Pathology - Journal Articles
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Item A novel locus for restless legs syndrome maps to chromosome 19p in an Irish pedigree(Springer, 2021-03-14) Skehan, Evelyn B.; Abdulrahim, Manal M. A.; Parfrey, Nollaig A.; Hand, Collette K.Restless legs syndrome (RLS) is a common, sleep-related movement disorder. The symptoms follow a circadian pattern, worsening in the evening or night, leading to sleep disruption and daytime somnolence. Familial forms of RLS have been described and usually display an autosomal dominant pattern of inheritance. To date, linkage analysis has identified nine RLS loci, but no specific causative gene has been reported. Association mapping has highlighted a further four genomic areas of interest. We have conducted a genome-wide linkage analysis in an Irish autosomal dominant RLS pedigree with 11 affected members. Significant linkage was found on chromosome 19p for a series of microsatellite markers, with a maximum two-point LOD score of 3.59 at θ = 0.0 for marker D19S878. Recombination events, identified by haplotype analysis, define a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to an interval of 2.5 Mb. This study provides evidence of a novel RLS locus and provides further evidence that RLS is a genetically heterogenous disorder.Item CALR-positive essential thrombocythaemia preceded by immune thrombocytopaenia(Irish Medical Organisation, 2021) Barrett, A.; Cahill, Mary R.Presentation: The patient initially presented with gum bleeding and a petechial rash. Diagnosis: The patient was found to be severely thrombocytopaenic and bone marrow biopsy showed a marked excess of megakaryocytes consistent with a diagnosis of immune thrombocytopaenia (ITP). She underwent splenectomy. Seven years following splenectomy, her platelet count began to rise again, and repeat bone marrow sampling revealed an increase in megakaryocytes with evidence of clustering. On further testing the calreticulin (CALR) exon 9 variant was found and a diagnosis of essential thrombocythaemia (ET) was made. Treatment: Thromboprophylaxis and cytoreductive therapy (hydroxyurea) were initiated following ET diagnosis. Discussion: Possible mechanisms of ET (platelet excess) following ITP (platelet deficiency) include the known associations of autoimmune conditions and malignancy and the effects of immunosuppression and splenectomy in tumorigenesis. To our knowledge, this is the first recorded case of ITP preceding later development of CALR- positive ET.Item Engagement of Fas on macrophages modulates poly I:C induced cytokine production with specific enhancement of IP-10(Public Library of Science, 2015) Lyons, Caitríona M.; Fernandes, Philana; Fanning, Liam J.; Houston, Aileen M.; Brint, Elizabeth K.; Science Foundation IrelandViral double-stranded RNA (dsRNA) is recognised by pathogen recognition receptors such as Toll-Like Receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), and results in cytokine and interferon production. Fas, a well characterised death receptor, has recently been shown to play a role in the inflammatory response. In this study we investigated the role of Fas in the anti-viral immune response. Stimulation of Fas on macrophages did not induce significant cytokine production. However, activation of Fas modified the response of macrophages to the viral dsRNA analogue poly I:C. In particular, poly I:C-induced IP-10 production was significantly enhanced. A similar augmentation of IP-10 by Fas was observed following stimulation with both poly A:U and Sendai virus. Fas activation suppressed poly I:C-induced phosphorylation of the MAP kinases p38 and JNK, while overexpression of the Fas adaptor protein, Fas-associated protein with death domain (FADD), activated AP-1 and inhibited poly I:C-induced IP-10 production. Consistent with an inhibitory role for AP-1 in IP-10 production, mutation of the AP-1 binding site on the IP-10 promoter resulted in augmented poly I:C-induced IP-10. These results demonstrate that engagement of the Fas receptor plays a role in modifying the innate immune response to viral RNA.