Search

Heparan sulfate in the glomerular basement membrane has been considered crucial for charge-selective filtration. In many proteinuric diseases, increased glomerular expression of heparanase is associated with decreased heparan sulfate. Here, we used mice overexpressing heparanase and evaluated the expression of different heparan sulfate domains in the kidney and other tissues measured with anti-heparan sulfate antibodies. Glycosaminoglycan-associated anionic sites were visualized by the cationic dye cupromeronic blue. Transgenic mice showed a differential loss of heparan sulfate domains in several tissues. An unmodified and a sulfated heparan sulfate domain resisted heparanase action in vivo and in vitro. Glycosaminoglycan-associated anionic sites were reduced about fivefold in the glomerular basement membrane of transgenic mice, whereas glomerular ultrastructure and renal function remained normal. Heparanase-resistant heparan sulfate domains may represent remnant chains or chains not susceptible to cleavage. Importantly, the strong reduction of glycosaminoglycan-associated anionic sites in the glomerular basement membrane without development of a clear renal phenotype questions the primary role of heparan sulfate in charge-selective filtration. We cannot, however, exclude that overexpression of heparanase and heparan sulfate loss in the basement membrane in glomerular diseases contributes to proteinuria.Kidney International (2008) 73, 278–287; doi:10.1038/sj.ki.5002706; published online 28 November 2007 [ABSTRACT FROM AUTHOR]

Heparan sulfate (HS) proteoglycans by playing key roles in the leukocyte–endothelial interactions are thought to mediate inflammatory cell influx in proliferative glomerulonephritis. Here, we evaluated the specific features within glomerular endothelial HS that promote leukocyte adhesion. Mouse and human glomerular endothelial cells activated by tumor necrosis factor (TNF)-α or interleukin (IL)-1β increased expression of inflammatory N- and 6-O-sulfated HS domains. In addition, altered expression of HS-modifying enzymes occurred, a feature also found in mouse kidneys with anti-glomerular basement membrane disease or lupus nephritis. Inhibition of the nuclear factor (NF)-κB pathway repressed cytokine-induced alterations in HS and gene expression of modifying enzymes. Firm adhesion of leukocytes to activated mouse glomerular endothelial cells decreased after removal of endothelial HS or addition of sulfated heparinoids. Specific antibodies that block N- and 6-O-sulfated HS domains on activated mouse endothelial cells reduced the number of rolling and firmly adhering leukocytes under dynamic flow conditions, while they increased the average leukocyte-rolling velocity. Our study shows that N- and 6-O-sulfated domains in HS on activated glomerular endothelium are crucial for leukocyte trafficking and are possible therapeutic targets.Kidney International (2008) 73, 52–62; doi:10.1038/sj.ki.5002573; published online 3 October 2007 [ABSTRACT FROM AUTHOR]

Heparanase is an endo-β(1–4)-D-glucuronidase that degrades heparan sulfate (HS) polysaccharide side chains. The role of heparanase in metastasis, angiogenesis, and inflammation has been established. Recent data suggest a role for heparanase in several proteinuric diseases and an increased glomerular heparanase expression is associated with loss of HS in the glomerular basement membrane (GBM). Furthermore, an increase in heparanase activity was detected in urine from proteinuric patients. Mice with transgenic heparanase overexpression developed mild proteinuria. Glomerular heparanase activity is proposed to lead to loss of HS in the GBM and proteinuria. Because the primary role of GBM HS for charge-selective permeability has been questioned recently, heparanase may induce or enhance proteinuria by (i) changes in the glomerular cell–GBM interactions, due to loss of HS; (ii) release of HS-bound factors and HS fragments in glomeruli; or (iii) intracellular signaling by binding of heparanase to glomerular cells. Which of these mechanisms is prevailing requires further research. The precise mechanisms leading to increased heparanase expression in the different glomerular cell types remain elusive, but may involve hyperglycemia, angiotensin II, aldosterone, and reactive oxygen species. This review focuses on the role of heparanase in HS degradation in proteinuric diseases and the possibility/feasibility of heparanase inhibitors, such as heparin(oids), as treatment options.Kidney International (2007) 72, 543–548; doi:10.1038/sj.ki.5002337; published online 23 May 2007 [ABSTRACT FROM AUTHOR]

During the heterologous phase of experimental anti-glomerular basement membrane (anti-GBM) nephritis, leukocyte influx peaks within hours, whereas albuminuria occurs within 1 day. In the subsequent autologous phase, endogenous anti-GBM IgG develops and albuminuria persists. Heparan sulfate (HS) proteoglycans like syndecan-1 play multiple roles during inflammation and we evaluate its role in experimental anti-GBM disease using syndecan-1 knockout (sdc-1−/−) mice. During the heterologous phase, glomerular leukocyte/macrophage influx was significantly higher in the sdc-1−/− mice and this was associated with higher glomerular endothelial expression of specific HS domains. In the autologous phase, glomerular influx of CD4+/CD8+ T cells was higher in the sdc-1−/− mice and these mice had persistently higher albuminuria and serum creatinine levels than wild-type mice. This resulted in a more sever glomerular injury and increased expression of extracellular matrix proteins. The sdc-1−/− mice developed higher plasma levels and glomerular deposits of total mouse Ig and IgG1 anti-rabbit IgG, whereas the levels of mouse IgG2a anti-rabbit IgG were lower. Furthermore, decreased Th1 and higher Th2 renal cytokine/chemokine expression were found in the sdc-1−/− mice. Our studies show that syndecan-1 deficiency exacerbates anti-GBM nephritis shifting the Th1/Th2 balance towards a Th2 response.Kidney International (2007) 72, 1204–1215; doi:10.1038/sj.ki.5002514; published online 5 September 2007 [ABSTRACT FROM AUTHOR]

Trainers often use information from previous learning sessions to design or redesign a course. Although universities conducted numerous research integrity training in the past decades, information on what works and what does not work in research integrity training are still scattered. The latest meta-reviews offer trainers some information about effective teaching and learning activities. Yet they lack information to determine which activities are plausible for specific target groups and learning outcomes and thus do not support course design decisions in the best possible manner. This article wants to change this status quo and outlines an easy-to-use taxonomy for research integrity training based on Kirkpatrick's four levels of evaluation to foster mutual exchange and improve research integrity course design. By describing the taxonomy for research integrity training (TRIT) in detail and outlining three European projects, their intended training effects before the project started, their learning outcomes, teaching and learning activities, and their assessment instruments, this article introduces a unified approach. This article gives practitioners references to identify didactical interrelations and impacts and (knowledge) gaps in how to (re-)design an RI course. The suggested taxonomy is easy to use and enables an increase in tailored and evidence-based (re-)designs of research integrity training., (© 2023. The Author(s).)

This article presents a Quality Checklist for Responsible Conduct of Research (RCR) education. The Checklist is a tool for teachers and educational developers in RCR education containing the results of eleven reviews on the impact of RCR education. It makes these data accessible in a layered way, such that users can quickly find the information that they are interested in. The tool can complement the Predictive Modeling Tool , which allows users to fill out information about a course and provides recommendations on how the course's efficacy can be improved. We present our approach to developing the Quality Checklist prototype tool, the tool itself and how it can be used. We compare it to the PMT and discuss the added value of the Quality Checklist prototype tool, as well as its limitations. Finally, we indicate some of the ways in which the prototype tool could be further improved.

A core idea underlying nudging is that it helps individuals to achieve their own goals, yet many nudges actually aim at collective goals or specifically target the benefit of others. An example is nudging healthcare workers to be vaccinated against influenza. I distinguish between self-regarding nudges, which primarily benefit the nudgee, and other-regarding nudges, which mainly benefit others, and argue that the default justificatory reason to legitimize self-regarding nudges, namely the 'as judged by themselves' standard, does not apply and that we need to look for other justifications. I examine several possible moral justifications to support strong other-regarding nudges, namely beneficence, the harm principle and solidarity., (© 2020 The Authors. Bioethics published by John Wiley & Sons Ltd.)

As the complexity of ultrasound signal processing algorithms increases, it becomes more difficult to demonstrate their added value and thus robust validation strategies are required. We propose a method of manufacturing ultrasonic vascular phantoms mimicking an atheromatous plaque in an internal carotid artery bifurcation for applications in flow imaging and elastography. During the fabrication process, a soft inclusion mimicking a stenotic lipid pool was embedded within the vascular wall. Mechanical testing measured Young's moduli of the vascular wall and soft inclusion at 342  ±  25 kPa and 17  ±  3 kPa, respectively. B-mode, color Doppler, power Doppler, shear wave elastography, and strain elastography images of the different phantoms were produced to show the validity of the fabrication process. Because of their realistic geometries and mechanical properties, those phantoms may become advantageous for fluid-structure experimental modeling and validation of new ultrasound-based imaging technologies.

Ultrasound noninvasive vascular elastography (NIVE) has shown its potential to measure strains of carotid arteries to predict plaque instability. When two-dimensional (2D) strain estimation is performed, either in longitudinal or cross-sectional view, only in-plane motions are considered. The motions in elevation direction (i.e. perpendicular to the imaging plane), can induce estimation artifacts affecting the accuracy of 2D NIVE. The influence of such out-of-plane motions on the performance of axial strain and axial shear strain estimations has been evaluated in this study. For this purpose, we designed a diseased carotid bifurcation phantom with a 70% stenosis and an in vitro experimental setup to simulate orthogonal out-of-plane motions of 1 mm, 2 mm and 3 mm. The Lagrangian speckle model estimator (LSME) was used to estimate axial strains and shears under pulsatile conditions. As anticipated, in vitro results showed more strain estimation artifacts with increasing magnitudes of motions in elevation. However, even with an out-of-plane motion of 2.0 mm, strain and shear estimations having inter-frame correlation coefficients higher than 0.85 were obtained. To verify findings of in vitro experiments, a clinical LSME dataset obtained from 18 participants with carotid artery stenosis was used. Deduced out-of-plane motions (ranging from 0.25 mm to 1.04 mm) of the clinical dataset were classified into three groups: small, moderate and large elevational motions. Clinical results showed that pulsatile time-varying strains and shears remained reproducible for all motion categories since inter-frame correlation coefficients were higher than 0.70, and normalized cross-correlations (NCC) between radiofrequency (RF) images were above 0.93. In summary, the performance of LSME axial strain and shear estimations appeared robust in the presence of out-of-plane motions (<2 mm) as encountered during clinical ultrasound imaging.

In daily practice, pharmacists are regularly confronted with moral problems in which deciding what to do is not always a straightforward decision. In this contribution we show how the use of a specific method for moral deliberation can (in retrospect or prospective) aid moral judgements. We use the case of dispensing isotretinoin to demonstrate one ethical reflection method, namely the Utrecht Method.

Background: Transcranial magnetic stimulation (TMS) has proved effective in the treatment of depression. However, the step that was needed to progress from positive research results to the actual use of TMS to treat patients has raised a number of ethical concerns. The concerns extend beyond matters such as the safety of the technique, the patient's right of access to therapy and the patient's informed consent; ethics are involved because the new treatment can be mind-bending and can interfere with the patient's autonomy and decision-making capacity., Aim: To discuss ethical issues raised by the use of TMS in the treatment of depression., Method: We reviewed the relevant scientific literature., Results: The effects of the treatment on the patient's genuine wishes and on his or her views on the efficacy of the treatment are technique-related ethical issues that have not yet been adequately addressed. Furthermore, the effects of TMS on the patient's autonomy and mental capacity and the 'last resort' argument in relation to the effectiveness of the therapy are context-related considerations that warrant further discussion., Conclusion: There will have to be more research and discussion among researchers and clinicians about specific ethical questions before TMS can take its rightful place in clinical practice.

Heparan sulfate (HS) in the glomerular basement membrane (GBM) is important for regulation of the charge-dependent permeability. Heparanase has been implicated in HS degradation in several proteinuric diseases. This study analyzed the role of heparanase in HS degradation in Adriamycin nephropathy (AN), a model of chronic proteinuria-induced renal damage. Expression of heparanase, HS, and the core protein of agrin (to which HS is attached) was determined on kidney sections from rats with AN in different experiments. First, expression was examined in a model of unilateral AN in a time-course study at 6-wk intervals until week 30. Second, rats were treated with the hydroxyl radical scavenger dimethylthiourea (DMTU) during bilateral AN induction. Finally, 6 wk after AN induction, rats were treated with angiotensin II receptor type 1 antagonist (AT1A) or vehicle for 2 wk. Heparanase expression was increased in glomeruli of rats with AN, which correlated with HS reduction at all time points and in all experiments. Treatment with DMTU prevented the increased heparanase expression, the loss of GBM HS, and reduced albuminuria. Finally, treatment of established proteinuria with AT1A significantly reduced heparanase expression and restored glomerular HS. In conclusion, an association between heparanase expression and reduction of glomerular HS in AN was observed. The effects of DMTU suggest a role for reactive oxygen species in upregulation of heparanase. Antiproteinuric treatment by AT1A decreased heparanase expression and restored HS expression. These results suggest involvement of radicals and angiotensin II in the modulation of GBM permeability through HS and heparanase expression.

Purpose: Recognition of hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial carcinoma from sporadic carcinoma by histologic features as compared with colonic cases., Study Design: Case-control study., Methods and Materials: From the files of the Nijmegen Hereditary Cancer Clinic, HNPCC-related (n = 6) endometrial and colorectal (n = 18) carcinomas were selected. For every HNPCC-related tumor, 2 sporadic control cases were included. The tumors were evaluated for the following 7 pathologic features: tumor differentiation, T-stage, growth pattern, presence of Crohn-like lymphoid reaction, mucinous differentiation, presence of lymphangioinvasive growth, and the amount of tumor-infiltrating lymphocytes., Results: HNPCC-related endometrial carcinomas were significantly more often poorly differentiated (83% versus 27%), more often showed the presence of a Crohn-like lymphoid reaction (100% versus 13%) and lymphangioinvasive growth (67% versus 0%), and high number of tumor-infiltrating lymphocytes were more often present (100% versus 36%) compared with sporadic endometrial carcinomas. The differences between HNPCC and sporadic colorectal cancer specimens were less discriminating., Conclusions: HNPCC-related endometrial carcinomas are characterized by poor differentiation, more frequent Crohn-like lymphoid reaction, lymphangioinvasive growth and more tumor-infiltrating lymphocytes. These features therefore might form the basis for selecting patients for counseling in a hereditary cancer clinic or testing for microsatellite instability or mutation analysis of mismatch repair genes, especially when they are of relatively young age.

IFN-gamma plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-gamma production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-gamma production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% down-modulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-gamma response and promoting the infiltration of the site of infection by monocytes.

Objectives: Quality of online health resources remains a much debated topic, despite considerable international efforts. The lack of a systematic and comprehensive conceptual analysis is hindering further progress. Therefore we aim at clarifying the origins, nature and interrelations of pertinent concepts. Further, we claim that quality is neither a necessary nor a sufficient condition for Internet health resources to produce an effect offline. As users' trust is also required, we examine the relation of quality aspects to trust building online., Methods: We reviewed and analyzed the key documentation and deliverables of quality initiatives, as well as relevant scientific publications. Using the insights of philosophy, we identified the elementary dimensions which underlie the key concepts and theories presented so far in the context of online health information quality. We examined the interrelations of various perspectives and explored how trust as a phenomenon relates to these dimensions of quality., Results: Various aspects associated with the quality of online health resources originate from four conceptual dimensions: epistemic, ethical, economic and technological. We propose a conceptual framework that incorporates all these perspectives. We argue that total quality exists only if all four dimensions have been addressed adequately and that high total quality is conducive to warranted trust., Conclusions: Quality and trust are intertwined, but distinct concepts, and their relation is not always straightforward. Ideally, trust should track quality. Apprehending the composition of these concepts will help to understand and guide the behavior of both users and providers of online information, as well as to foster warranted trust in online resources. The framework we propose provides a conceptual starting point for further deliberations and empirical work.