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Background: Subarachnoid hemorrhage (SAH) is mainly caused by ruptured cerebral aneurysms but in up to 15% of patients with SAH no bleeding source could be identified. Our objective was to analyze patient characteristics, clinical outcome and prognostic factors in patients suffering from non-aneurysmal SAH.
Methods: From 1999 to 2009, data of 125 patients with non-aneurysmal SAH were prospectively entered into a database. All patients underwent repetitive cerebral angiography. Outcome was assessed according to the modified Rankin Scale (mRS) (mRS 0-2 favorable vs. 3-6 unfavorable). Also, patients were divided in two groups according to the distribution of blood in the CT scan (perimesencephalic and non-perimesencephalic SAH).
Results: 106 of the 125 patients were in good WFNS grade (I-III) at admission (85%). Overall, favorable outcome was achieved in 104 of 125 patients (83%). Favorable outcome was associated with younger age (P < 0.001), good admission status (P < 0.0001), and absence of hydrocephalus (P = 0.001).73 of the 125 patients suffered from perimesencephalic SAH, most patients (90%) were in good grade at admission, and 64 achieved favorable outcome.52 of the 125 patients suffered from non-perimesencephalic SAH and 40 were in good grade at admission. Also 40 patients achieved favorable outcome.
Conclusions: Patients suffering from non-aneurysmal SAH have better prognosis compared to aneurysm related SAH and poor admission status was the only independent predictor of unfavorable outcome in the multivariate analysis. Patients with a non-perimesencephalic SAH have an increased risk of a worse neurological outcome. These patients should be monitored attentively.
Background: Hereditary angioedema (HAE) due to C1 inhibitor deficiency is a rare but serious and potentially life-threatening disease marked by spontaneous, recurrent attacks of swelling. The study objective was to characterize direct and indirect resource utilization associated with HAE from the patient perspective in Europe.
Methods: The study was conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE via a cross-sectional survey of HAE patients, including direct and indirect resource utilization during and between attacks for patients and their caregivers over the past 6 months. A regression model examined predictors of medical resource utilization.
Results: Overall, 164 patients had an attack in the past 6 months and were included in the analysis. The most significant predictor of medical resource utilization was the severity of the last attack (OR 2.6; p < 0.001). Among patients who sought medical care during the last attack (23%), more than half utilized the emergency department. The last attack prevented patients from their normal activities an average of 4-12 hours. Patient and caregiver absenteeism increased with attack severity and frequency. Among patients who were working or in school (n = 120), 72 provided work/school absenteeism data, resulting in an estimated 20 days missing from work/school on average per year; 51% (n = 84) indicated that HAE has hindered their career/educational advancement.
Conclusion: HAE poses a considerable burden on patients and their families in terms of direct medical costs and indirect costs related to lost productivity. This burden is substantial at the time of attacks and in between attacks.
Background: Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed.
Methods: We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients.
Results: We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b.
Conclusions: In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype.
Modeling the effects of neuronal morphology on dendritic chloride diffusion and GABAergic inhibition
(2014)
Poster presentation at the Twenty Third Annual Computational Neuroscience Meeting: CNS*2014 Québec City, Canada. 26-31 July 2014.
Gamma-aminobutyric acid receptors (GABAARs) are ligand-gated chloride (Cl−) channels which mediate the majority of inhibitory neurotransmission in the CNS. Spatiotemporal changes of intracellular Cl− concentration alter the concentration gradient for Cl− across the neuronal membrane and thus affect the current flow through GABAARs and the efficacy of GABAergic inhibition. However, the impact of complex neuronal morphology on Cl− diffusion and the redistribution of intracellular Cl− is not well understood. Recently, computational models for Cl− diffusion and GABAAR-mediated inhibition in realistic neuronal morphologies became available [1-3]. Here we have used computational models of morphologically complex dendrites to test the effects of spines on Cl− diffusion. In all dendritic morphologies tested, spines slowed down longitudinal Cl− diffusion along dendrites and decreased the amount and spatial spread of synaptically evoked Cl− changes. Spine densities of 2-10 spines/µm decreased the longitudinal diffusion coefficient of Cl− to 80-30% of its value in smooth dendrites, respectively. These results suggest that spines are able to limit short-term ionic plasticity [4] at dendritic GABAergic synapses.
Poster presentation at The Twenty Third Annual Computational Neuroscience Meeting: CNS*2014 Québec City, Canada. 26-31 July 2014: We study random strongly heterogeneous recurrent networks of firing rate neurons, introducing the notion of cohorts: groups of co-active neurons, who compete for firing with one another and whose presence depends sensitively on the structure of the input. The identities of neurons recruited to and dropped from an active cohort changes smoothly with varying input features. We search for network parameter regimes in which the activation of cohorts is robust yet easily switchable by the external input and which exhibit large repertoires of different cohorts. We apply these networks to model the emergence of orientation and direction selectivity in visual cortex. We feed these random networks with a set of harmonic inputs that vary across neurons only in their temporal phase, mimicking the feedforward drive due to a moving grating stimulus. The relationship between the phases that carries the information about the orientation of the stimulus determines which cohort of neurons is activated. As a result the individual neurons acquire non-monotonic orientation tuning curves which are characterized by high orientation and direction selectivity. This mechanism of emergence for direction selectivity differs from the classical motion detector scheme, which is based on the nonlinear summation of the time-shifted inputs. In our model these two mechanisms coexist in the same network, but can be distinguished by their different frequency and contrast dependences. In general, the mechanism we are studying here converts temporal phase sequence into population activity and could therefore be used to extract and represent also various other relevant stimulus features.
Understanding the diverging opinions of academic experts, stakeholders and the public is important for effective conservation management. This is especially so when a consensus is needed for action to minimize future risks but the knowledge upon which to base this action is uncertain or missing. How to manage non-native, invasive species (NIS) is an interesting case in point: the issue has long been controversial among stakeholders, but publicly visible, major disagreement among experts is recent. To characterize the multitude of experts’ understanding and valuation of non-native, NIS we performed structured qualitative interviews with 26 academic experts, 13 of whom were invasion biologists and 13 landscape experts. Within both groups, thinking varied widely, not only about basic concepts (e.g., non-native, invasive) but also about their valuation of effects of NIS. The divergent opinions among experts, regarding both the overall severity of the problem in Europe and its importance for ecosystem services, contrasted strongly with the apparent consensus that emerges from scientific synthesis articles and policy documents. We postulate that the observed heterogeneity of expert judgments is related to three major factors: (1) diverging conceptual understandings, (2) lack of empirical information and high scientific uncertainties due to complexities and contingencies of invasion processes, and (3) missing deliberation of values. Based on theory from science studies, we interpret the notion of an NIS as a boundary object, i.e., concepts that have a similar but not identical meaning to different groups of experts and stakeholders. This interpretative flexibility of a concept can facilitate interaction across diverse groups but bears the risk of introducing misunderstandings. An alternative to seeking consensus on exact definitions and risk assessments would be for invasive species experts to acknowledge uncertainties and engage transparently with stakeholders and the public in deliberations about conflicting opinions, taking the role of honest brokers of policy alternatives rather than of issue advocates.
Climate is frequently used to predict the outcome of species introductions based on the results from species distribution models (SDMs). However, despite the widespread use of SDMs for pre- and post-border risk assessments, data that can be used to validate predictions is often not available until after an invasion has occurred. Here we explore the potential for using historical forestry trials to assess the performance of climate-based SDMs. SDMs were parameterized based on the native range distribution of 36 Australian acacias, and predictions were compared against both the results of 150 years of government forestry trials, and current invasive distribution in southern Africa using true skill statistic, sensitivity and specificity. Classification tree analysis was used to evaluate why some Australian acacias failed in trials while others were successful. Predicted suitability was significantly related to the invaded range (sensitivity = 0.87) and success in forestry trials (sensitivity = 0.80), but forestry trial failures were under-predicted (specificity = 0.35). Notably, for forestry trials, the success in trials was greater for species invasive somewhere in the world. SDM predictions also indicate a considerable invasion potential of eight species that are currently naturalized but not yet widespread. Forestry trial data clearly provides a useful additional source of data to validate and refine SDMs in the context of risk assessment. Our study identified the climatic factors required for successful invasion of acacias, and accentuates the importance of integration of status elsewhere for risk assessment.
A hybrid form of tilapia was introduced into Port Sulphur, Louisiana and was subsequently managed by treatment with rotenone and stocking of native predatory fishes. Measurements of tilapia from before this management event were compared to measurements of tilapia in the two years after the treatment. Post-management tilapia were consistently deeper in body and had greater weight per unit length (condition) when compared to pre-management fish. Procrustes generalized least squares data supported this by consistently finding post-management tilapia to be consistently deeper in body and head shape than pre-management fish. Although this could indicate the effectiveness of stocking native predators, several other factors, including two cold winters, seasonal effects, and less competition, may have contributed to this result.
NeoBiota, Volume 22 (2014)
(2014)
NeoBiota, Volume 21 (2014)
(2014)
NeoBiota, Volume 20 (2014)
(2014)
Tuning and optimization of the field distribution for 4-rod radio frequency quadrupole linacs
(2014)
In this thesis, the tuning process of the 4-rod Radio Frequency Quadrupole has been analyzed and a theory for the prediction of the tuning plate's influence on the longitudinal voltage distribution was developed together with RF design options for the optimization of the fringe fields.
The basic principles of the RFQ's particle dynamics and resonant behavior are introduced in the theory part of this thesis. All studies that are presented are based on the work on four RFQs of recent linac projects. These RFQs are described in one chapter. Here, the projects are introduced together with details about the RFQ parameters and performance. In the meantime two of these RFQs are in full operation at NSCL at MSU and FNAL. One is operating in the test phase of the MedAustron Cancer Therapy Center and the fourth one for LANL is about to be built. The longitudinal voltage distribution has been studied in detail with a focus on the influence of the RF design with tuning elements and parameters like the electrodes overlap or the distance between stems. The theory for simulation methods for the field flatness that were developed as part of this thesis, as well as its simulation with CST MWS have been analyzed and compared to measurements. The lumped circuit model has proven to predict results with an accuracy that can be used in the tuning process of 4-rod RFQs. Together with results from the tuning studies, the studies on the fringe fields of the 4-rod structure lead to a proposal for a 4-rod RFQ model with an improved field distribution in the transverse and longitudinal electric field.
Ribosome biogenesis in yeast requires 75 small nucleolar RNAs (snoRNAs) and a myriad of cofactors for processing, modification, and folding of the ribosomal RNAs (rRNAs). For the 19 RNA helicases implicated in ribosome synthesis, their sites of action and molecular functions have largely remained unknown. Here, we have used UV cross-linking and analysis of cDNA (CRAC) to reveal the pre-rRNA binding sites of the RNA helicase Rok1, which is involved in early small subunit biogenesis. Several contact sites were identified in the 18S rRNA sequence, which interestingly all cluster in the “foot” region of the small ribosomal subunit. These include a major binding site in the eukaryotic expansion segment ES6, where Rok1 is required for release of the snR30 snoRNA. Rok1 directly contacts snR30 and other snoRNAs required for pre-rRNA processing. Using cross-linking, ligation and sequencing of hybrids (CLASH) we identified several novel pre-rRNA base-pairing sites for the snoRNAs snR30, snR10, U3, and U14, which cluster in the expansion segments of the 18S rRNA. Our data suggest that these snoRNAs bridge interactions between the expansion segments, thereby forming an extensive interaction network that likely promotes pre-rRNA maturation and folding in early pre-ribosomal complexes and establishes long-range rRNA interactions during ribosome synthesis.
Expressivist theories of punishment, according to which a penal sanction articulates or expresses a certain meaning to the offender, to the victim and to society, become more and more prominent among the traditional theories of punishment as retribution or deterrence. What these theories have in common is the idea that the conveyance of the meaning is in need of a communicative action, and that the penal sanction is such a communicative act. This article argues that pure communicative theories of punishment face great difficulties in generating any justification for hard treatment. One challenge is that certain types of sanctions – in particularly, hard treatment – restrict the communicative opportunities of the incarcerated individual; which generates a paradox, in that it turns punishment into a communicative action of non-communication. Beyond that, moreover, all practices of hard treatment potentially become unnecessary, if expressing the moral message of censure constitutes a kind of action in itself, and as such, itself a treatment of the offender, embedded in a communicative relationship between offender, victim and society; such that we may be able to think of the history of punishment as a development where hard treatment becomes more and more unnecessary for the conveyance of the message.
Fast nuclei are ionizing radiation which can cause deleterious effects to irradiated cells. The modelling of the interactions of such ions with matter and the related effects are very important to physics, radiobiology, medicine and space science and technology. A powerful method to study the interactions of ionizing radiation with biological systems was developed in the field of microdosimetry. Microdosimetry spectra characterize the energy deposition to objects of cellular size, i.e., a few micrometers.
In the present thesis the interaction of ions with tissue-like media was investigated using the Monte Carlo model for Heavy-Ion Therapy (MCHIT) developed at the Frankfurt Institute for Advanced Studies. MCHIT is a Geant4-based application intended to benchmark the physical models of Geant4 and investigate the physical properties of therapeutic ion beams. We have implemented new features in MCHIT in order to calculate microdosimetric quantities characterizing the radiation fields of accelerated nucleons and nuclei. The results of our Monte Carlo simulations were compared with recent experimental microdosimetry data.
In addition to microdosimetry calculations with MCHIT, we also investigated the biological properties of ion beams, e.g. their relative biological effectiveness (RBE), by means of the modified Microdosimetric-Kinetic model (MKM). The MKM uses microdosimetry spectra in describing cell response to radiation. MCHIT+MKM allowed us to study the physical and biological properties of ion beams. The main results of the thesis are as follows:
MCHIT is able to describe the spatial distribution of the physical dose in tissue-like media and microdosimetry spectra for ions with energies relevant to space research and ion-beam cancer therapy; MCHIT+MKM predicts a reduction of the biological effectiveness of ions propagating in extended medium due to nuclear fragmentation reactions; We predicted favourable biological dose-depth profiles for monoenergetic helium and lithium beams similar to the one for carbon beam. Well-adjusted biological dose distributions for H-1, He-4, C-12 and O-16 with a very flat spread-out Bragg peak (SOBP) plateau were calculated with MCHIT+MKM; MCHIT+MKM predicts less damage to healthy tissues in the entrance channel for SOBP He-4 and C-12 beams compared to H-1 and O-16 ones. No definitive advantages for oxygen ions with respect to carbon were found.
Bei ca. 95% der chronisch myeloischen Leukämie (CML) und 20-30% der akuten lymphatischen Leukämie (ALL) des Erwachsenen liegt eine reziproke Chromosomentranslokation t(9;22)(q34;q11) vor, in deren Rahmen das BCR (Breakpoint Cluster Region) Gen auf Chromosom 22 mit dem ABL (Abelson-Leukämie-Virus) Gen auf Chromosom 9 fusioniert. Auf Chromosom 22 gibt es zwei verschiedene Bruchpunkte, die somit zur Bildung von unterschiedlichen Fusionsgenen führen. Bei der CML findet man den sogenannten „großen“ Bruchpunkt (M-bcr), während bei der Ph+ ALL der sogenannte „kleine“ Bruchpunkt (m-bcr) vorkommt. Das hybride Fusionsgen auf Chromosom 22q+ (Philadelphia-Chromosom) kodiert für das jeweilige BCR/ABL Protein, während das Fusionsgen auf Chromosom 9q+ für das reziproke ABL/BCR Protein kodiert. Das ABL-Protein ist eine Nicht-Rezeptor Tyrosinkinase, die eine wichtige Rolle in der Signaltransduktion und der Regulation des Zellwachstums spielt. Im BCR/ABL Fusionsprotein wird die Kinase-Aktivität von ABL, die im Normalfall streng reguliert ist, durch die Fusion mit BCR konstitutiv aktiv. Dadurch kommt es zur Deregulierung intrazellulärer Signalwege, welche die maligne Transformation hämatopoetischer Zellen verursacht. Eine zielgerichtete Inhibierung von BCR/ABL mittels ABL-Kinase-Inhibitoren induziert Apoptose in BCR/ABL transformierten Zellen, was eine komplette Remission im größten Teil Ph+ Leukämie Patienten zur Folge hat.
Na+/H+ antiporters are integral membrane proteins that are present in almost every cell and in every kingdom of life. They are essential for the regulation of intracellular pH-value, Na+-concentration and cell volume. These secondary active transporters exchange sodium ions against protons via an alternating access mechanism, which is not understood in full detail. Na+/H+ antiporters show distinct species-specific transport characteristics and regulatory properties that correlate with respective physiological functions. Here we present the characterization of the Na+/H+ antiporter NhaA from Salmonella enterica serovar Thyphimurium LT2, the causing agent of food-born human gastroenteritis and typhoid like infections. The recombinant antiporter was functional in vivo and in vitro. Expression of its gene complemented the Na+-sensitive phenotype of an E. coli strain that lacks the main Na+/H+ antiporters. Purified to homogeneity, the antiporter was a dimer in solution as accurately determined by size-exclusion chromatography combined with multi-angle laser-light scattering and refractive index monitoring. The purified antiporter was fully capable of electrogenic Na+(Li+)/H+-antiport when reconstituted in proteoliposomes and assayed by solid-supported membrane-based electrophysiological measurements. Transport activity was inhibited by 2-aminoperimidine. The recorded negative currents were in agreement with a 1Na+(Li+)/2H+ stoichiometry. Transport activity was low at pH 7 and up-regulation above this pH value was accompanied by a nearly 10-fold decrease of KmNa (16 mM at pH 8.5) supporting a competitive substrate binding mechanism. K+ does not affect Na+ affinity or transport of substrate cations, indicating that selectivity of the antiport arises from the substrate binding step. In contrast to homologous E. coli NhaA, transport activity remains high at pH values above 8.5. The antiporter from S. Typhimurium is a promising candidate for combined structural and functional studies to contribute to the elucidation of the mechanism of pH-dependent Na+/H+ antiporters and to provide insights in the molecular basis of species-specific growth and survival strategies.
Colors and odors are associated; for instance, people typically match the smell of strawberries to the color pink or red. These associations are forms of crossmodal correspondences. Recently, there has been discussion about the extent to which these correspondences arise for structural reasons (i.e., an inherent mapping between color and odor), statistical reasons (i.e., covariance in experience), and/or semantically-mediated reasons (i.e., stemming from language). The present study probed this question by testing color-odor correspondences in 6 different cultural groups (Dutch, Netherlands-residing-Chinese, German, Malay, Malaysian-Chinese, and US residents), using the same set of 14 odors and asking participants to make congruent and incongruent color choices for each odor. We found consistent patterns in color choices for each odor within each culture, showing that participants were making non-random color-odor matches. We used representational dissimilarity analysis to probe for variations in the patterns of color-odor associations across cultures; we found that US and German participants had the most similar patterns of associations, followed by German and Malay participants. The largest group differences were between Malay and Netherlands-resident Chinese participants and between Dutch and Malaysian-Chinese participants. We conclude that culture plays a role in color-odor crossmodal associations, which likely arise, at least in part, through experience.
ND3, ND1 and 39kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I
(2014)
An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) form to the de-active (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I+III2+IV (S1) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.