Polymorph Function in Ankylosing Spondylitis

The possible role of gram-negative bacteria in the causation of seronegative spondyloarthropathies, and the response of polymorphs to gram-negative bacteria in ankylosing spondylitis, forms the basis of this study. Polymorph response to arthritogenic gram-negative bacteria in ankylosing spondylitis patients were examined by comparing them to HLA-B27 positive and negative healthy controls, and to a group of rheumatoid arthritis patients. Bacteria used in the assays had either a speculative or clear association with the seronegative spondyloarthropathies. Three different assays were used in this study to evaluate i) Polymorph motility ii) Polymorph chemiluminescence response to various stimuli and iii) Phagocytic ingestion of radio-labelled gram-negative bacteria. No difference was shown in motility between ankylosing spondylitis and normal polymorphs, although a culture filtrate of K. pneumoniae was shown to have some chemotactic quality. In addition phagocytic ingestion of enteric bacteria by polymorphs from ankylosing spondylitis patients was similar to normals. Therefore no abnormalities were shown in either the motility or phagocytic capacity of ankylosing spondylitis polymorphs. Initial studies using isolated polymorphs showed no difference in chemiluminescence response between patients and normal controls. A whole blood assay was then refined for use in this study, and chemiluminescence basal response was shown to be significantly increased in ankylosing spondylitis polymorphs compared to normal polymorphs. This indicated a pre-activation of normal polymorphs during the cell separation procedure, in our initial studies; thus concealing any inherent difference in chemiluminescence response between patient and normal polymorphs. Subsequent assays also showed a significantly enhanced chemiluminescence response in ankylosing spondylitis patients polymorphs compared to normals following stimulation with gram-negative bacteria and S. aureus. Contrastingly polymorphs from patients with rheumatoid arthritis showed an increase only to S. aureus. These results could indicate that gram-negative bacteria may contribute to an enhanced chemiluminescence response in ankylosing spondylitis patients, which is not specific. In addition, chemiluminescence response did not differ between HLA-B27 positive and negative normals, suggesting that enhanced activation develops with disease, rather than being inherent. Conclusions suggest a chronic activation and exposure of ankylosing spondylitis to gram-negative triggers

Interrogating the relationship between poverty, attainment and mental health and wellbeing : the importance of social networks and support - a Scottish case study

The poverty-related attainment gap is an internationally recognised problem. It resides within a culture of performativity in which international comparators, underpinned by neo-liberal ideology, drive national policy. This conceptual paper interrogates the relationship between poverty, attainment and children’s mental health and wellbeing to inform public policy and practice in Scotland and beyond. A key theme identified from the analysis of the literature is the nature, quality and strength of social and support networks around schools, families and children. This is contextualised within a discussion of the nature of childhood poverty and mental health in children in Scotland and the response of the Scottish Government. A focus on educational policy and schools alone will not in itself address the poverty-related attainment gap. What is required is a holistic focus on public policy, informed by interdisciplinary research, and a focus on building a strong infrastructure of support around schools, families and communities

'Closing the gap' : systems leadership is no leadership at all without a moral compass - a Scottish perspective

This conceptual paper provides a critical analysis of the current convergence of major policy initiatives in Scotland to improve learning and teaching, promote greater equity and close the attainment gap through systems level leadership and change. It is neither an empirical study nor a literature review but synthesises across a range of fields – social justice, poverty, social mobility, school improvement, leadership and policy – in order to cast light on the problem and to inform public policy and practice. However system level leadership is not unproblematic, with the terms system and leadership seen as malleable concepts (Boylan 2016), nor can it be seen as a panacea for all ills. The paper argues that educational policy needs to be seen as residing within wider social policy. Without recourse to addressing systemic inequalities in society and building the infrastructure and support structures around schools, schools, on their own, are unlikely to rise to the challenge. The paper argues for a melding of distributive leadership (with emancipatory intent and purpose) with systems leadership, characterised by meaningful collaboration and partnerships from 'within – to between – and beyond' schools (Chapman 2014), imbued with moral purpose

Identification and characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene trapped isoform

<p>Abstract</p> <p>Background</p> <p>The Dlc1 (deleted in liver cancer 1) tumour suppressor gene codes for a RhoGTPase activating protein that is found inactivated in many tumour types. Several transcriptional isoforms have been described but the functional significance and tissue distribution of each form is presently poorly understood. Also, differences in the number of isoforms and splice variants reported still exist between different mammalian species. In order to better understand the number and function of the different variants of the Dlc1 gene in the mouse, we have carried out a detailed analysis. Extensive 3' RACE experiments were carried out in order to identify all possible Dlc1 isoforms and splice variants in the mouse. In addition, we have generated a gene trapped mouse that targets one of these isoforms in order to study its biological function. The effect of this gene trap insertion on the splicing of other isoforms has also been studied.</p> <p>Results</p> <p>In addition to the known 6.1 and 6.2 Kb transcripts of Dlc1, our study revealed the existence of a novel 7.6 Kb transcriptional isoform in the mouse, which corresponds to the human 7.4 Kb (KIAA1723) cDNA transcript. A gene trapped embryonic cell line, with an insertion between Exon 1 and 2 of the 6.1 Kb transcriptional isoform, was used to generate a transgenic mouse. This line showed a significant reduction in the expression of the trapped isoform. However, reduced expression of the other isoforms was not seen. Mice heterozygous for the gene trapped allele were phenotypically normal, but homozygous mutant embryos did not survive beyond 10.5 days post coitum. Dlc1^gt/gtembryos showed defects in the brain, heart, and placental blood vessels. Cultured serum-free mouse embryo cells from Dlc1 deficient embryos had elevated RhoA activity and displayed alterations in the organization of actin filaments and focal adhesions. The Dlc1 deficient cells also exhibited increased wound closure in an <it>in vitro </it>scratch assay.</p> <p>Conclusions</p> <p>The mouse has three major transcriptional isoforms of the Dlc1 gene that are differentially expressed in various tissues. A mouse with exon 1 of the 6.1 Kb transcript gt resulted in hypomorphic expression of Dlc1 protein and an embryonic lethal phenotype in the homozygous condition, which indicates that this isoform plays a major role in mouse development. The Dlc1 deficient cells showed altered cytoskeleton structure, increased RhoA activity and cellular migration.</p

Diagnostic work-up of patients presenting in primary care with lower abdominal symptoms:which faecal test and triage strategy should be used?

Bowel endoscopy referrals from primary care have increased steadily over recent years. However, most patients do not have significant colorectal disease (SCD). Therefore, strategies to select those who would benefit most from endoscopy are of current interest. A recent study developed a multivariable diagnostic model for SCD with routine clinical information, extended with quantitative faecal calprotectin (f-C) point-of-care (POC) testing and/or qualitative POC faecal immunochemical test (FIT) for haemoglobin (f-Hb) results. This study used POC tests for both f-C and f-Hb; however, POC tests have many disadvantages and there are several reasons why quantitative measurements of f-Hb are advantageous. Quantitative faecal immunochemical tests have been used very successfully in triage of patients presenting in primary care as a rule-out test. Studies have compared f-C and f-Hb in this clinical context and consider that f-C is not required in diagnosis. A single quantitative f-Hb result, without any clinical information, could be sufficient to decide whom to refer for endoscopy and, because of the significant overlap of symptoms in those with and without SCD, could be the primary investigation performed. Please see related article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0684-5