Development of an erythropoietin prescription simulator to improve abilities for the prescription of erythropoietin stimulating agents: is it feasible?

BACKGROUND: The increasing use of erythropoietins with long half-lives and the tendency to lengthen the administration interval to monthly injections call for raising awareness on the pharmacokinetics and risks of new erythropoietin stimulating agents (ESA). Their pharmacodynamic complexity and individual variability limit the possibility of attaining comprehensive clinical experience. In order to help physicians acquiring prescription abilities, we have built a prescription computer model to be used both as a simulator and education tool. METHODS: The pharmacokinetic computer model was developed using Visual Basic on Excel and tested with 3 different ESA half-lives (24, 48 and 138 hours) and 2 administration intervals (weekly vs. monthly). Two groups of 25 nephrologists were exposed to the six randomised combinations of half-life and administration interval. They were asked to achieve and maintain, as precisely as possible, the haemoglobin target of 11-12 g/dL in a simulated naïve patient. Each simulation was repeated twice, with or without randomly generated bleeding episodes. RESULTS: The simulation using an ESA with a half-life of 138 hours, administered monthly, compared to the other combinations of half-lives and administration intervals, showed an overshooting tendency (percentages of Hb values > 13 g/dL 15.8 ± 18.3 vs. 6.9 ± 12.2; P < 0.01), which was quickly corrected with experience. The prescription ability appeared to be optimal with a 24 hour half-life and weekly administration (ability score indexing values in the target 1.52 ± 0.70 vs. 1.24 ± 0.37; P < 0.05). The monthly prescription interval, as suggested in the literature, was accompanied by less therapeutic adjustments (4.9 ± 2.2 vs. 8.2 ± 4.9; P < 0.001); a direct correlation between haemoglobin variability and number of therapy modifications was found (P < 0.01). CONCLUSIONS: Computer-based simulations can be a useful tool for improving ESA prescription abilities among nephrologists by raising awareness about the pharmacokinetic characteristics of the various ESAs and recognizing the factors that influence haemoglobin variability.

ConnectomeViewer - Multi-Modal Multi-Level Network Visualization and Analysis.

Introduction: The field of Connectomic research is growing rapidly, resulting from methodological advances in structural neuroimaging on many spatial scales. Especially progress in Diffusion MRI data acquisition and processing made available macroscopic structural connectivity maps in vivo through Connectome Mapping Pipelines (Hagmann et al, 2008) into so-called Connectomes (Hagmann 2005, Sporns et al, 2005). They exhibit both spatial and topological information that constrain functional imaging studies and are relevant in their interpretation. The need for a special-purpose software tool for both clinical researchers and neuroscientists to support investigations of such connectome data has grown. Methods: We developed the ConnectomeViewer, a powerful, extensible software tool for visualization and analysis in connectomic research. It uses the novel defined container-like Connectome File Format, specifying networks (GraphML), surfaces (Gifti), volumes (Nifti), track data (TrackVis) and metadata. Usage of Python as programming language allows it to by cross-platform and have access to a multitude of scientific libraries. Results: Using a flexible plugin architecture, it is possible to enhance functionality for specific purposes easily. Following features are already implemented: * Ready usage of libraries, e.g. for complex network analysis (NetworkX) and data plotting (Matplotlib). More brain connectivity measures will be implemented in a future release (Rubinov et al, 2009). * 3D View of networks with node positioning based on corresponding ROI surface patch. Other layouts possible. * Picking functionality to select nodes, select edges, get more node information (ConnectomeWiki), toggle surface representations * Interactive thresholding and modality selection of edge properties using filters * Arbitrary metadata can be stored for networks, thereby allowing e.g. group-based analysis or meta-analysis. * Python Shell for scripting. Application data is exposed and can be modified or used for further post-processing. * Visualization pipelines using filters and modules can be composed with Mayavi (Ramachandran et al, 2008). * Interface to TrackVis to visualize track data. Selected nodes are converted to ROIs for fiber filtering The Connectome Mapping Pipeline (Hagmann et al, 2008) processed 20 healthy subjects into an average Connectome dataset. The Figures show the ConnectomeViewer user interface using this dataset. Connections are shown that occur in all 20 subjects. The dataset is freely available from the homepage (connectomeviewer.org). Conclusions: The ConnectomeViewer is a cross-platform, open-source software tool that provides extensive visualization and analysis capabilities for connectomic research. It has a modular architecture, integrates relevant datatypes and is completely scriptable. Visit www.connectomics.org to get involved as user or developer.

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations.

BACKGROUND: In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines. METHODS: To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol. In addition, a battery of questionnaires and neuropsychological tests was selected, optimally suited to the deficits found most prevalent in aSAH patients that was available in different languages and standardized. RESULTS: We propose a baseline inpatient neuropsychological screening using the Montreal Cognitive Assessment (MoCA) between days 14 and 28 after aSAH. In an outpatient setting at 3 and 12 months after bleeding, we recommend a neuropsychological examination, testing all relevant domains including attention, speed of information processing, executive functions, verbal and visual learning/memory, language, visuo-perceptual abilities, and premorbid intelligence. In addition, a detailed assessment capturing anxiety, depression, fatigue, symptoms of frontal lobe affection, and quality of life should be performed. CONCLUSIONS: This standardized neuropsychological assessment will lead to a more comprehensive assessment of the patient, facilitate the detection and subsequent treatment of previously unrecognized but relevant impairments, and help to determine the incidence, characteristics, modifiable risk factors, and the clinical course of these impairments after aSAH.

Programming of marginal zone B-cell fate by basic Kruppel-like factor (BKLF/KLF3).

Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.

Language lateralization in early and late bilinguals using an international vocabulary

In lateralized Lexical Decision Tasks (LDT), accuracy is commonly higher and reaction times are commonly faster for right visual field (RVF) than left visual field (LVF) presentations. This visual field differences are thought to demonstrate the left hemisphere's dominance for language. Unfortunately, different tasks and words are used between studies and languages making direct comparisons difficult. For example, high frequency words show a performance advantage over low frequency words. Moreover, demographic variables impact on lateralized behavior such as language knowledge (one versus several, early acquired versus late acquired). We here aim to alleviate some of these obstacles by presenting results from a lateralized LDT for which we selected words between 4 and 6 letters used in five different languages, i.e. English, French, German, Dutch and Italian. In this first study using these words, we compared performance of right- and left-handed students being either early or late bilinguals (acquired before or after the age of 6 years) from a French-speaking University in Switzerland. Results showed a left hemispheric advantage (accuracy, reaction times) for all groups, with a trend for early as compared to late bilinguals to be less accurate and taking longer in lexical decisions. These results show that the current words result in solid visual field differences, and do so irrespective of how many languages are spoken. While early bilinguals might experience a slight performance disadvantage, it was not affecting visual field differences.

Emotion, Affect, Sentiment: The Language and Aesthetics of Feeling

Bringing together experts from linguistics, medieval and modern literary studies, this volume offers a transhistorical look at the language and cultural work of emotion in a variety of written, oral and visual texts. Contributors engage with the recent so-called affective turn, but also examine the language and use of emotion from a variety of perspectives, touching on issues such as Romantic and Modernist aesthetics, the history of emotions, melodramatic and the Gothic, reception aesthetics, rudeness, and medicine.

Dyslexia in a French-Spanish bilingual girl: behavioural and neural modulations following a visual attention span intervention.

We report the case study of a French-Spanish bilingual dyslexic girl, MP, who exhibited a severe visual attention (VA) span deficit but preserved phonological skills. Behavioural investigation showed a severe reduction of reading speed for both single items (words and pseudo-words) and texts in the two languages. However, performance was more affected in French than in Spanish. MP was administered an intensive VA span intervention programme. Pre-post intervention comparison revealed a positive effect of intervention on her VA span abilities. The intervention further transferred to reading. It primarily resulted in faster identification of the regular and irregular words in French. The effect of intervention was rather modest in Spanish that only showed a tendency for faster word reading. Text reading improved in the two languages with a stronger effect in French but pseudo-word reading did not improve in either French or Spanish. The overall results suggest that VA span intervention may primarily enhance the fast global reading procedure, with stronger effects in French than in Spanish. MP underwent two fMRI sessions to explore her brain activations before and after VA span training. Prior to the intervention, fMRI assessment showed that the striate and extrastriate visual cortices alone were activated but none of the regions typically involved in VA span. Post-training fMRI revealed increased activation of the superior and inferior parietal cortices. Comparison of pre- and post-training activations revealed significant activation increase of the superior parietal lobes (BA 7) bilaterally. Thus, we show that a specific VA span intervention not only modulates reading performance but further results in increased brain activity within the superior parietal lobes known to housing VA span abilities. Furthermore, positive effects of VA span intervention on reading suggest that the ability to process multiple visual elements simultaneously is one cause of successful reading acquisition.

Exploration of the visual system: Part 1: Dissection of the mouse eye for RNA, protein, and histological analyses

Due to the power of genetics, the mouse has become a widely used animal model in vision research. However, its eyeball has an axial length of only about 2 mm. The present protocol describes how to easily dissect the small rodent eye post mortem. This allows collecting different tissues of the eye, i.e., cornea, lens, iris, retina, optic nerve, retinal pigment epithelium (RPE), and sclera. We further describe in detail how to process these eye samples in order to obtain high‐quality RNA for RNA expression profiling studies. Depending on the eye tissue to be analyzed, we present appropriate lysis buffers to prepare total protein lysates for immunoblot and immuno‐precipitation analyses. Fixation, inclusion, embedding, and cryosectioning of the globe for routine histological analyses (HE staining, DAPI staining, immunohistochemistry, in situ hybridization) is further presented. These basic protocols should allow novice investigators to obtain eye tissue samples rapidly for their experiments.

Fetal programming and epigenetic mechanisms in arterial hypertension.

PURPOSE OF REVIEW: To provide an overview of available evidence of the potential role of epigenetics in the pathogenesis of hypertension and vascular dysfunction. RECENT FINDINGS: Arterial hypertension is a highly heritable condition. Surprisingly, however, genetic variants only explain a tiny fraction of the phenotypic variation and the term 'missing heritability' has been coined to describe this phenomenon. Recent evidence suggests that phenotypic alteration that is unrelated to changes in DNA sequence (thereby escaping detection by classic genetic methodology) offers a potential explanation. Here, we present some basic information on epigenetics and review recent work consistent with the hypothesis of epigenetically induced arterial hypertension. SUMMARY: New technologies that enable the rigorous assessment of epigenetic changes and their phenotypic consequences may provide the basis for explaining the missing heritability of arterial hypertension and offer new possibilities for treatment and/or prevention.

Electrostimulation mapping of comprehension of auditory and visual words.

In order to spare functional areas during the removal of brain tumours, electrical stimulation mapping was used in 90 patients (77 in the left hemisphere and 13 in the right; 2754 cortical sites tested). Language functions were studied with a special focus on comprehension of auditory and visual words and the semantic system. In addition to naming, patients were asked to perform pointing tasks from auditory and visual stimuli (using sets of 4 different images controlled for familiarity), and also auditory object (sound recognition) and Token test tasks. Ninety-two auditory comprehension interference sites were observed. We found that the process of auditory comprehension involved a few, fine-grained, sub-centimetre cortical territories. Early stages of speech comprehension seem to relate to two posterior regions in the left superior temporal gyrus. Downstream lexical-semantic speech processing and sound analysis involved 2 pathways, along the anterior part of the left superior temporal gyrus, and posteriorly around the supramarginal and middle temporal gyri. Electrostimulation experimentally dissociated perceptual consciousness attached to speech comprehension. The initial word discrimination process can be considered as an "automatic" stage, the attention feedback not being impaired by stimulation as would be the case at the lexical-semantic stage. Multimodal organization of the superior temporal gyrus was also detected since some neurones could be involved in comprehension of visual material and naming. These findings demonstrate a fine graded, sub-centimetre, cortical representation of speech comprehension processing mainly in the left superior temporal gyrus and are in line with those described in dual stream models of language comprehension processing.