Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.Peer reviewe

The relevance of model-driven engineering thirty years from now

International audienceAlthough model-driven engineering (MDE) is now an established approach for developing complex software systems, it has not been universally adopted by the software industry. In order to better understand the reasons for this, as well as to identify future opportunities for MDE, we carried out a week-long design thinking experiment with 15 MDE experts. Participants were facilitated to identify the biggest problems with current MDE technologies, to identify grand challenges for society in the near future, and to identify ways that MDE could help to address these challenges. The outcome is a reflection of the current strengths of MDE, an outlook of the most pressing challenges for society at large over the next three decades, and an analysis of key future MDE research opportunities

Caring Leadership: A Heideggerian Perspective

This paper develops the idea of caring leadership based on Heidegger’s philosophy of care. From this perspective, caring leadership is grounded in the practices of ‘leaping-in’ and ‘leaping-ahead’ as modes of intervention in the affairs of the world and the efforts of others. This involves gauging and taking responsibility for the ramifications of intervention, balancing the urge for certainty of outcome and visibility of contribution with the desire to encourage and enable others. Our analysis suggests several twists to contemporary leadership debates. We argue that the popular models of transactional and transformational leadership are to be critiqued not for their over-reliance, but rather, their under-reliance on agency. This is a different kind of agency to that of heroic or charismatic models. It involves tolerance of complexity and ambivalence; a rich sense of temporal trajectory; concern for one’s presence in the world; and crucially, the ability to resist the soothing normativity of ‘best practice’. From this position, we argue that the problem with the growing scholarly interest in an ethic of care is that it provides too tempting a recipe to follow. In a Heideggerian view, caring leadership has little to do with compassion, kindness or niceness; it involves and requires a fundamental organization and leadership of self

Measurement of complement receptor 1 on neutrophils in bacterial and viral pneumonia

BACKGROUND: A reliable prediction of the causative agent of community-acquired pneumonia (CAP) is not possible based on clinical features. Our aim was to test, whether the measurement of the expression of complement receptors or Fcγ receptors on neutrophils and monocytes would be a useful preliminary test to differentiate between bacterial and viral pneumonia. METHODS: Sixty-eight patients with CAP were studied prospectively. Thirteen patients had pneumococcal pneumonia; 13 patients, influenza A pneumonia; 5 patients, atypical pneumonia, and 37 patients, aetiologically undefined pneumonia. Leukocyte receptor expression was measured within 2 days of hospital admission. RESULTS: The mean expression of complement receptor 1 (CR1) on neutrophils was significantly higher in the patients with pneumococcal pneumonia than in those with influenza A pneumonia. The mean expression of CR1 was also significantly higher in aetiologically undefined pneumonia than in influenza A pneumonia, but there was no difference between pneumococcal and undefined pneumonia. CONCLUSION: Our results suggest that the expression of CR1 is higher in classical bacterial pneumonia than in viral pneumonia. Determination of the expression of CR1 may be of value as an additional rapid tool in the aetiological diagnosis, bacterial or viral infection, of CAP. These results are preliminary and more research is needed to assess the utility of this new method in the diagnostics of pneumonia

Integration of DFDs into a UML - based model-driven engineering approach

The main aim of this article is to discuss how the functional and the object-oriented views can be inter-played to represent the various modeling perspectives of embedded systems.We discuss whether the object-oriented modeling paradigm, the predominant one to develop software at the present time, is also adequate for modeling embedded software and how it can be used with the functional paradigm.More specifically, we present how the main modeling tool of the traditional structured methods, data flow diagrams, can be integrated in an object-oriented development strategy based on the unified modeling language. The rationale behind the approach is that both views are important for modeling purposes in embedded systems environments, and thus a combined and integrated model is not only useful, but also fundamental for developing complex systems. The approach was integrated in amodel-driven engineering process, where tool support for the models used was provided. In addition, model transformations have been specified and implemented to automate the process.We exemplify the approach with an IPv6 router case study.FEDER -Fundação para a Ciência e a Tecnologia(HH-02-383

Formal verification of safety protocol in train control system

In order to satisfy the safety-critical requirements, the train control system (TCS) often employs a layered safety communication protocol to provide reliable services. However, both description and verification of the safety protocols may be formidable due to the system complexity. In this paper, interface automata (IA) are used to describe the safety service interface behaviors of safety communication protocol. A formal verification method is proposed to describe the safety communication protocols using IA and translate IA model into PROMELA model so that the protocols can be verified by the model checker SPIN. A case study of using this method to describe and verify a safety communication protocol is included. The verification results illustrate that the proposed method is effective to describe the safety protocols and verify deadlocks, livelocks and several mandatory consistency properties. A prototype of safety protocols is also developed based on the presented formally verifying method

Injection therapy and denervation procedures for chronic low-back pain: a systematic review

Injection therapy and denervation procedures are commonly used in the management of chronic low-back pain (LBP) despite uncertainty regarding their effectiveness and safety. To provide an evaluation of the current evidence associated with the use of these procedures, a systematic review was performed. Existing systematic reviews were screened, and the Cochrane Back Review Group trial register was searched for randomized controlled trials (RCTs) fulfilling the inclusion criteria. Studies were included if they recruited adults with chronic LBP, evaluated the use of injection therapy or denervation procedures and measured at least one clinically relevant outcome (such as pain or functional status). Two review authors independently assessed studies for eligibility and risk of bias (RoB). A meta-analysis was performed with clinically homogeneous studies, and the GRADE approach was used to determine the quality of evidence. In total, 27 RCTs were included, 14 on injection therapy and 13 on denervation procedures. 18 (66%) of the studies were determined to have a low RoB. Because of clinical heterogeneity, only two comparisons could be pooled. Overall, there is only low to very low quality evidence to support the use of injection therapy and denervation procedures over placebo or other treatments for patients with chronic LBP. However, it cannot be ruled out that in carefully selected patients, some injection therapy or denervation procedures may be of benefit

An experimental study investigating the effect of pain relief from oral analgesia on lumbar range of motion, velocity, acceleration and movement irregularity

Background Movement alterations are often reported in individuals with back pain. However the mechanisms behind these movement alterations are not well understood. A commonly cited mechanism is pain. The aim of this study was to investigate the effect of pain reduction, from oral analgesia, on lumbar kinematics in individuals with acute and chronic low back pain. Methods A prospective, cross-sectional, experimental repeated-measures design was used. Twenty acute and 20 chronic individuals with low back pain were recruited from General Practitioner and self-referrals to therapy departments for low back pain. Participants complained of movement evoked low back pain. Inertial sensors were attached to the sacrum and lumbar spine and used to measure kinematics. Kinematic variables measured were range of motion, angular velocity and angular acceleration as well as a determining movement irregularity (a measure of deviation from smooth motion). Kinematics were investigated before and after administration of oral analgesia to instigate pain reduction. Results Pain was significantly reduced following oral analgesia. There were no significant effects on the kinematic variables before and after pain reduction from oral analgesia. There was no interaction between the variables group (acute and chronic) and time (pre and post pain reduction). Conclusion The results demonstrate that pain reduction did not alter lumbar range of motion, angular velocity, angular acceleration or movement irregularity questioning the role of pain in lumbar kinematics

Co-occurrence of diabetes and hopelessness predicts adverse prognosis following percutaneous coronary intervention

We examined the impact of co-occurring diabetes and hopelessness on 3-year prognosis in percutaneous coronary intervention patients. Consecutive patients (n = 534) treated with the paclitaxel-eluting stent completed a set of questionnaires at baseline and were followed up for 3-year adverse clinical events. The incidence of 3-year death/non-fatal myocardial infarction was 3.5% in patients with no risk factors (neither hopelessness nor diabetes), 8.2% in patients with diabetes, 11.2% in patients with high hopelessness, and 15.9% in patients with both factors (p = 0.001). Patients with hopelessness (HR: 3.28; 95% CI: 1.49-7.23) and co-occurring diabetes and hopelessness (HR: 4.89; 95% CI: 1.86-12.85) were at increased risk of 3-year adverse clinical events compared to patients with no risk factors, whereas patients with diabetes were at a clinically relevant but not statistically significant risk (HR: 2.40; 95% CI: 0.82-7.01). These results remained, adjusting for baseline characteristics an