Search

Vascular Ehlers–Danlos syndrome or Ehlers–Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by COL3A1 mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and/or haploinsufficiency mutations in COL3A1 deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing COL3A1 mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect COL3A1 pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature COL3A1 mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target COL3A1 exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons. [ABSTRACT FROM AUTHOR]

Down syndrome is a genetic-based disorder that results from the triplication of chromosome 21, leading to an overexpression of many triplicated genes, including the gene encoding Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A). This protein has been observed to regulate numerous cellular processes, including cell proliferation, cell functioning, differentiation, and apoptosis. Consequently, an overexpression of DYRK1A has been reported to result in cognitive impairment, a key phenotype of individuals with Down syndrome. Therefore, downregulating DYRK1A has been explored as a potential therapeutic strategy for Down syndrome, with promising results observed from in vivo mouse models and human clinical trials that administered epigallocatechin gallate. Current DYRK1A inhibitors target the protein function directly, which tends to exhibit low specificity and selectivity, making them unfeasible for clinical or research purposes. On the other hand, antisense oligonucleotides (ASOs) offer a more selective therapeutic strategy to downregulate DYRK1A expression at the gene transcript level. Advances in ASO research have led to the discovery of numerous chemical modifications that increase ASO potency, specificity, and stability. Recently, several ASOs have been approved by the U.S. Food and Drug Administration to address neuromuscular and neurological conditions, laying the foundation for future ASO therapeutics. The limitations of ASOs, including their high production cost and difficulty delivering to target tissues can be overcome by further advances in ASO design. DYRK1A targeted ASOs could be a viable therapeutic approach to improve the quality of life for individuals with Down syndrome and their families. [ABSTRACT FROM AUTHOR]

Objective: The objective of the scoping review will be to understand and describe risk factors associated with surgical site infection (SSI) in an orthopaedic surgery population in Sub-Saharan Africa and South Africa. This paper describes the protocol that will be used for the scoping review. Method: A comprehensive literature search will be conducted using MEDLINE (PubMed), CINAHL (EBSCO), Embase and Cochrane Libraries to identify articles meeting the inclusion criteria, including both published and grey literature, in order to provide a broad overview of the reported risk factors associated with patients who have undergone an orthopaedic surgery with an outcome of SSI within 90 days of a procedure. Additional studies will be sourced by exploring the reference list of included eligible studies. By using a combination of the Population, Exposure, Outcome framework, terms and synonyms related to each category, in different variations, along with Boolean operators (AND, OR, NOT) in the search strategy, identified comprehensive and relevant literature for the scoping review. Results: It is anticipated the results will provide a baseline of risk factors that will inform the development of a risk assessment tool for clinical use. Conclusion: This protocol will inform the development of a scoping review to describe factors associated with SSIs following orthopaedic surgery in Sub-Saharan Africa and South Africa. [ABSTRACT FROM AUTHOR]

This paper explores the implications of emotional labour for workers with disabilities, drawing on qualitative data from interviews with 59 respondents who had disabilities and who worked in service sector occupations. The analysis illustrates that employer demands for emotional labour may prove difficult for workers with a range of disabilities, including psychiatric diagnoses, learning difficulties and physical impairments. Analysis also points to the ways in which the non-accommodating nature of many workplaces often forces workers with disabilities to engage in "extra" emotion work in the interests of fitting in and concealing/ downplaying their impairments. (Contains 2 tables and 3 notes.)