Botulinumtoxin bei nichtneurogenen Blasenfunktionsstörungen

Zusammenfassung: Die nichtneurogene überaktive Harnblase mit oder ohne Detrusorüberaktivität und/oder Inkontinenz ist ein belastendes Symptom für viele Menschen, das bis vor wenigen Jahren nur mit anticholinergen Medikamenten oder operativ behandelt werden konnte. Intradetrusorinjektionen mit BotulinumtoxinTypA stellen eine minimal-invasive Alternative für Patienten dar, die auf Anticholinergika nicht ansprechen oder diese nicht vertragen. Dieser Übersichtsartikel fasst die relevanten Arbeiten der letzten 6Jahre zu diesem Thema zusammen und gibt Auskunft über die Wirksamkeit, die Nebenwirkungen, die verwendeten Dosierungen und Injektionstechniken. Insgesamt zeigte sich eine gute initiale Wirksamkeit, die etwa ab dem 4. Tag nach Injektion beginnt und durchschnittlich bis zu 31Wochen anhalten kann. Es ist allerdings je nach Dosis mit einer Erhöhung der Restharnmengen zu rechnen, die auch die Anwendung von intermittierendem Selbstkatheterismus notwendig machen können. Die Anwendung von Botulinumtoxin in der Harnblase ist noch immer keine offiziell zugelassene Therapi

The facilitatory effect of duloxetine combined with pelvic floor muscle training on the excitability of urethral sphincter motor neurons

INTRODUCTION AND HYPOTHESIS: Aim of this study was to investigate the excitability of sphincter motor neurons under the influence of pelvic floor muscle training (PFMT) and duloxetine. Due to their mechanisms of action, there might be a synergistic effect of duloxetine and PFMT in regard to the facilitation of spinal reflexes controlling urethral sphincter contractions and hence continence. METHODS: In ten healthy female subjects, clitoral electric stimulation (CES) and transcranial magnetic stimulation (TMS) were used to determine individual motor thresholds for external urethral sphincter (EUS) contractions before and after PFMT, duloxetine, and PFMT + duloxetine. RESULTS: PFMT and duloxetine alone significantly decreased the motor thresholds for EUS contractions during CES and TMS. However, the combined treatment reduced the motor threshold for EUS contractions significantly stronger compared to PFMT or duloxetine alone. CONCLUSIONS: The results are suggestive for a synergistic facilitatory effect of PFMT and duloxetine on sphincter motor neuron activation

Verifying object-oriented programs with higher-order separation logic in Coq

We present a shallow Coq embedding of a higher-order separation logic with nested triples for an object-oriented programming language. Moreover, we develop novel specification and proof patterns for reasoning in higher-order separation logic with nested triples about programs that use interfaces and interface inheritance. In particular, we show how to use the higher-order features of the Coq formalisation to specify and reason modularly about programs that (1) depend on some unknown code satisfying a specification or that (2) return objects conforming to a certain specification. All of our results have been formally verified in the interactive theorem prover Coq

Supported ionic liquid silica nanoparticles (SILnPs) as an efficient and recyclable heterogeneous catalyst for the dehydration of fructose to 5-hydroxymethylfurfural

Supported ionic liquid nanoparticles (SILnPs) having particle size ranging from 293 ± 2 to 610 ± 11 nm have been prepared by immobilization of ionic liquid, 1-(tri-ethoxy silyl-propyl)- 3-methyl-imidazolium hydrogen sulfate (IL-HSO4) on the surface of silica nanoparticles. The catalytic activity of the prepared SILnPs was investigated for the dehydration of fructose to 5-hydroxymethylfurfural (HMF) in the presence of dimethylsulfoxide (DMSO) as a solvent. The reaction temperature and amount of catalyst have been optimized for dehydration of fructose over SILnPs using experimental design leading to 99.9% fructose conversion and 63.0% HMF yield using silica SILnPs (d = 610 ± 11) nm at 130.0 ◦C in 30 min reaction time. The SILnPs catalysts developed in this study present improved performances over other zeolites and strong acid ion exchange resin catalysts, and they have been efficiently and very easily recycled over seven times without any significant loss in fructose conversion and HMF yield

Zircon ages in granulite facies rocks: decoupling from geochemistry above 850 °C?

Granulite facies rocks frequently show a large spread in their zircon ages, the interpretation of which raises questions: Has the isotopic system been disturbed? By what process(es) and conditions did the alteration occur? Can the dates be regarded as real ages, reflecting several growth episodes? Furthermore, under some circumstances of (ultra-)high-temperature metamorphism, decoupling of zircon U–Pb dates from their trace element geochemistry has been reported. Understanding these processes is crucial to help interpret such dates in the context of the P–T history. Our study presents evidence for decoupling in zircon from the highest grade metapelites (> 850 °C) taken along a continuous high-temperature metamorphic field gradient in the Ivrea Zone (NW Italy). These rocks represent a well-characterised segment of Permian lower continental crust with a protracted high-temperature history. Cathodoluminescence images reveal that zircons in the mid-amphibolite facies preserve mainly detrital cores with narrow overgrowths. In the upper amphibolite and granulite facies, preserved detrital cores decrease and metamorphic zircon increases in quantity. Across all samples we document a sequence of four rim generations based on textures. U–Pb dates, Th/U ratios and Ti-in-zircon concentrations show an essentially continuous evolution with increasing metamorphic grade, except in the samples from the granulite facies, which display significant scatter in age and chemistry. We associate the observed decoupling of zircon systematics in high-grade non-metamict zircon with disturbance processes related to differences in behaviour of non-formula elements (i.e. Pb, Th, U, Ti) at high-temperature conditions, notably differences in compatibility within the crystal structure

Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Cancer Survivors’ Social Context in the Return to Work Process:Narrative Accounts of Social Support and Social Comparison Information

Purpose: Returning to work is a process that is intertwined with the social aspects of one’s life, which can influence the way in which that person manages their return to work and also determines the support available to them. This study aimed to explore cancer patients’ perceptions of the role of their social context in relation to returning to work following treatment. Methods: Twenty-three patients who had received a diagnosis of either urological, breast, gynaecological, or bowel cancer participated in semi-structured interviews examining general perceptions of cancer, work values and perceptions of the potential impact of their cancer diagnosis and treatment on work. Interviews were analysed using the iterative process of Framework Analysis. Results: Two superordinate themes emerged as influential in the return to work process: Social support as a facilitator of return to work (e.g. co-workers’ support and support outside of the workplace) and Social comparison as an appraisal of readiness to return to work (e.g. comparisons with other cancer patients, colleagues, and employees in other organisations or professions). Conclusions: Two functions of the social context of returning to work after cancer were apparent in the participants’ narrative: the importance of social support as a facilitator of returning to work and the utilisation of social comparison information in order to appraise one’s readiness to return to work. The role of social context in returning to work has largely been absent from the research literature to date. The findings of this study suggest that social support and social comparison mechanisms may have a significant impact on an individual’s successful return to the workplace

Crystal structure of SEL1L: Insight into the roles of SLR motifs in ERAD pathway

Terminally misfolded proteins are selectively recognized and cleared by the endoplasmic reticulum-associated degradation (ERAD) pathway. SEL1L, a component of the ERAD machinery, plays an important role in selecting and transporting ERAD substrates for degradation. We have determined the crystal structure of the mouse SEL1L central domain comprising five Sel1-Like Repeats (SLR motifs 5 to 9; hereafter called SEL1Lcent). Strikingly, SEL1Lcent forms a homodimer with two-fold symmetry in a head-to-tail manner. Particularly, the SLR motif 9 plays an important role in dimer formation by adopting a domain-swapped structure and providing an extensive dimeric interface. We identified that the full-length SEL1L forms a self-oligomer through the SEL1Lcent domain in mammalian cells. Furthermore, we discovered that the SLR-C, comprising SLR motifs 10 and 11, of SEL1L directly interacts with the N-terminus luminal loops of HRD1. Therefore, we propose that certain SLR motifs of SEL1L play a unique role in membrane bound ERAD machinery.ope

Cortical substrate of bladder control in SCI and the effect of peripheral pudendal stimulation

We investigate (i) the central representation of lower urinary tract (LUT) control and (ii–iii) the acute and 23 short-term central neuromodulatory effect of peripheral pudendal nerve stimulation in incomplete spinal 24 cord injured (SCI) patients using functional magnetic resonance imaging (fMRI). The urinary bladder of eight 25 SCI patients has been passively filled and emptied using a catheter, to identify the neural substrate of bladder 26 control (i), and with simultaneous peripheral pudendal nerve stimulation to investigate its acute central 27 neuromodulatory effect (ii). To identify the potential effects of pudendal nerve stimulation treatment (iii), 28 six patients underwent a 2-week training using pudendal nerve stimulation followed by another fMRI 29 session of bladder filling. The pre- and post-training fMRI results have been compared and correlated with 30 the patient's pre- and post-training urological status. Our results suggest that the central representation of 31 bladder filling sensation is preserved in the subacute stage of incomplete SCI. However, compared to earlier 32 data from healthy subjects, it shows decreased neural response in right prefrontal areas and increased in left 33 prefrontal regions, indicating diminished inhibitory micturition control as well as, compensatory or de- 34 compensatory reorganization of bladder control. We also provide evidence for a neuromodulatory effect of 35 acute pudendal nerve stimulation, which was most prominent in the right posterior insula, a brain region 36 implicated in homeostatic interoception in human. Pudendal stimulation training also induced significant 37 neuromodulation, predominantly signal increases, in the normal cortical network of bladder control. 38 Correlations with the patient's urological status indicate that this neuromodulatory effect may reflect the 39 clinical improvement following training