs. 4,5%, p=0,006). In der univariaten Analyse waren relevante Faktoren für die Entwicklung einer Pneumonie ein höheres Alter der Patienten (48 Jahre vs. 36 Jahre; p = 0,018), die zunehmende Höhe des Beatmungsspitzendruckes (p<0,01) sowie der Hämoglobinwert bei Aufnahme (Rs -0,28; p=0,004). Umgekehrt war eine Transfusion von Blutprodukten am ersten Behandlungstag mit einem erhöhten Pneumonierisiko verbunden (p<0,05), dies galt auch für die Verabreichung der einzelnen Komponenten, EKs (p=0,027), FFP (p=0,037) sowie von TKs (p=0,046). Keine signifikante Korrelation zur Entwicklung einer Pneumonie hatte die Verletzungsschwere (ISS) sowie die Höhe des PEEP oder der Grad der Oxygenierungsstörung (paO2/FiO2) in den ersten fünf Behandlungstagen. In der multivariaten Analyse, mit der Entwicklung einer Pneumonie als abhängigen Faktor, adjustiert auf ISS und Alter der Patienten zeigte sich als unabhängige Risikofaktoren die Gabe von EKs (OR 3,646 95%CI 1,074-12,383), die Ernährung mit >5000kcal in den ersten fünf Behandlungstagen (OR 3,219 95%CI 1,033-10,034) sowie die Höhe des Beatmungsspitzendruckes (OR 1,135 95%CI 1,010-1,275).
In Zusammenschau war ein primärer Erfolg des Konzeptes, dass kein Patient im Verlauf ein moderates oder schweres ARDS entwickelt hat. Es konnte durch die Anpassung des Behandlungsstandards sowohl die Beatmungszeit als auch die Verweildauer auf der ITS signifikant reduziert werden. Auch die Pneumonierate konnte nach einem Anstieg im Jahr 2006 bis 2009 deutlich reduziert werden. Als Risikofaktoren für die Entwicklung einer Pneumonie zeigten sich aus der Literatur bekannte Parameter wie das Alter der Patienten und die Invasivität der Beatmung sowie die Transfusion von Blutprodukten. In der multivariaten Analyse bestätigte sich dies für die Gabe von EKs, die Invasivität der Beatmung sowie der Ernährung mit kumulativ > 5000 kcal in den ersten fünf Tagen.
Patienten, die mit dem in dieser Arbeit beschrieben Protokoll behandelt wurden, zeigten aber kein signifikant erhöhtes Pneumonierisiko in Abhängigkeit zur Verletzungsschwere als Polytrauma (ISS) oder zum Grad der Oxygenierungsstörung in den ersten Tagen.
Lactate is an essential component of carbon metabolism in mammals. Recently, lactate was shown to signal through the G protein coupled receptor 81 (GPR81) and to thus modulate inflammatory processes. This study demonstrates that lactate inhibits pro-inflammatory signaling in a GPR81-independent fashion. While lipopolysaccharide (LPS) triggered expression of IL-6 and IL-12 p40, and CD40 in bone marrow-derived macrophages, lactate was able to abrogate these responses in a dose dependent manner in Gpr81-/- cells as well as in wild type cells. Macrophage activation was impaired when glycolysis was blocked by chemical inhibitors. Remarkably, lactate was found to inhibit LPS-induced glycolysis in wild type as well as in Gpr81-/- cells. In conclusion, our study suggests that lactate can induce GPR81-independent metabolic changes that modulate macrophage pro-inflammatory activation.
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 03/2016
(2016)
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 04/2016
(2016)
In the complex network of nuclear hormone receptors, the long non-coding RNAs (lncRNAs) are emerging as critical determinants of hormone action. Here we investigated the involvement of selected cancer-associated lncRNAs in Estrogen Receptor (ER) signaling. Prior studies by Chromatin Immunoprecipitation (ChIP) Sequencing showed that in prostate cancer cells ERs form a complex with the endothelial nitric oxide synthase (eNOS) and that in turn these complexes associate with chromatin in an estrogen-dependent fashion. Among these associations (peaks) we focused our attention on those proximal to the regulatory region of HOTAIR and MALAT1. These transcripts appeared regulated by estrogens and able to control ERs function by interacting with ERα/ERβ as indicated by RNA-ChIP. Further studies performed by ChIRP revealed that in unstimulated condition, HOTAIR and MALAT1 were present on pS2, hTERT and HOTAIR promoters at the ERE/eNOS peaks. Interestingly, upon treatment with17β-estradiol HOTAIR recruitment to chromatin increased significantly while that of MALAT1 was reduced, suggesting an opposite regulation and function for these lncRNAs. Similar results were obtained in cells and in an ex vivo prostate organotypic slice cultures. Overall, our data provide evidence of a crosstalk between lncRNAs, estrogens and estrogen receptors in prostate cancer with important consequences on gene expression regulation.
Background: Archaeal membranes have phytanyl ether lipids instead of common fatty acid-glycerol esters in bacterial and eukaryotic cells. Sulfolobus and Thermoplasma species have unique membrane-spanning tetraether lipids (TEL), which form stable liposomes. Recently, we cultured Thermoplasma species from the Indonesian volcano Tangkuban Perahu and isolated TEL. The purpose of this in vitro study is to investigate the transfer of fluorescent dye from stable TEL liposomes to cultured colon carcinoma cells.
Methods: TEL was extracted from cultured cells with chloroform-methanol (1:1), then it was fractionated and purified via diethylaminoethyl-cellulose-acetate columns and activated charcoal for the formation of stable liposomes. For the fluorescence exchange assay, TEL liposomes were loaded with water-soluble carboxyfluorescein (CF). Staining experiments were conducted with various cell cultures, and T84 colon carcinoma cells were chosen for the main experiments. Liposome stability was tested by light scattering and electron microscopic size determinations as well as by unspecific CF release at low pH (6.0–7.4) and increased temperature (4–50°C/70°C).
Results: TEL liposomes exhibit high stability and extremely low proton permeability at low pH. CF staining of cultured T84 colon carcinoma cells appeares more intensive from TEL liposomes than from dipalmitoylphosphatidylcholine liposomes.
Conclusion: The results of this in vitro study demonstrate CF staining of colon carcinoma cells and high stability of TEL liposomes at low pH, matching the condition in the gastro-intestinal (GI) route and in the urogentital (UG) tract. For this reason, in vivo studies on liposomal fluorescent photosensitizers for topical application of photodynamic cancer therapy in the GI and UG tracts should be carried out.
Nosological delineation of congenital ocular motor apraxia type Cogan : an observational study
(2016)
Background: The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom.
Methods: We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA.
Results: Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups.
Conclusions: Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment.
Introduction: This study reports about antenatal characteristics of Roma minority population. The study was designed to investigate data about health behaviours known to be associated with reproductive outcomes of Roma women that have very good living conditions and relatively high resource availability.
Methods: A retrospective study included 204 Roma and 408 non-Roma hospitalised singleton births that occurred in the Maternity Ward of the General Hospital Virovitica in the period from 1991 to 2010. Data about women’s age, marital status, smoking, reproductive health (abortions, delivery), antenatal care, perinatal complications and gestational age were taken from hospital records and analysed.
Results: Roma women were averagely more than three years younger than non-Roma women, only 10.8% were married. Smoking was more frequent. The average number of births of Roma and non-Roma women was similar, averagely two children per woman. The rate of induced abortions in the Roma women was higher, while the frequency of spontaneous abortions was equal. Inadequate antenatal care of Roma women was associated with two times higher incidence of perinatal complications. A higher frequency of deliveries at home without professional assistance in Roma pregnancy resulted in lower perinatal outcomes. It was confirmed that Roma mothers give birth earlier (38+6 vs. 39+4 weeks) and have a higher incidence of premature births (9.3% vs. 2.2%).
Conclusions: In the comparison of antenatal parameters between the two researched groups, poorer prenatal outcomes in the Roma population were found, despite full integration and considerable improvement in living standards of this ethnic Roma population.
Infectious diseases remain a remarkable health threat for humans and animals. In the past, the epidemiology, etiology and pathology of infectious agents affecting humans and animals have mostly been investigated in separate studies. However, it is evident, that combined approaches are needed to understand geographical distribution, transmission and infection biology of “zoonotic agents”. The genus Bartonella represents a congenial example of the synergistic benefits that can arise from such combined approaches: Bartonella spp. infect a broad variety of animals, are linked with a constantly increasing number of human diseases and are transmitted via arthropod vectors. As a result, the genus Bartonella is predestined to play a pivotal role in establishing a One Health concept combining veterinary and human medicine.
Klinische Frühergebnisse nach endoskopischer Lobektomie (VATS-Lobektomie versus daVinci-Lobektomie)
(2016)
In der vorliegenden Untersuchung wurden zwei operative Techniken zur endoskopischen Lobektomie miteinander hinsichtlich der Frühergebnisse verglichen. In die Untersuchung wurden alle Patienten einbezogen, die an der Abteilung für Thoraxchirurgie der Goethe Universität Frankfurt am Main zwischen April 2010 und Dezember 2012 wegen pulmonaler Karzinome minimal-invasiv lobektomiert wurden. Dabei wurden 34 Patienten einer Roboter-unterstützten Lobektomie sowie 25 Patienten einer VATS-Lobektomie unterzogen.
Es fanden sich keine signifikanten Differenzen in den präoperativen Daten und dem Risikoprofil der Patienten. Auch die intraoperativen Ergebnisse zeigten keine statistisch signifikanten Unterschiede. Postoperativ fand sich eine Tendenz zu höheren Tumorstadien sowie eine geringere Schmerzintensität bei den RATS-Patienten. Die Nachblutungsmenge war bei beiden Verfahren gering. Das klinische Outcome war vergleichbar, ebenso die geringe Morbidität und Komplikationsrate bei den beiden Verfahren.
Weitere Untersuchungen mit höheren Patientenzahlen sind erforderlich, um die Unterschiede zwischen den Verfahren zu untersuchen. Prinzipiell sind beide Verfahren geeignet um Patienten mit nicht-kleinzelligen Lungenkarzinomen in niedrigen Tumorstadien zu operieren.
Zur weiteren Verbesserung der Ergebnisse müssten für die RATS-Lobektomien spezielle Instrumente angefertigt werden. Die derzeit verwendeten Instrumente wurden ursprünglich für Koronargefäße oder urologische Operationen entwickelt, die sich in der Thoraxchirurgie oft als unzureichend erweisen. Zudem ist das Robotersystem stets in Entwicklung. Es sind kürzlich neue Instrumente eingeführt worden wie z.B. Klammernahtgeräte oder Instrumente, die für die automatische Durchtrennung kleinerer Gefäße zuständig sind. Manche Autoren beschreiben den Stapler, der eingesetzt wurde, noch als „mangelhaft“. Aus technischer Sicht fehlt immer noch das taktile Feedback, was jedoch teils durch die Erfahrung des Operateurs und mit Hilfe des 3-Dimensionalen Sehens kompensiert wird.
Diese Arbeit soll den ersten Grundbaustein bezüglich des postoperativen Schmerzmittelverbrauches nach einer videoassistierten- und roboterassoziierten Lobektomie legen. Wir sind uns sicher, dass dieses Thema in Zukunft weiter und noch detaillierter ausgearbeitet wird.
Nach den Studien von Flores und Alam wurden am Ende die Fragen gestellt:
➢ „Kann der Eingriff rein robotisch durchgeführt werden?
➢ Sind Op-Zeiten und Krankenhausaufenthalt kürzer?
➢ Sind die Inzisionen kleiner?
➢ Sind die postoperativen Schmerzen geringer?
➢ Ist das Verfahren billiger?“
Mit dieser vorliegenden Arbeit können die ersten vier Punkte aus der oben erwähnten Studie positiv bestätigt werden. Die Zugangswege sind kleiner bzw. gleich groß. In der Studie Kumar et al. wird ausdrücklich erwähnt, dass jedes Verfahren, welches durch die VATS geführt wird, mit dem Roboter noch besser auszuführen sei. Ein Problem stellen die Kosten dar. Wenn diese ebenfalls gesenkt werden können, würde einer flächendeckenden Verbreitung des Roboterverfahren nichts im Wege stehen. Die daVinci-Lobektomie ist zumindest eine geeignete Alternative im Vergleich zu der VATS-Lobektomie.
ANGIOGENES : knowledge database for protein-coding and noncoding RNA genes in endothelial cells
(2016)
Increasing evidence indicates the presence of long noncoding RNAs (lncRNAs) is specific to various cell types. Although lncRNAs are speculated to be more numerous than protein-coding genes, the annotations of lncRNAs remain primitive due to the lack of well-structured schemes for their identification and description. Here, we introduce a new knowledge database “ANGIOGENES” (http://angiogenes.uni-frankfurt.de) to allow for in silico screening of protein-coding genes and lncRNAs expressed in various types of endothelial cells, which are present in all tissues. Using the latest annotations of protein-coding genes and lncRNAs, publicly-available RNA-seq data was analyzed to identify transcripts that are expressed in endothelial cells of human, mouse and zebrafish. The analyzed data were incorporated into ANGIOGENES to provide a one-stop-shop for transcriptomics data to facilitate further biological validation. ANGIOGENES is an intuitive and easy-to-use database to allow in silico screening of expressed, enriched and/or specific endothelial transcripts under various conditions. We anticipate that ANGIOGENES serves as a starting point for functional studies to elucidate the roles of protein-coding genes and lncRNAs in angiogenesis.
Positive Effekte körperliche Aktivität als komplementäre Therapie in der Onkologie wurden in den letzten Jahren in zahlreichen Studien aufgezeigt. Hierbei zeigte sich ein Anstieg der körperlichen Fitness und Muskelmasse, eine Steigerung der Lebensqualität, eine Reduktion des Fatigue-Syndroms, aber auch eine verbesserte Therapieverträglichkeit sowie einer Rezidiv-Prophylaxe (Backman et al., 2014; Meyerhardt et al., 2006; Segal et al., 2001). Daraufhin wurden Empfehlungen für körperliche Aktivität im Rahmen der onkologischen Therapie ausgesprochen, welche 150 Minuten moderate körperliche Aktivität pro Woche umfassen. Diese Empfehlungen basieren auf entitätsunspezifische Studienkollektive mit meist Tumorstadium I und II. Eine Vielzahl an Studien verdeutlichen, dass gerade Patienten in fortgeschrittenen Tumorstadien mit zahlreichen therapie- sowie tumorbedingten Nebenwirkungen zu kämpfen haben und dadurch ein stärkerer Abbau der körperlichen Fitness, der Muskulatur, aber auch der funktionellen Eigenschaften vorzufinden ist. Hierbei stellen Patienten mit fortgeschrittenen gastrointestinalen Tumoren (GIT) ein stark belastetes Kollektiv dar, da 80 Prozent dieser Patienten eine Tumorkachexie erleiden. Zusätzliche wurde in einer Querschnittsuntersuchung aufgezeigt, dass Patienten mit fortgeschrittenen GIT bereits vor Therapiestart einen deutlich verminderten körperlichen und funktionellen Status im Vergleich zu Mammakarzinom-Patientinnen und Gesunden aufweisen (Stuecher et al., 2016). In der vorliegenden randomisiert kontrollierten Untersuchung wurde erstmals ein heimbasiertes Training ohne Supervision zur Steigerung der körperlichen Aktivität bei Patienten mit fortgeschrittenen GIT durchgeführt und dieses mit einer leitliniengetreuen onkologischen Therapie ohne komplementäre Bewegungstherapie verglichen. Dabei wurden der körperliche und funktionelle Status sowie die Aktivitäten des täglichen Lebens verglichen.
Zweiundvierzig Patienten mit fortgeschrittenen GIT (UICC ≥ III, 67,1 ± 6,8 Jahre, 45,2 % weiblich) wurden vor ihrer geplanten first-line Chemotherapie (CT) in die zweiarmige randomisiert kontrollierte Studie eingeschlossen. Eine der Gruppen (I) erhielt, entsprechend der ACSM-Guidelines für onkologische Patienten, die Vorgabe ein wöchentliches Laufprogramm mit einem Umfang von 150 Minuten moderater Intensität pro Woche. Die zweite Gruppe diente als Kontrollgruppe (K) und erhielt am Ende der Studiendauer entsprechende Empfehlungen. Die Interventionsdurchführung wurde mittels Trainingstagebuch und Pedometer begleitet. Vor Beginn (T0), nach zwei CT-zyklen (T1) sowie nach zwölf Wochen (T2) wurde der funktionelle und körperliche Status sowie die Alltagsbewältigung der Patienten erfasst.
Bei einer Dropoutrate von 36 Prozent konnten 28 (K: 15; I; 13) Patienten die Studie komplett durchlaufen. Die mittlere Adhärenzrate lag bei 81,3 Prozent. Im Untersuchungszeitraum konnten die folgenden sign. Veränderungen (p< 0,05) der einzelnen Parameter gezeigt werden. Die posturale Stabilität (COPLänge) konnte sowohl ein Gruppeneffekt, als auch ein Zeiteffekt nachgewiesen werden. Die Interventionsgruppe verbesserte sich im Zeitraum T0-T1 (-71,47mm) sowie im Gesamtzeitraum T0-T2 (-74,13 mm), wohingegen die Kontrollgruppe sich im Gesamtzeitraum T0-T2 (+72,83) verschlechterte. Die Gruppen unterschieden sich daher sowohl in den Zeiträumen T0-T1 ((K)+38,61; (I)-71,47 mm) sowie T0-T2 ((K)+72,83; (I) -74,13mm). Bezüglich des körperlichen Status konnte sich die Interventionsgruppe von T1-T2 (+4,03 kg) sowie von T0-T2 (+4,04 kg) verbessern, sodass sich die Gruppen zwischen den Zeitpunkten T1-T2 ((K) -0,49; (I)+4,03 kg) und T0-T2 ((K) 0,19; 4,04 kg) unterschieden. Der iADL-Fragebogen erbrachte eine Verbesserung der Interventionsgruppe im Gesamtmesszeitraum T0-T2 (+0,12), daraus resultierte ein zusätzlicher Gruppenunterschied in diesem Zeitraum ((K) -0,89; (I) +0,12). Der Ernährungszustand zeigte auch einen unterschiedlichen Verlauf der beiden Gruppen. Zwischen T1-T2 ((K) -0,59; + 1,74) sowie T0-T2 ((K) -0,55; (I) +2,39) unterschieden sich die Gruppen.
Obgleich es für einige Patienten schwierig war die Laufintervention gemäß den Empfehlungen durchzuführen, weisen die Teilnehmer der Interventionsgruppe sowohl in den Parametern des körperlichen, als auch des funktionellen Status Verbesserungen auf. Demnach scheint ein durchschnittlicher Umfang von zwei Stunden moderater körperlicher Aktivität während einer Tumortherapie ausreichend zu sein. Es veranschaulicht, dass eine komplementäre Bewegungstherapie in der onkologischen Therapie bei Patienten mit fortgeschrittenen GIT sinnvoll ist und sowohl einen Benefit in der Körperzusammensetzung, als auch der funktionellen Eigenschaften mitsichbringt. Dies hat wiederum einen positiven Einfluss auf die Alltagsbewältigung. Da einige Barrieren das Laufprogramm der Patienten einschränkten oder gar zum Laufabbruch führten, sollte versucht werden diese zu mindern. Hierbei sind vor allem klima- und wetterbedingte Barrieren ein möglicher Ansatzpunkt, da Nebenwirkungen kaum vermeidbar sind. Dennoch sollten die Patienten auch nach nebenwirkungsbedingten Laufpausen motiviert werden das Programm weiterzuführen. Diese Studie gibt zudem erste Hinweise, dass durch eine komplementäre Bewegungstherapie mit moderater körperlicher Aktivität die Toxizität der CT bei Patienten mit fortgeschrittenen GIT vermindert werden kann. Da der klinische Benefit, welcher in einigen Studien anderer Tumorentitäten postuliert wurde, in dieser Untersuchung nicht objektiv erfasst wurde, wäre dies ein möglicher Ansatzpunkt für Folgestudien.
Long noncoding RNAs (lncRNAs) are non-protein coding RNAs regulating gene expression. Although for some lncRNAs a relevant role in hypoxic endothelium has been shown, the regulation and function of lncRNAs is still largely unknown in the vascular physio-pathology. Taking advantage of next-generation sequencing techniques, transcriptomic changes induced by endothelial cell exposure to hypoxia were investigated. Paired-end sequencing of polyadenylated RNA derived from human umbilical vein endothelial cells (HUVECs) exposed to 1% O2 or normoxia was performed. Bioinformatics analysis identified ≈2000 differentially expressed genes, including 122 lncRNAs. Extensive validation was performed by both microarray and qPCR. Among the validated lncRNAs, H19, MIR210HG, MEG9, MALAT1 and MIR22HG were also induced in a mouse model of hindlimb ischemia. To test the functional relevance of lncRNAs in endothelial cells, knockdown of H19 expression was performed. H19 inhibition decreased HUVEC growth, inducing their accumulation in G1 phase of the cell cycle; accordingly, p21 (CDKN1A) expression was increased. Additionally, H19 knockdown also diminished HUVEC ability to form capillary like structures when plated on matrigel. In conclusion, a high-confidence signature of lncRNAs modulated by hypoxia in HUVEC was identified and a significant impact of H19 lncRNA was shown.
Background: Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating a variety of physiological and pathological functions. However, their implication in heart failure is still largely unknown. The aim of this study is to identify and characterize lncRNAs deregulated in patients affected by ischemic heart failure.
Methods: LncRNAs were profiled and validated in left ventricle biopsies of 18 patients affected by non end-stage dilated ischemic cardiomyopathy and 17 matched controls. Further validations were performed in left ventricle samples derived from explanted hearts of end-stage heart failure patients and in a mouse model of cardiac hypertrophy, obtained by transverse aortic constriction. Peripheral blood mononuclear cells of heart failure patients were also analyzed. LncRNA distribution in the heart was assessed by in situ hybridization. Function of the deregulated lncRNA was explored analyzing the expression of the neighbor mRNAs and by gene ontology analysis of the correlating coding transcripts.
Results: Fourteen lncRNAs were significantly modulated in non end-stage heart failure patients, identifying a heart failure lncRNA signature. Nine of these lncRNAs (CDKN2B-AS1/ANRIL, EGOT, H19, HOTAIR, LOC285194/TUSC7, RMRP, RNY5, SOX2-OT and SRA1) were also confirmed in end-stage failing hearts. Intriguingly, among the conserved lncRNAs, h19, rmrp and hotair were also induced in a mouse model of heart hypertrophy. CDKN2B-AS1/ANRIL, HOTAIR and LOC285194/TUSC7 showed similar modulation in peripheral blood mononuclear cells and heart tissue, suggesting a potential role as disease biomarkers. Interestingly, RMRP displayed a ubiquitous nuclear distribution, while H19 RNA was more abundant in blood vessels and was both cytoplasmic and nuclear. Gene ontology analysis of the mRNAs displaying a significant correlation in expression with heart failure lncRNAs identified numerous pathways and functions involved in heart failure progression.
Conclusions: These data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF.
Der 21. Mai 2015 ist für Claudia und Timothy Pillar ein besonderer Tag. Seitdem verbindet das Paar mehr als die Erlebnisse einer fast vierzigjährigen Ehe und ein gemeinsamer Sohn. Tim Pillar hat seiner Frau eine Niere gespendet und ihr damit wieder ein (fast) normales Leben ermöglicht. Inzwischen spricht sie von ihrer Krankheit in der Vergangenheitsform.
Organspenden retten und verlängern Leben : Prof. Dr. Ingeborg Hauser im Interview mit Dr. Anne Hardy
(2016)
This position paper is the second ESCMID Consensus Document on this subject and aims to provide intensivists, infectious disease specialists, and emergency physicians with a standardized approach to the management of serious travel-related infections in the intensive care unit (ICU) or the emergency department. This document is a cooperative effort between members of two European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study groups and was coordinated by Hakan Leblebicioglu and Jordi Rello for ESGITM (ESCMID Study Group for Infections in Travellers and Migrants) and ESGCIP (ESCMID Study Group for Infections in Critically Ill Patients), respectively. A relevant expert on the subject of each section prepared the first draft which was then edited and approved by additional members from both ESCMID study groups. This article summarizes considerations regarding clinical syndromes requiring ICU admission in travellers, covering immunocompromised patients.
BACKGROUND: Polyclonal anti-thymocyte globulins (ATGs) are immunosuppressive drugs widely used in induction of immunosuppression and treatment of acute rejection after solid organ transplantation. We have previously demonstrated that ATGs bind to endothelial cells in vitro, and are able to modulate ECs. The aim of this study was to investigate the binding of ATGs to endothelial cells under in vivo conditions.
MATERIAL AND METHODS: Muscle biopsies from extremities of cynomolgus monkeys were obtained after ischemia/reperfusion at 4°C. ATGs (Thymoglobulin, Sanofi-Aventis, France; 1 mg/kg) were added to the blood 30 min prior to the reperfusion. Biopsies (n=10) of patients undergoing heart transplantation and preoperatively treated with ATGs (Thymoglobulin, Sanofi-Aventis, France; 1.5 mg/kg) as induction therapy were also analyzed 6 hours and 7 days after induction. Binding of ATGs to ECs was analyzed with an anti-rabbit IgG antibody by means of immunohistochemistry.
RESULTS: Binding of ATGs to endothelial cells could be demonstrated in vivo in our animal experiments 4 hours after reperfusion, as well as in the clinical biopsies 6 hours after induction of immunosuppression in heart transplant patients, showing a preferred localization in post-capillary veins. No expression of ATGs on the endothelial surface could be observed after 7 days, suggesting that ATGs may be washed out from the endothelial surface in a time-dependent manner.
CONCLUSIONS: Our results show that ATGs are able to bind to endothelial cells in an experimental model and in clinical practice, supporting preconditioning strategies with ATGs in solid organ transplantation.
Bone losses are common as a consequence of unloading and also in patients with chronic obstructive pulmonary disease (COPD). Although hypoxia has been implicated as an important factor to drive bone loss, its interaction with unloading remains unresolved. The objective therefore was to assess whether human bone loss caused by unloading could be aggravated by chronic hypoxia.
In a cross-over designed study, 14 healthy young men underwent 21-day interventions of bed rest in normoxia (NBR), bed rest in hypoxia (HBR), and hypoxic ambulatory confinement (HAmb). Hypoxic conditions were equivalent to 4000 m altitude. Bone metabolism (NTX, P1NP, sclerostin, DKK1) and phospho-calcic homeostasis (calcium and phosphate serum levels and urinary excretion, PTH) were assessed from regular blood samples and 24-hour urine collections, and tibia and femur bone mineral content was assessed by peripheral quantitative computed tomography (pQCT).
Urinary NTX excretion increased (P < 0.001) to a similar extent in NBR and HBR (P = 0.69) and P1NP serum levels decreased (P = 0.0035) with likewise no difference between NBR and HBR (P = 0.88). Serum total calcium was increased during bed rest by 0.059 (day D05, SE 0.05 mM) to 0.091 mM (day D21, P < 0.001), with no additional effect by hypoxia during bed rest (P = 0.199). HAmb led, at least temporally, to increased total serum calcium, to reduced serum phosphate, and to reduced phosphate and calcium excretion.
In conclusion, hypoxia did not aggravate bed rest-induced bone resorption, but led to changes in phospho-calcic homeostasis likely caused by hyperventilation. Whether hyperventilation could have mitigated the effects of hypoxia in this study remains to be established.
The effects of acute physical exercise on memory, peripheral BDNF, and cortisol in young adults
(2016)
In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.
Objective: To estimate health status utility (preference) weights for hereditary angioedema (HAE) during an attack and between attacks using data from the Hereditary Angioedema Burden of Illness Study in Europe (HAE-BOIS-Europe) survey. Utility measures quantitatively describe the net impact of a condition on a patient’s life; a score of 0.0 reflects death and 1.0 reflects full health.
Study design and methods: The HAE-BOIS-Europe was a cross-sectional survey conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE from the patient perspective. Survey items that overlapped conceptually with the EuroQol 5-Dimensions (EQ-5D) domains (pain/discomfort, mobility, self-care, usual activities, and anxiety/depression) were manually crosswalked to the corresponding UK population-based EQ-5D utility weights. EQ-5D utilities were computed for each respondent in the HAE-BOIS-Europe survey for acute attacks and between attacks.
Results: Overall, a total of 111 HAE-BOIS-Europe participants completed all selected survey items and thus allowed for computation of EQ-5D-based utilities. The mean utilities for an HAE attack and between attacks were 0.44 and 0.72, respectively. Utilities for an acute attack were dependent on the severity of pain of the last attack (0.61 for no pain or mild pain, 0.47 for moderate pain, and 0.08 for severe pain). There were no significant differences across countries. Mean utilities derived from the study approach compare sensibly with other disease states for both acute attacks and between attacks.
Conclusion: The impacts of HAE translate into substantial health status disutilities associated with acute attacks as well as between attacks, documenting that the detrimental effects of HAE are meaningful from the patient perspective. Results were consistent across countries with regard to pain severity and in comparison to similar disease states. The results can be used to raise awareness of HAE as a serious disease with wide-ranging personal and social impacts.
The Escherichia coli sensor kinase EnvZ modulates porin expression in response to various stimuli, including extracellular osmolarity, the presence of procaine and interaction with an accessory protein, MzrA. Two major outer membrane porins, OmpF and OmpC, act as passive diffusion-limited pores that allow compounds, including certain classes of antibiotics such as β-lactams and fluoroquinolones, to enter the bacterial cell. Even though the mechanisms by which EnvZ detects and processes the presence of various stimuli are a fundamental component of microbial physiology, they are not yet fully understood. Here, we assess the role of TM1 during signal transduction in response to the presence of extracellular osmolarity. Various mechanisms of transmembrane communication have been proposed including rotation of individual helices within the transmembrane domain, dynamic movement of the membrane-distal portion of the cytoplasmic domain and regulated intra-protein unfolding. To assess these possibilities, we have created a library of single-Cys-containing EnvZ proteins in order to facilitate sulfhydryl-reactivity experimentation. Our results demonstrate that the major TM1-TM1' interface falls along a single surface consisting of residue positions 19, 23, 26, 30 and 34. In addition, we show that Cys substitutions within the N- and C-terminal regions of TM1 result in drastic changes to EnvZ signal output. Finally, we demonstrate that core residues within TM1 are responsible for both TM1 dimerisation and maintenance of steady-state signal output. Overall, our results suggest that no major rearrangement of the TM1-TM1' interface occurs during transmembrane communication in response to extracellular osmolarity. We conclude by discussing these results within the frameworks of several proposed models for transmembrane communication.
Introduction: Sepsis remains associated with a high mortality rate. Endotoxin has been shown to influence viscoelastic coagulation parameters, thus suggesting a link between endotoxin levels and the altered coagulation phenotype in septic patients. This study evaluated the effects of systemic polyspecific IgM-enriched immunoglobulin (IgM-IVIg) (Pentaglobin® [Biotest, Dreieich, Germany]) on endotoxin activity (EA), inflammatory markers, viscoelastic and conventional coagulation parameters.
Methods: Patients with severe sepsis were identified by daily screening in a tertiary, academic, surgical ICU. After the inclusion of 15 patients, the application of IgM-IVIg (5 mg/kg/d over three days) was integrated into the unit’s standard operation procedure (SOP) to treat patients with severe sepsis, thereby generating “control” and “IgM-IVIg” groups. EA assays, thrombelastometry (ROTEM®) and impedance aggregometry (Multiplate®) were performed on whole blood. Furthermore, routine laboratory parameters were determined according to unit’s standards.
Results: Data from 26 patients were included. On day 1, EA was significantly decreased in the IgM-IVIg group following 6 and 12 hours of treatment (0.51 ±0.06 vs. 0.26 ±0.07, p<0.05 and 0.51 ±0.06 vs. 0.25 ±0.04, p<0.05) and differed significantly compared with the control group following 6 hours of treatment (0.26 ±0.07 vs. 0.43 ±0.07, p<0.05). The platelet count was significantly higher in the IgM-IVIg group following four days of IgM-IVIg treatment (200/nl ±43 vs. 87/nl ±20, p<0.05). The fibrinogen concentration was significantly lower in the control group on day 2 (311 mg/dl ±37 vs. 475 mg/dl ±47 (p = 0.015)) and day 4 (307 mg/dl ±35 vs. 420 mg/dl ±16 (p = 0.017)). No differences in thrombelastometric or aggregometric measurements, or inflammatory markers (interleukin-6 (IL-6), leukocyte, lipopolysaccharide binding protein (LBP)) were observed.
Conclusion: Treatment with IgM-enriched immunoglobulin attenuates the EA levels in patients with severe sepsis and might have an effect on septic thrombocytopenia and fibrinogen depletion. Viscoelastic, aggregometric or inflammatory parameters were not influenced.
The aim of this clinical study was to describe the quality of posterior composite restorations (n = 329) performed on a group of patients (n=219) during an observation period of three years at various intervals (6, 12, 18, 24 and 36 months) after application.
The parameters were assessed both In vivo and In vitro using clinical examinations, impressions and photography according to modified FDI criteria. For the statistical analysis of the results, the Wilcoxon test with a significance level of p = 0.05 was applied.
After three years, In vivo five from the seven parameters exhibited significant changes. Only "retention" and "approximal contact" remained unchanged. In vitro studied parameters "anatomical form", "occlusal contour/wear" and "approximal contact" did not result in any significant changes, however "marginal adaptation", "surface luster" and "overhangs" deteriorated significantly.
In summary, the results of this study show that composite posterior restorations were clinically acceptable in terms of specific parameters. However, unsatisfactory results have arisen in relation to the handling of composites, stated In vivo and In vitro especially in the reconstruction of the marginal adaptation, surface and overfilling.
Background: Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring.
Methods: In this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis.
Results: Besides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment.
Conclusions: Extended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring.
The ubiquitin-binding zinc finger (UBZ) is a type of zinc-coordinating β-β-α fold domain found mainly in proteins involved in DNA repair and transcriptional regulation. Here, we report the crystal structure of the UBZ domain of Y-family DNA polymerase (pol) η and the crystal structure of the complex between the UBZ domain of Werner helicase-interacting protein 1 (WRNIP1) and ubiquitin, crystallized using the GFP fusion technique. In contrast to the pol η UBZ, which has been proposed to bind ubiquitin via its C-terminal α-helix, ubiquitin binds to a novel surface of WRNIP1 UBZ composed of the first β-strand and the C-terminal α-helix. In addition, we report the structure of the tandem UBZ domains of Tax1-binding protein 1 (TAX1BP1) and show that the second UBZ of TAX1BP1 binds ubiquitin, presumably in a manner similar to that of WRNIP1 UBZ. We propose that UBZ domains can be divided into at least two different types in terms of the ubiquitin-binding surfaces: the pol η type and the WRNIP1 type.
Estimates suggest that more than 25,000 to 125,000 people die annually from snakebite envenomation worldwide. In contrast to this major disease burden, thorough bibliometric studies do not exist so far that illustrate the overall research activity over a long time span. Therefore, the NewQIS-platform conducted an analysis on snakebite envenoming using the Thomson Reuters database Web of Science. To determine and assess changes regarding the scientific activities and to specifically address the more recent situation we analyzed two time intervals (t). During the first time interval from 1900 to 2007 (t1) 13,015 publications (p) were identified. In the following period (2008–2016 = t2) 4,982 publications were identified by the same search strategy. They originate from 114 (t1) respectively 121 countries (t2), with the USA (p = 3518), Brazil (p = 1100) and Japan (p = 961) being most productive in the first period, and the USA (p = 1087), Brazil (p = 991) and China (p = 378) in the second period, respectively. Setting the publication numbers in relation to GDP/capita, Brazil leads with 92 publications per 10,000 Int$GDP/capita, followed by India with 79 publications per 10000 Int$GDP/capita (t1). Comparing the country’s publication activity with the Human Development Index level indicates that the majority of the publications is published by highly developed countries. When calculating the average citation rates (citations per published item = CR) mainly European countries show the highest ranks: From 1900–2007 Sweden ranks first with a CR = 27, followed by the Netherlands (CR = 24.8), Switzerland (CR = 23), Spain, Austria and the USA (CR = 22). From 2008 to 2016 the highest rate achieves Switzerland with a value of 24.6, followed by Belgium (CR = 18.1), Spain (CR = 16.7), Costa Rica (CR = 14.9) and Netherlands (CR = 14). Compared with this, the USA was placed at rank 13 (CR = 9,5).
In summary, the present study represents the first density-equalizing map projection and in-depth scientometric analysis of the global research output on snakebites and its venoms. So it draws a sketch of the worldwide publication architecture and indicates that countries with a high incidence of snakebites and a low economical level still need to be empowered in carrying out research in this area.
The current intense political and public debate about the financing system for academic medicine in Germany lacks one major argument concerning the output of university hospitals and medical faculties. The following research project presents an economic discussion about the benefits of Academic Medicine Frankfurt am Main by determining the value-added, employment and tax effects for public authorities in addition to the pre-economic effects in 10 identified performance areas, with three core areas: teaching, patient care and research.