Endogenously released adenosine-5'-triphosphate (ATP) is a key regulator of physiological function and inflammatory responses in the kidney. Genetic or pharmacological inhibition of purinergic ...receptors has been linked to attenuation of inflammatory disorders and hence constitutes promising new avenues for halting and reverting inflammatory renal diseases. However, the involvement of purinergic receptors in glomerulonephritis (GN) has only been incompletely mapped. Here, we demonstrate that induction of GN in an experimental antibody-mediated GN model results in a significant increase of urinary ATP-levels and an upregulation of P2Y2R expression in resident kidney cells as well as infiltrating leukocytes pointing toward a possible role of the ATP/P2Y2R-axis in glomerular disease initiation. In agreement, decreasing extracellular ATP-levels or inhibition of P2R during induction of antibody-mediated GN leads to a reduction in all cardinal features of GN such as proteinuria, glomerulosclerosis, and renal failure. The specific involvement of P2Y2R could be further substantiated by demonstrating the protective effect of the lack of P2Y2R in antibody-mediated GN. To systematically differentiate between the function of P2Y2R on resident renal cells versus infiltrating leukocytes, we performed bone marrow-chimera experiments revealing that P2Y2R on hematopoietic cells is the main driver of the ATP/P2Y2R-mediated disease progression in antibody-mediated GN. Thus, these data unravel an important pro-inflammatory role for P2Y2R in the pathogenesis of GN.
Background and Purpose
First‐generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, ...given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required.
Experimental Approach
We report the high‐throughput screening (HTS)‐based discovery of a second generation of sGC stimulators from a novel imidazo1,2‐apyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY‐747). The pharmacokinetic profile of BAY‐747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension.
Key Results
BAY‐747 is a highly potent sGC stimulator in vitro. In addition, BAY‐747 showed an excellent pharmacokinetic profile with long half‐life and low peak‐to‐trough ratio. BAY‐747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY‐747 caused a dose‐related and long‐lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY‐747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY‐747 caused a dose‐related and long‐lasting (>6 h) MAP decrease.
Conclusion and Implications
BAY‐747 is a potent, orally available sGC stimulator. BAY‐747 shows long‐acting pharmacodynamic effects with a very low peak‐to‐trough ratio. BAY‐747 could be a treatment alternative for patients with hypertension, especially those not responding to standard‐of‐care therapy.
Pro Kind is a German adaptation of the US Nurse Family Partnership program. It is an intervention based on home visits targeting first-time mothers from disadvantaged populations. Pro Kind was ...implemented as a randomized control trial from 2006 to 2012 with N = 755 first-time mothers (TG n = 394, CG n = 391). The 7-8-year follow-up aims to assess the mid-term effects of the program.
Mid-term outcomes are being assessed by trained assessors. In a multimethod approach telephone interviews, on-site interviews, observations and developmental tests will be held in order to assess children's and mothers' life satisfaction, mental health, cognitive and social development, parenting behavior, signs of child abuse or neglect as well as the family's socio-economic status. Furthermore, administrative data will be accessed to obtain information regarding the mother's usage of pediatric health care, welfare usage and employment history.
Results regarding the mid-term effects of the intervention from the Pro Kind Follow-up will provide a scientific basis for future primary prevention programs as well as help stakeholders legitimizing early childhood investments.
German Clinical Trial Registration DRKS-ID, ID: DRKS00007554 . Registered on 11 June 2015, updated on 6 October 2017.
A system framework for gamified Cost Engineering Zimmerling, Eric; Höflinger, Patrick J.; Sandner, Philipp G. ...
Information systems frontiers,
12/2016, Letnik:
18, Številka:
6
Journal Article
Recenzirano
This study develops a system framework and an enterprise IT solution for integrating gamification elements to efficiently implement and continuously perform Cost Engineering. Cost Engineering is a ...systematic approach to manage knowledge and competencies regarding costs reduction measures throughout the life cycle of products and is technology, resource and time intensive. Gamification as a non-monetary multidimensional incentive system holds great potential to implement and establish Cost Engineering in a novel and less resource demanding manner and stipulate knowledge sharing and dissemination. Building on a review of the relevant literature we conducted 20 interviews with experts from eight companies of the German and Austrian high-tech manufacturing industry to examine the system requirements from an organizational perspective. Analyzing the interviews, we found that companies need a flexible platform where the game elements help to align management objectives with concrete tasks, meet legislative regulations and have different evaluation methods. Our proposed system framework combines the organizational and IT requirements with gamification elements to efficiently steer Cost Engineering methods and best manage knowledge and competencies.
Die fortschreitende Digitalisierung hat nun auch das Geldsystem erreicht. Das Aufkommen von Kryptowerten hat zahlreiche Vorteile aufgezeigt, die nun auch in das konventionelle Geldsystem übertragen ...werden sollen.
Vein graft disease (VGD) impairs graft patency rates and long-term outcomes after coronary artery bypass grafting (CABG). DuraGraft is a novel endothelial-damage inhibitor developed to efficiently ...protect the structural and functional integrity of the vascular endothelium. The DuraGraft registry will evaluate the long-term clinical outcomes of DuraGraft in patients undergoing CABG procedures.
This ongoing multicentre, prospective observational registry will enrol 3000 patients undergoing an isolated CABG procedure or a combined procedure (ie, CABG plus valve surgery or other surgery) with at least one saphenous vein grafts or one free arterial graft (ie, radial artery or mammary artery). If a patient is enrolled, all free grafts (SVG and arterial will be treated with DuraGraft. Data on baseline, clinical, and angiographic characteristics as well as procedural and clinical events will be collected. The primary outcome measure is the occurrence of a major adverse cardiac event (MACE; defined as death, non-fatal myocardial-infarction, or need for repeat-revascularisation). Secondary outcome measures are the occurrence of major adverse cardiac and cerebrovascular events (MACCE; defined as death, non-fatal myocardial-infarction, repeat-revascularisation, or stroke), patient-reported quality of life, and health-economic data. Patient assessments will be performed during hospitalisation, at 1-month, 1-year, and annually thereafter to 5 years post-CABG. Events will be adjudicated by an independent clinical events committee. This European, multi-institutional registry will provide detailed insights into clinical outcome associated with DuraGraft.
This European, multi-institutional registry will provide detailed insights into clinical outcome associated with the use of DuraGraft. Beyond that, and given the comprehensive data sets comprising of patient, procedural, and graft parameters that are being collected, the registry will enable for multiple subgroup analyses targeting focus groups or specific clinical questions. These may include analysis of subpopulations such as patients with diabetes or multimorbid high-risk patients (patient level), evaluation of relevance of harvesting technique including endoscopic versus open conduit harvesting (procedural level), or particular graft-specific aspects (conduit level).
ClinicalTrials.gov NCT02922088 . Registered October 3, 2016.
The regional ethics committees have approved the registry. Results will be submitted for publication.
Axonal bridging across a lesion in the injured spinal cord requires a growth substrate and guidance cues. Using alginate hydrogels with capillary channels we show that poly-l-ornithine and laminin ...can be stably bound and improve cell adhesion and neurite growth
, and axon growth
by enhancing host cell infiltration in the injured spinal cord. Filling of coated hydrogels with postnatal astrocytes further increases short-distance axon growth and results in a continuous astroglial substrate across the host/graft interface. Thus, positively charged bioactive molecules can be stably bound to anisotropic capillary alginate hydrogels and early astrocytes further promote tissue integration.
The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase ...inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials.
We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method.
Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib (
= 33), lenvatinib (
= 53), and pazopanib (
= 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib.
Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.
Introduction
After primary total knee arthroplasty (TKA), local periarticular infiltration anaesthesia (LIA) is a fast and safe method for postoperative pain control. Moreover, ultrasound-guided ...regional anaesthesia (USRA) with femoral and popliteal block is a standard procedure in perioperative care. Two analgesic regimens for TKA—LIA versus URSA with dexmedetomidine—were compared as an additive to ropivacaine. We hypothesised that the use of URSA provides a superior opioid sparing effect for TKA compared with LIA.
Methods
Fifty patients (planned 188 participants; safety analysis was performed after examining the first 50 participants) were randomised. These patients received LIA into the knee capsule during surgery with 60 ml of ropivacaine 0.5% and 1 ml of dexmedetomidine (100 µg ml
−1
) or two single-shot URSA blocks (femoral and popliteal block) before surgery with 15 ml of ropivacaine 0.5% and 0.5 ml of dexmedetomidine for each block. Postoperative opioid consumption in the first 48 h, pain assessment and complications were analysed.
Results
In the safety analysis, there was a significantly higher need for opioids in the LIA group, with a median oral morphine equivalent of 42.0 interquartile range (IQR) 23.5–57.0 mg versus 27.0 IQR 0.0–33.5 mg (
P
= 0.022). Due to this finding, the study was terminated for ethical considerations according to the protocol.
Conclusion
This is the first study presenting data on LIA application in combination with dexmedetomidine. A superior opioid-sparing effect of URSA was observed when compared with LIA in TKA when dexmedetomidine is added to local anaesthetics. Also, a longer lasting opioid-sparing effect in the LIA group was observed when compared with the recently published literature; this difference could be attributed to the addition of dexmedetomidine. Therefore, multimodal analgesia regimens could be further improved when LIA or USRA techniques are combined with dexmedetomidine.
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