P1 Large scale three-dimensional cartilage tissue engineering using adult bone marrow stem cells from OA patients

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Pharmacological characterization of allosteric modulators: a case for chemokine receptors

Chemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued, most prospective drugs failed in the follow-up studies due to clinical inefficacy, and hence there is a clear need for alternative approaches. Allosteric modulators of receptor function represent an excellent opportunity for novel drugs, as they modulate receptor activation in a controlled manner and display increased selectivity, and their pharmacological profile can be insurmountable. Here, we discuss allosteric ligands and their pharmacological characterization for modulation of chemokine receptors. Ligands are included if (1) they show clear signs of allosteric modulation in vitro and (2) display evidence of binding in a topologically distinct manner compared to endogenous chemokines. We discuss how allosteric ligands affect binding of orthosteric (endogenous) ligands in terms of affinity as well as binding kinetics in radioligand binding assays. Moreover, their effects on signaling events in functional assays and how their binding site can be elucidated are specified. We substantiate this with examples of published allosteric ligands targeting chemokine receptors and hypothetical graphs of pharmacological behavior. This review should serve as an effective starting point for setting up assays for characterizing allosteric ligands to develop safer and more efficacious drugs for chemokine receptors and, ultimately, other G protein-coupled receptors.Medicinal Chemistr

Propulsive force in front crawl swimming

To evaluate the propulsive forces in front crawl arm swimming, derived from a three-dimensional kinematic analysis, these values were compared with mean drag forces. The propulsive forces during front crawl swimming using the arms only were calculated using three-dimensional kinematic analysis combined with lift and drag coefficients obtained in fluid laboratories. Since, for any constant swimming speed, the mean propulsive force should be equal to the mean drag force acting on the body of the swimmer, mean values of the calculated propulsive forces were compared with the mean drag forces obtained from measurements on a Measuring Active Drag (MAD) system. The two methods yielded comparable results, the mean difference between them being only 5% (2 N). We conclude that propulsive forces obtained from three-dimensional kinematic analysis provide realistic values. The calculation of the propulsive force appears to be rather sensitive to the point on the hand at which the velocity is estimated and less sensitive to the orientation of the hand

Use of skin substitute dressings in the treatment of staphylococcal scalded skin syndrome in neonates and young infants

Background: Staphylococcal scalded skin syndrome (SSSS) is a rare toxin-mediated skin disease caused by Staphylococcus aureus and seen in infants and children younger than 5 years. Objectives: The supportive role of skin substitutes in SSSS is stressed as a new and relatively unknown method. Methods: Retrospective observational case-series study, in neonates and young infants diagnosed with SSSS. Results: Seven infants with SSSS, treatment with antibiotics, skin substitutes, strict pain relief strategy and prognosis were described. One of them was severely affected and deceased. Conclusion: This study describes 7 infants with SSSS and stresses the important role of skin substitutes as Omiderm® and Suprathel® as valuable adjuvant treatment modality. Copyrigh

CGtag: Complete genomics toolkit and annotation in a cloud-based Galaxy

Background: Complete Genomics provides an open-source suite of command-line tools for the analysis of their CG-formatted mapped sequencing files. Determination of; for example, the functional impact of detected variants, requires annotation with various databases that often require command-line and/or programming experience; thus, limiting their use to the average research scientist. We have therefore implemented this CG toolkit, together with a number of annotation, visualisation and file manipulation tools in Galaxy called CGtag (Complete Genomics Toolkit and Annotation in a Cloud-based Galaxy).Findings: In order to provide research scientists with web-based, simple and accurate analytical and visualisation applications for the selection of candidate mutations from Complete Genomics data, we have implemented the open-source Complete Genomics tool set, CGATools, in Galaxy. In addition we implemented some of the most popular command-line annotation and visualisation tools to allow research scientists to select candidate pathological mutations (SNV, and indels). Furthermore, we have developed a cloud-based public Galaxy instance to host the CGtag toolkit and other associated modules.Conclusions: CGtag provides a user-friendly interface to all research scientists wishing to select candidate variants from CG or other next-generation sequencing platforms' data. By using a cloud-based infrastructure, we can also assure sufficient and on-demand computation and storage resources to handle the analysis tasks. The tools are freely available for use from an NBIC/CTMM-TraIT (The Netherlands Bioinformatics Center/Center for Translational Molecular Medicine) cloud-based Galaxy instance, or can be installed to a local (production) Galaxy via the NBIC Galaxy tool shed

Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive

Het Lagekostenbedrijf in 1999

In dit rapport zijn de resultaten en de ervaringen van het Lagekostenbedrijf in 1999 beschreven

Design of an RCT on cost-efectiveness of group schema therapy versus individual schema therapy for patients with Cluster-C personality disorder: the QUEST-CLC study protocol

Background Given the high prevalence of Cluster-C Personality Disorders (PDs) in clinical populations, disease burden, high societal costs and poor prognosis of comorbid disorders, a major gain in health care can be achieved if Cluster-C PDs are adequately treated. The only controlled cost-effectiveness study published so far found Individual Schema Therapy (IST) to be superior to Treatment as Usual (TAU). Group ST (GST) might improve cost-effectiveness as larger numbers can be treated in (>50%) less time compared to IST. However, to date there is no RCT supporting its (cost-) effectiveness. The overall aim of this study is to assess the evidence for GST for Cluster-C PDs and to improve treatment allocation for individual patients. Three main questions are addressed: 1) Is GST for Cluster-C PDs (cost-) effective compared to TAU? 2) Is GST for Cluster-C PDs (cost-) effective compared to IST? 3) Which patient-characteristics predict better response to GST, IST, or TAU? Methods In a multicenter RCT, the treatment conditions GST, IST, and TAU are compared in 378 Cluster-C PD patients within 10 sites. GST and IST follow treatment protocols and are completed within 1 year. TAU is the optimal alternative treatment available at the site according to regular procedures. Severity of the Cluster-C PD is the primary outcome, assessed with clinical interviews by independent raters blind for treatment. Functioning and wellbeing are important secondary outcomes. Assessments take place at week 0 (baseline), 17 (mid-GST), 34 (post-GST), 51 (postbooster sessions of GST), and 2 years (FU). Patient characteristics predicting better response to a specifc treatment are studied, e.g., childhood trauma, autistic features, and introversion. A tool supporting patients and clinicians in matching treatment to patient will be developed. An economic evaluation investigates the cost-effectiveness and costutility from a societal perspective. A process evaluation by qualitative methods explores experiences of participants, loved ones and therapists regarding recovery, quality of life, and improving treatment. Discussion This study will determine the (cost-)effectiveness of treatments for Cluster-C PDs regarding treatment type as well as optimal matching of patient to treatment and deliver insight into which aspects help Cluster-C-PD patients recover and create a fulfilling life. Trial registration Dutch Trial Register: NL9209. Registered on 28-01-2021