Differential regulation of bladder pain and voiding function by sensory afferent populations revealed by selective optogenetic activation

Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function in vivo via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons (Trpv1Cre;Ai32, the majority of nociceptors) and Nav1.8+ neurons (Scn10aCre;Ai32, nociceptors and some mechanosensitive fibers). In spinal cord, eYFP+ fibers in Trpv1Cre;Ai32 mice were observed predominantly in dorsal horn (DH) laminae I-II, while in Scn10aCre;Ai32 mice they extended throughout the DH, including a dense projection to lamina X. Fiber density correlated with number of retrogradely-labeled eYFP+ dorsal root ganglion neurons (82.2% Scn10aCre;Ai32 vs. 62% Trpv1Cre;Ai32) and degree of DH excitatory synaptic transmission. Photostimulation of peripheral afferent terminals significantly increased visceromotor responses to noxious bladder distension (30–50 mmHg) in both transgenic lines, and to non-noxious distension (20 mmHg) in Scn10aCre;Ai32 mice. Depolarization of ChR2+ afferents in Scn10aCre;Ai32 mice produced low- and high-amplitude bladder contractions respectively in 53% and 27% of stimulation trials, and frequency of high-amplitude contractions increased to 60% after engagement of low threshold (LT) mechanoreceptors by bladder filling. In Trpv1Cre;Ai32 mice, low-amplitude contractions occurred in 27% of trials before bladder filling, which was pre-requisite for light-evoked high-amplitude contractions (observed in 53.3% of trials). Potential explanations for these observations include physiological differences in the thresholds of stimulated fibers and their connectivity to spinal circuits

Approach for the development and application of target process module sets

The implementation of agile frameworks, such as SAFe, in large companies causes conflicts between the overall product development process with a rigid linkage to the calendar cycles and the continuous agile project planning. To resolve these conflicts, adaptive processes can be used to support the creation of realistic target-processes, i.e. project plans, while stabilizing process quality and simplifying process management. This enables the usage of standardisation methods and module sets for design processes. The objective of this contribution is to support project managers to create realistic target-processes through the usage of target-process module sets. These target-process module sets also aim to stabilize process quality and to simplify process management. This contribution provides an approach for the development and application of target-process module sets, in accordance to previously gathered requirements and evaluates the approach within a case study with project managers at AUDI AG (N=21) and an interview study with process authors (N=4) from three different companies

METHOD for the IDENTIFICATION of REQUIREMENTS for DESIGNING REFERENCE PROCESSES

A reference process should consider to the needs and behaviours of the process users, as well as all relevant restrictions and boundary conditions within the company and its environment. Therefore, this contribution provides a method to synthesize relevant requirements on reference processes and supports the consideration of these requirements during the design of a new, company-specific reference process based on meta-models. The developed method was used to design a reference process for automotive predevelopment projects and its applicability and usefulness was evaluated successfully

Mismatch-based delayed thrombolysis: a meta-analysis

<p><b>Background and Purpose</b>: Clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. The use of "mismatch" imaging to identify patients for delayed treatment has face validity and has been used in case series and clinical trials. We undertook a meta-analysis of relevant trials to examine whether present evidence supports delayed thrombolysis among patients selected according to mismatch criteria.</p> <p><b>Methods</b>: We collated outcome data for patients who were enrolled after 3 hours of stroke onset in thrombolysis trials and had mismatch on pretreatment imaging. We selected the trials on the basis of a systematic search of the Web of Knowledge. We compared favorable outcome, reperfusion and/or recanalization, mortality, and symptomatic intracerebral hemorrhage between the thrombolyzed and nonthrombolyzed groups of patients and the probability of a favorable outcome among patients with successful reperfusion and clinical findings for 3 to 6 versus 6 to 9 hours from poststroke onset. Results are expressed as adjusted odds ratios (a-ORs) with 95% CIs. Heterogeneity was explored by test statistics for clinical heterogeneity, I2 (inconsistency), and L’Abbé plot.</p> <p><b>Results</b>: We identified articles describing the DIAS, DIAS II, DEDAS, DEFUSE, and EPITHET trials, giving a total of 502 mismatch patients thrombolyzed beyond 3 hours. The combined a-ORs for favorable outcomes were greater for patients who had successful reperfusion (a-OR=5.2; 95% CI, 3 to 9; I2=0%). Favorable clinical outcome was not significantly improved by thrombolysis (a-OR=1.3; 95% CI, 0.8 to 2.0; I2=20.9%). Odds for reperfusion/recanalization were increased among patients who received thrombolytic therapy (a-OR=3.0; 95% CI, 1.6 to 5.8; I2=25.7%). The combined data showed a significant increase in mortality after thrombolysis (a-OR=2.4; 95% CI, 1.2 to 4.9; I2=0%), but this was not confirmed when we excluded data from desmoteplase doses that were abandoned in clinical development (a-OR=1.6; 95% CI, 0.7 to 3.7; I2=0%). Symptomatic intracerebral hemorrhage was significantly increased after thrombolysis (a-OR=6.5; 95% CI, 1.2 to 35.4; I2=0%) but not significant after exclusion of abandoned doses of desmoteplase (a-OR=5.4; 95% CI, 0.9 to 31.8; I2=0%).</p> <p><b>Conclusions</b>: Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalization. Recanalization/reperfusion is associated with improved outcomes. However, delayed thrombolysis in mismatch patients was not confirmed to improve clinical outcome, although a useful clinical benefit remains possible. Thrombolysis carries a significant risk of symptomatic intracerebral hemorrhage and possibly increased mortality. Criteria to diagnose mismatch are still evolving. Validation of the mismatch selection paradigm is required with a phase III trial. Pending these results, delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.</p&gt

A variational approach to Givental's nonlinear Maslov index

In this article we consider a variant of Rabinowitz Floer homology in order to define a homological count of discriminant points for paths of contactomorphisms. The growth rate of this count can be seen as an analogue of Givental's nonlinear Maslov index. As an application we prove a Bott-Samelson type obstruction theorem for positive loops of contactomorphisms.Comment: 14 page

Understanding the complex phase diagram of uranium: the role of electron-phonon coupling

We report an experimental determination of the dispersion of the soft phonon mode along [1,0,0] in uranium as a function of pressure. The energies of these phonons increase rapidly, with conventional behavior found by 20 GPa, as predicted by recent theory. New calculations demonstrate the strong pressure (and momentum) dependence of the electron-phonon coupling, whereas the Fermi-surface nesting is surprisingly independent of pressure. This allows a full understanding of the complex phase diagram of uranium, and the interplay between the charge-density wave and superconductivity

Selection of reference system elements in the model of PGE - Product generation engineering: Method for the integration of customer and user satisfaction in product planning

In the development of mechatronic systems, it is important to differentiate the products to be developed from those of the competitors, but also from the own product generations already available on the market. However, there are uncertainties regarding the correct features to be differentiated from the customer and user perspective and how these features should be designed. Nevertheless, despite the high impact, decisions must be taken early in the development process. Within this publication, a method to support in this respect was derived based on the findings of the Model of PGE - Product Generation Engineering and the Kano-Model. Therefore, experienceable product features and reference system elements as characteristics of these are evaluated according to the Kano-Model and thus made comparable with regard to the customers and user satisfaction. The objective is to select the product features to be differentiated and the corresponding reference system elements in such a way that a desired level of customer and user satisfaction is achieved. In order to evaluate the method, it was applied in a real development project. It was found that the application of the method led to a reduction of the existing uncertainty

Transparency of a geographically distributed test platform for fuel cell electric vehicle powertrain systems based on x-in-the-loop approach

X-in-the-loop is a new vehicle development and validation method for increasingly complex vehicle systems, which integrates the driver and the environment. In view of recent developments in fuel cell electric vehicle powertrain systems, Tongji University and Karlsruhe Institute of Technology have jointly developed a set of distributed test platforms based on the X-in-the-loop approach. This platform contains models and test equipment for a fuel cell electric vehicle powertrain system. Due to the involvement of remote connection and the Internet, test with connected test benches will suffer great uncertainty cause of signal transfer delay. To figure out this uncertainty, the concept of transparency is introduced. Four parameters were selected as transparency parameters in this distributed test platform. These include vehicle speed, fuel cell output power, battery output power, and electric motor torque under several different configuration settings. With the help of transparency theory and statistical methodology, especially Analysis of Variance (ANOVA), the transparency of these four parameters was established, vehicle speed, electric motor torque, battery power, and fuel cell power are affected by network state, the degree of influence is enhanced in turn. Using new defined parametric and non-parametric methods, this paper identifies the statistical significance and the transparency limitations caused by Internet under these several configurations. These methods will generate inputs for developer setting the distributed test configuration. These results will contribute to optimize the process of geographically distributed validation and joint development