FcgammaRIIb: Signalling aspects and implications for autoimmune disease

Fc receptors (FcRs) provide a critical link between the humoral and cellular arms of the immune system through the targeting of antigen-antibody complexes to effector cells and modulation of an immune response. B cells express a low affinity IgG Fc receptor, FcgammaRIIb, which negatively regulates antigen receptor-mediated proliferative signalling through the binding of IgG- containing immune complexes. Co-ligation of the B cell antigen receptor (BCR) complex with FcyRIIb promotes the induction of B cell growth arrest in the G1 phase of the cell cycle and this ultimately results in commitment to apoptosis. Furthermore, FcgammaRIIb co-ligation also acts as an important negative feedback mechanism to switch off ongoing B cell responses once the pathogen has been cleared. Thus, on resting B cells, FcgammaRIIb acts to prevent aberrant B cell activation by immune complexes and suppresses the potential induction of autoimmunity. It was therefore the aim of this study to identify and characterise the key signalling pathways responsible for FcgammaRIIb-mediated negative regulation of BCR-mediated proliferation. During the course of this study, it emerged that in normal splenic B cells, FcgammaRIIb signalling appears to act by modulating the BCR signalling threshold, via the rapid recruitment and phosphorylation of a variety of phosphatases that ultimately result in the uncoupling of the BCR from MAPKinase activation. We have corroborated these published findings that the tyrosine kinases SHP-1 and SHP-2 and the inositol 5'-phosphatase, SHIP-1, are recruited during FcgammaRIIb signalling and we have extended these studies in that we have generated novel data regarding their mechanism of action. We now also show that FcgammaRIIb co-ligation, in addition to preventing the initiation of MAPKinase signalling, induces the rapid recruitment and activation of the MAPKinase phosphatase, Pac-1, resulting in the abrogation of ongoing ErkMAPK signalling. Furthermore, we show for the first time that FcgammaRIIb coligation results in the activation of the inositol 3'-phosphatase, PTEN, with kinetics which suggest that recruitment of this tumour suppressor element antagonises BCR-coupiing to the PI-3-K/Akt pathway and hence abrogates pro survival mechanisms in B cells. Taken together, this dual pronged mechanism of FcgammaRIIb-mediated abrogation of the ErkMAPKinase and Akt pathways provides a molecular rationale for the biological consequences of BCR-FcgammaRIIb co-ligation, namely commitment to growth arrest and apoptosis. Finally, analysis of potential downstream molecular targets of ErkMAPKinase and Akt revealed that FcgammaRIIb-signalling not only inhibits the phosphorylation and activation of the tumour suppressor protein, retinoblastoma (Rb), but also induces the phosphorylation and activation of the pro-apoptotic tumour suppressor protein, p53 and disruption of mitochondrial potential. Inhibition of Rb activation and consequent induction of genes required for the transition to S phase, is consistent with the observed FcgammaRIIb-mediated arrest in the G1 phase of the cell cycle. Similarly induction of p53 and collapse of mitochondrial integrity provide insight into the effector mechanisms underlying FcgammaRIIb-driven commitment to B cell apoptosis.To maintain homeostasis and tolerance to self-antigens, B cells require a balance of signals via activatory and inhibitory co-receptors. Thus, aberrant signalling through FcgammaRIIb during B cell development could lead to the induction of autoimmunity and/or promote the progression of certain autoimmune diseases. Consistent with this, recently published studies in FcgammaRIIb-deficient mice suggested that this lesion could result in collagen-induced arthritis (CIA) in normally resistant strains of mice. (Abstract shortened by ProQuest.)

The impact on complication rates of delayed routine pessary reviews during the COVID-19 pandemic

INTRODUCTION AND HYPOTHESIS: During the COVID-19 pandemic, guidance was issued in the United Kingdom advising a delay in routine pessary reviews. The impact of this has not been fully explored. The null hypothesis for this study is that delayed routine pessary reviews during the COVID-19 pandemic did not result in a statistically significant increase in complication rate. METHODS: A retrospective comparative cohort study was conducted in NHS Tayside, Scotland, involving 150 patients pre-pandemic and 150 patients during the COVID-19 pandemic (before exclusions). Their notes were reviewed identifying age, care provider, pessary type, length of pessary usage, review date, time elapsed since the previous review, bleeding/infection/ulceration, removal issues, pessary replacement and outcome. Patients excluded were those with no pessary in situ at review, reviews at ≤4 months and >8 months (pre-pandemic) and reviews at ≤8 months (COVID-19 pandemic). RESULTS: The pre-pandemic group (n=106) had average review times of 10.1,6.2 and 6.2 months for cubes, rings and all others. Overall rates of bleeding/infection/ulceration; reported removal issues; and pessary subsequently not replaced were 9.4%, 11.3% and 5.7% respectively. The COVID-19 pandemic group (n=125) had average review times of 14.7, 10.8 and 11.4 months for cubes, rings and all others. Overall rates of bleeding/infection/ulceration; reported removal issues; and pessary subsequently not replaced were 21.6%, 16.0%, and 12.0% respectively. CONCLUSIONS: Overall, there was a significant increase in rates of bleeding/ulceration/infection (p=0.01). When individual pessaries were considered, this only remained true for rings (p=0.02). Our data would suggest that routine ring pessary reviews should not be extended beyond 6 months or risk bleeding/ulceration/infection

The Causes and Consequences of a Colonising Pollinator

Relatório de estágio do mestrado em Ensino da Educação Física dos Ensinos Básicos e Secundário, apresentado à Faculdade de Ciências do Desporto e da Educação Física da Universidade de CoimbraO Relatório Final de Estágio insere-se no âmbito da unidade curricular Relatório de Estágio, do 2º ano do Mestrado em Ensino da Educação Física dos Ensinos Básico e Secundário, da Faculdade de Ciências do Desporto e Educação Física da Universidade de Coimbra. Esta etapa representa o culminar da formação académica em que são colocados em prática, em contexto real, todos os conhecimentos adquiridos até ao momento. Todas as experiências vivenciadas, aprendizagens e conhecimentos adquiridos permitem-nos hoje o desempenho de uma prática pedagógica de mestria na área da Educação Física. O Relatório Final de Estágio pretende a realização de uma reflexão por parte do estagiário, relativa às atividades desenvolvidas e aprendizagens realizadas durante o estágio pedagógico, contemplando sempre as suas expectativas iniciais. Este documento contempla três grandes capítulos. O primeiro é uma área essencialmente descritiva relativamente à contextualização pedagógica. O segundo consiste numa reflexão crítica das práticas pedagógicas realizadas. Por último, o terceiro capítulo pretende ser um aprofundamento de um tema/problema. O tema/problema selecionado foram as atitudes dos alunos sem deficiência face inclusão de alunos com necessidades educativas especiais na Educação Física. O Estágio Pedagógico foi realizado na Escola Básica com Secundário José Falcão de Miranda do Corvo, no ano letivo de 2013/2014, para a disciplina de Educação Física ao 7º ano de escolaridade. The Final Training Report falls within the scope of the Course Training Report, the 2nd year of the Master in Teaching Physical Education Primary and Secondary Education, Faculty of Sport Sciences and Physical Education, University of Coimbra. This step is the culmination of academic training in which are put into practice, in the real world, all the knowledge acquired so far. All the experiences, skills and knowledge acquired today allow us the performance of a pedagogical practice of mastery in the area of Physical Education. The main goal of the Final Training Report is to conduct to a reflection of the trainee on the developed and knowledge acquired during the practicum activities, always contemplating their initial expectations. This document contains three main chapters. The first is an essentially descriptive area regarding pedagogical context. The second is a critical reflection on the practices carried out. Finally, the third chapter will be a deepening of an issue / problem. The issue / problem selected were the attitudes of students without disabilities face inclusion of pupils with special educational needs in physical education. The Pedagogical Training was conducted in Secondary School with Joseph Falcon Miranda do Corvo, in school year 2013/2014, to the discipline of Physical Education through the 7th grade

Stages of development and injury: an epidemiological survey of young children presenting to an emergency department

<p><b>Background:</b> The aim of our study was to use a local (Glasgow, west of Scotland) version of a Canadian injury surveillance programme (CHIRPP) to investigate the relationship between the developmental stage of young (pre-school) children, using age as a proxy, and the occurrence (incidence, nature, mechanism and location) of injuries presenting to a Scottish hospital emergency department, in an attempt to replicate the findings of a recent study in Kingston, Canada.</p> <p><b>Methods:</b> We used the Glasgow CHIRPP data to perform two types of analyses. First, we calculated injury rates for that part of the hospital catchment area for which reasonably accurate population denominators were available. Second, we examined detailed injury patterns, in terms of the circumstances, mechanisms, location and types of injury. We compared our findings with those of the Kingston researchers.</p> <p><b>Results:</b> A total of 17,793 injury records for children aged up to 7 years were identified over the period 1997–99. For 1997–2001, 6,188 were used to calculate rates in the west of the city only. Average annual age specific rates per 1000 children were highest in both males and females aged 12–35 months. Apart from the higher rates in Glasgow, the pattern of injuries, in terms of breakdown factors, mechanism, location, context, and nature of injury, were similar in Glasgow and Kingston.</p> <p><b>Conclusion:</b> We replicated in Glasgow, UK, the findings of a Canadian study demonstrating a correlation between the pattern of childhood injuries and developmental stage. Future research should take account of the need to enhance statistical power and explore the interaction between age and potential confounding variables such as socio-economic deprivation. Our findings highlight the importance of designing injury prevention interventions that are appropriate for specific stages of development in children.</p&gt

The effect of 14 weeks of vitamin D3 supplementation on antimicrobial peptides and proteins in athletes

Heavy training is associated with increased respiratory infection risk and antimicrobial proteins are important in defence against oral and respiratory tract infections. We examined the effect of 14 weeks of vitamin D3 supplementation (5000 IU/day) on the resting plasma cathelicidin concentration and the salivary secretion rates of secretory immunoglobulin A (SIgA), cathelicidin, lactoferrin and lysozyme in athletes during a winter training period. Blood and saliva were obtained at the start of the study from 39 healthy men who were randomly allocated to vitamin D3 supplement or placebo. Blood samples were also collected at the end of the study; saliva samples were collected after 7 and 14 weeks. Plasma total 25(OH)D concentration increased by 130% in the vitamin D3 group and decreased by 43% in the placebo group (both P=0.001). The percentage change of plasma cathelicidin concentration in the vitamin D3 group was higher than in the placebo group (P=0.025). Only in the vitamin D3 group, the saliva SIgA and cathelicidin secretion rates increased over time (both P=0.03). A daily 5000 IU vitamin D3 supplement has a beneficial effect in up-regulating the expression of SIgA and cathelicidin in athletes during a winter training period which could improve resistance to respiratory infections

Simple and objective prediction of survival in patients with lung cancer: staging the host systemic inflammatory response

Background. Prediction of survival in patients diagnosed with lung cancer remains problematical. The aim of the present study was to examine the clinical utility of an established objective marker of the systemic inflammatory response, the Glasgow Prognostic Score, as the basis of risk stratification in patients with lung cancer. Methods. Between 2005 and 2008 all newly diagnosed lung cancer patients coming through the multidisciplinary meetings (MDTs) of four Scottish centres were included in the study. The details of 882 patients with a confirmed new diagnosis of any subtype or stage of lung cancer were collected prospectively. Results. The median survival was 5.6 months (IQR 4.8–6.5). Survival analysis was undertaken in three separate groups based on mGPS score. In the mGPS 0 group the most highly predictive factors were performance status, weight loss, stage of NSCLC, and palliative treatment offered. In the mGPS 1 group performance status, stage of NSCLC, and radical treatment offered were significant. In the mGPS 2 group only performance status and weight loss were statistically significant. Discussion. This present study confirms previous work supporting the use of mGPS in predicting cancer survival; however, it goes further by showing how it might be used to provide more objective risk stratification in patients diagnosed with lung cancer

Interventions to improve antibiotic prescribing practices for hospital inpatients

Background Antibiotic resistance is a major public health problem. Infections caused by multidrug-resistant bacteria are associated with prolonged hospital stay and death compared with infections caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients. Objectives To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015. Selection criteria We included randomised controlled trials (RCTs) and non-randomised studies (NRS). We included three non-randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non- randomised trials (NRT), controlled before-after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention. Data collection and analysis Two review authors extracted data and assessed study risk of bias. We performed meta-analysis and meta-regression of RCTs and meta-regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria. Main results This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias. More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high-certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention. The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high-certainty evidence) from 11.0 days. Information from non-randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI -1% to 0%; 28 RCTs; 15,827 participants; moderate-certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate-certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low-certainty evidence). Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high-certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate-certainty evidence). There was very low-certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median -48.6%, interquartile range -80.7% to -19.2%; 7 studies). This was also the case for resistant gram-negative bacteria (median -12.9%, interquartile range -35.3% to 25.2%; 11 studies) and resistant gram-positive bacteria (median -19.3%, interquartile range -50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use. Heterogeneity of intervention effect on prescribing outcomes We analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high-certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect. Authors' conclusions We found high-certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions