Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients

<p>Abstract</p> <p>Background</p> <p>Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.2 mg/kg/eow). An assessment report from the European Medicines Agency (EMA) raised serious concerns about an increase in adverse events at lower dosages of agalsidase beta. We determined the influence of the shortage on clinical event incidence and the most sensitive biochemical marker (lysoGb3) in Dutch Fabry patients.</p> <p>Methods</p> <p>The incidence of clinical events per person per year was calculated from start of agalsidase beta treatment until the shortage, and was compared to the incidence of clinical events during the shortage period. In addition, plasma lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires were analysed.</p> <p>Results</p> <p>All thirty-five Dutch Fabry patients using agalsidase beta (17 males) were included. Mean clinical event incidence was unchanged: 0.15 events per person per year before versus 0.15 during the shortage (p = 0.68). In total 28 clinical events occurred in 14 patients during 4.6 treatment years, compared to 7 events in 6 patients during the 1.3 year shortage period. eGFR and BPI scores were not significantly altered. Two SF-36 subscales were significantly but minimally reduced in females. In males, lysoGb3 increased with a median of 8.1 nM (range 2.5 - 29.2) after 1 year of shortage (p = 0.001). Increases in lysoGb3 were found in both patients switching to agalsidase alpha and on a reduced agalsidase beta dose. Antibody status, treatment duration or clinical event incidence showed no clear correlation to lysoGb3 increases.</p> <p>Conclusions</p> <p>No increase in clinical event incidence was found in the adult Dutch Fabry cohort during the agalsidase beta shortage. Increases in lysoGb3, however, suggest recurrence of disease activity.</p

Identifying the Added Value of Virtual Reality for Treatment in Forensic Mental Health: A Scenario-Based, Qualitative Approach

Background: Although literature and practice underline the potential of virtual reality (VR) for forensic mental healthcare, studies that explore why and in what way VR can be of added value for treatment of forensic psychiatric patients is lacking.Goals: This study aimed to identify (1) points of improvements in existing forensic mental health treatment of in- and outpatients, (2) possible ways of using VR that can improve current treatment, and (3) positive and negative aspects of the use of VR for the current treatment according to patients and therapists.Methods: Two scenario-based methods were used. First, semi-structured interviews were conducted with eight therapists and three patients to elicit scenarios from them. Based on these results, six scenarios about possibilities for using VR in treatment were created and presented to 89 therapists and 19 patients in an online questionnaire. The qualitative data from both methods were coded independently by two researchers, using the method of constant comparison.Results: In the interviews, six main codes with accompanying sub codes emerged. Ideas for improvement of treatment were grouped around the unique characteristics of the forensic setting, characteristics of the complex patient population, and characteristics of the type of treatment. For possibilities of VR, main codes were skills training with interaction, observation of situations or stimuli without interaction, and creating insight for others into the patient. The questionnaire resulted in a broad range of insights into potential positive and negative aspects of VR related to the current treatment, the patient, the content of a VR application, and practical matters.Conclusion: VR offers a broad range of possibilities for forensic mental health. Examples are offering training of behavioral and cognitive skills in a realistic context to bridge the gap between a therapy room and the real world, increasing treatment motivation, being able to adapt a VR application to individual patients, and providing therapists with new insights into a patient. These findings can be used to ground the development of new VR applications. Nevertheless, we should remain critical of when in the treatment process and for whom VR could be of added value

Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

The TGF-β family member GDF-15 promotes lesion formation and plaque instability in atherosclerosis-prone LDLr-deficient mice

A Disease-Associated MicroRNA Cluster Links Inflammatory Pathways and an Altered Composition of Leukocyte Subsets to Noninfectious Uveitis

PURPOSE. The cause of noninfectious uveitis (NIU) is poorly understood but is considered to be mediated by a complex interplay between genetic, environmental, and-relatively unexplored-epigenetic factors. MicroRNAs (miRNAs) are noncoding small RNAs that are important epigenetic regulators implicated in pathologic signaling. Therefore, we mapped the circulating miRNA-ome of NIU patients and studied miRNA perturbations within the broader context of the immune system.METHODS. We designed a strategy to robustly identify changes in the miRNA profiles of two independent cohorts totaling 54 untreated patients with active and eye-restricted disease and 26 age-matched controls. High-resolution miRNA-ome data were obtained by TaqMan OpenArray technology and subsequent RT-qPCR. Flow cytometry data, and proteomic data spanning the cellular immune system, were used to map the uveitis-miRNA signature to changes in the composition of specific leukocyte subsets in blood.RESULTS. Using stringent selection criteria, we identified and independently validated an miRNA cluster that is associated with NIU. Pathway enrichment analysis for genes targeted by this cluster revealed significant enrichment for the PI3K/Akt, MAPK, FOXO, and VEGF signaling pathways, and photoreceptor development. In addition, unsupervised multidomain analyses linked the presence of the uveitis-associated miRNA cluster to a different composition of leukocyte subsets, more specifically, CD16(+)CD11c(+)HLA-DR- cells.CONCLUSIONS. Together, this study identified a unique miRNA cluster associated with NIU that was related to changes in leukocyte subsets demonstrating systemic changes in epigenetic regulation underlying NIU

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

Rationale:Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.Objective:Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.Methods and Results:We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4(+) and CD8(+) T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells.Conclusions:This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease

Completion strategy or emphasis manipulation? Task support for teaching information problem solving

While most students seem to solve information problems effortlessly, research shows that the cognitive skills for effective information problem solving are often underdeveloped. Students manage to find information and formulate solutions, but the quality of their process and product is questionable. It is therefore important to develop instruction for fostering these skills. In this research, a 2-h online intervention was presented to first-year university students with the goal to improve their information problem solving skills while investigating effects of different types of built-in task support. A training design containing completion tasks was compared to a design using emphasis manipulation. A third variant of the training combined both approaches. In two experiments, these conditions were compared to a control condition receiving conventional tasks without built-in task support. Results of both experiments show that students' information problem solving skills are underdeveloped, which underlines the necessity for formal training. While the intervention improved students’ skills, no differences were found between conditions. The authors hypothesize that the effective presentation of supportive information in the form of a modeling example at the start of the training caused a strong learning effect, which masked effects of task support. Limitations and directions for future research are presented

Brood parasitism in the red-chested cuckoo Cuculus solitarius

Dissertation (M.Sc.) -- University of Stellenbosch, 1999.Full text to be digitised and attached to bibliographic record

Is there a future for livestock farming in Southern Namibia's communal lands?

Bibliography: leaves 26-31