Optimizing The Nasal Allergen Challenge Model For The Study Of Allergic Rhinitis

Background The Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC) uses a Nasal Allergen Challenge (NAC) model to study the pathophysiology of AR and provides proof of concept for novel therapeutics. The NAC model needs to ensure optimal participant qualification, allergen challenge, clinical symptoms capture and biological samples collection. Repeatability of the protocol is key to ensuring unbiased efficacy analysis of novel therapeutics. The effect of allergen challenge on IL-33 gene expression and its relation to IL1RL1 receptor and cytokine secretion was investigated. Methods Several iterations of the NAC protocol was tested, comparing variations of qualifying criteria based on the Total Nasal Symptom Score (TNSS) and Peak Nasal Inspiratory Flow (PNIF). The lowest allergen concentration was delivered and TNSS and PNIF recorded 15 minutes later. Participants qualified if the particular criteria for the protocol were met, otherwise the next higher allergen concentration (4-fold increase), was administered until the targets were reached. Participants returned for a NAC visit and received varying allergen challenge concentrations depending on the protocol, TNSS/PNIF were recorded at 15 minutes, 30 minutes, 1 hour, and hourly up to 12 hours, a 24 hour time point was added in later iterations. Repeatability was evaluated using a 3-4week interval between screening, NAC1, and NAC2 visits. Various biomarker samples were collected. Results A combined TNSS and PNIF criterion was more successful in qualifying participants. The cumulative allergen challenge (CAC) protocol proved more reliable in producing a robust clinical and biomarker response. Repeatability of the CAC protocol was achieved with a 3-week interval between visits, on a clinical and biological basis. IL-33 cytokine is an important biomarker in initiating the inflammatory response in AR in humans. IL-33 and IL1RL1 expression might employ a negative feedback mechanism in human nasal epithelial cells. Comparing the clinical and biological response to ragweed vs cat allergen challenge, proved the CAC protocol’s suitability for use employing different allergens. Conclusion The AR-CIC’s CAC protocol is an effective method of studying AR, capable of generating measurable and repeatable clinical and biomarker responses, enabling better understanding of AR pathophysiology and ensuring that any change would be purely due to medication under investigation in a clinical trial setting.

Differences in Abdominal and Liver Fat Accumulation Between Obesity-Matched Adults With and Without Type 2 Diabetes

Despite attempts to identify the mechanisms by which obesity leads to the development of Type 2 Diabetes (T2D), it remains unclear why some but not all adults with obesity develop T2D. Given the established associations between visceral adipose tissue (VAT) and liver fat with insulin resistance, we hypothesized that compared to age and obesity matched adults who were non-diabetic (NT2D), adults with T2D would have greater amounts of VAT and liver fat. The International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship with Cardiometabolic Risk/Intra-Abdominal Adiposity (INSPIRE ME IAA) aims to study the associations between VAT and liver fat and risk of developing T2D and cardiovascular disease. Four thousand, five hundred and four participants were initially recruited; from this, 2383 White and Asian adults were selected for this ancillary analysis. The NT2D and T2D groups were matched for age, body mass index (BMI) and waist circumference (WC). The T2D and NT2D groups were also compared to participants with either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT; IFG/IGT)). Abdominal adipose tissue was measured by computed tomography; liver fat was estimated using computed tomography-derived mean attenuation. Secondary analysis determined whether differences existed between NT2D and T2D groups in VAT and liver fat accumulation within selected BMI categories for Whites and Asians. We report across sex and race, T2D and IFG/IGT groups had elevated VAT and liver fat compared to the NT2D group (p<0.05). VAT was not different between IFG/IGT and T2D groups (p>0.05), however liver fat was greater in the T2D group compared to the IFG/IGT group in both Whites and Asians (p<0.05). Within each BMI category, the T2D group had elevated VAT and liver fat compared to the age and anthropometrically matched NT2D group in both Whites and Asians (p<0.05). With few exceptions, abdominal subcutaneous adipose tissue was not different in the T2D or IFG/IGT groups compared to the NT2D group independent of sex and race. Compared to age and obesity-matched adults who are NT2D, we observe that White and Asian adults with T2D, and those with IFG/IGT, present with greater levels of both VAT and liver fat.

Perceived and reported access to the general practitioner: an international comparison of universal access and mixed private/public systems.

Timely and convenient access to primary healthcare is essential for the health of the population as delays can incur additional health and financial costs. Access to health care is under increasing scrutiny as part of the drive to contain escalating costs, while attempting to maintain equity in service provision. The objective was to compare primary care services in Republic of Ireland and Northern Ireland, and to report on perceived and reported access to GP services in universal access and mixed private/public systems. A questionnaire study was performed in Northern Ireland (NI) and the Republic of Ireland (ROI). Patients of 20 practices in the ROI and NI were contacted (n = 22,796). Main outcome measures were overall satisfaction and the access to GP services. Individual responses and scale scores were derived using the General Practice Assessment Questionnaire (G-PAQ). The response rate was 52% (n = 11,870). Overall satisfaction with GP practices was higher in ROI than in NI (84.2% and 80.9% respectively). Access scores were higher in ROI than in NI (69.2% and 57.0% respectively) Less than 1 in 10 patients in ROI waited two or more working days to see a doctor of choice (8.1%) compared to almost half (45.0%) in NI. In NI overall satisfaction decreased as practice size increased; 82.8%, 80.4%, and 75.8%. In both systems, in large practices, accessibility is reduced when compared to smaller practices. The faster access to GP services in ROI may be due to the deterrent effect of the consultation charge freeing up services although, as it is the poorest and sickest who are deterred by the charge this improved accessibility may come at a significant cost in terms of equity. The underlying concern for policy makers centres around provision of equitable services.

Long-term hydroclimatic change and interannual variability in water sources, Apex River (Iqaluit), Baffin Island, Nunavut

The eastern Canadian Arctic is home to Canada’s largest Indigenous population, which depends on local freshwater sources for drinking water. However, small watersheds have rarely been analyzed for long-term hydrologic response to changing climate. This study aims to address this issue by examining the Apex River, a small watershed with a long hydroclimatic record, near Iqaluit, Nunavut. Particular emphasis was placed on the long-term changes in climate and river discharge, and the seasonal variability of water sources between two snapshots in time, 1983 and 2013. Long-term hydrological data were obtained from gauge station 10UH002, operated by Environment and Climate Change Canada, and long-term meteorological data were acquired from Environment Canada–operated stations near Iqaluit Airport. Breakpoint analysis suggested that long-term mean annual surface air temperatures have increased since 1994. In contrast, no long-term total precipitation or annual discharge changes were observed. However, river flow initiation and cessation analyses of the Apex River flow season indicates that flow extended into the autumn since the 2000s. The 2013 flow season lasted 44 days longer than the 1983 flow season. Systematic river sampling was undertaken throughout the 2013 thaw season to determine contributing proportions of event (snowmelt or rainfall) and pre-event (baseflow) water to river runoff. Results from the stable isotope hydrograph separation for 2013 were compared to findings for 1983. Snow was the main source of water to the river during the snowmelt period in 1983 and 2013, however baseflow was still an important contributor. Although there was high similarity of water sources early in the season in 1983 and 2013, the two years differed during the autumn. In 2013 there was a high rainfall runoff response that was not present in 1983, suggesting high release of late-season sub-surface water storage and an increased sensitivity to late-season rainfall events in 2013. This research provides insights into the hydrologic response of the Apex River to long-term climatic change, and highlights the need for high-quality precipitation and discharge data for effective long-term hydrological assessment.

The Function of Intestinal Afferent Neurons in Regulating Satiety During Health and Obesity

Background and aim: Within the gastrointestinal tract, vagal afferents regulate satiety and food intake via chemical and mechanical mechanisms. Cysteinyl Leukotrienes (CysLTs) are lipid mediators that are believed to regulate food intake and body weight. However, the involvement of vagal afferents in this effect remains to be established. Conversely, Glucagon like peptide-1 (GLP-1) is a satiety and incretin peptide hormone. The effect of obesity on GLP-1 mediated gut-brain signaling has yet to be investigated. Since intestinal vagal afferents’ activity is reduced during obesity, it is intriguing to investigate their responses to GLP-1 in such conditions. Methods: Extracellular recordings were performed on intestinal afferents from normal C57Bl6, low fat fed (LFF), and high fat fed (HFF) mice. To examine the effect on neuronal calcium signaling, calcium-imaging experiments were performed on isolated nodose ganglion neurons. Food intake experiments were conducted using LFF and HFF mice. Oral glucose tolerance tests (OGTT) were carried out. Whole cell patch clamp recordings were performed on nodose ganglion neurons from A) normal C57Bl mice to test the effect of CysLTs on membrane excitability, B) LFF and HFF mice to examine GLP-1 effect on membrane excitability during obesity. c-Fos immunohistochemical techniques were performed to measure the level of neuronal activation in the brainstem of both LFF and HFF mice in response to Ex-4. Results: CysLTs increased intestinal afferent firing rate and mechanosensitivity. In single nodose neuron experiments, CysLTs increased excitability. The GLP-1 agonist Ex-4 significantly decreased food intake in LFF but not HFF mice. However, Ex-4 markedly attenuated the rise in blood glucose in both LFF and HFF mice. The observed increase in nerve firing and mechanosensitivity following the application of GLP-1 and Ex-4 was abolished in HFF mice. Cell membrane excitability was significantly increased by Ex-4 in nodose from LFF but not HFF mice. Ex-4 significantly increased the number of activated neurons in the NTS area of LFF mice but not in their HFF counterparts. Conclusion: The previous observations indicate that the role CysLTs play in regulating satiety is likely to be vagally mediated. Also that satiety, but not incretin, effects of GLP-1 are impaired during obesity.

Understandings of citizenship education in Northern Ireland and the Republic of Ireland: Public discourses among stakeholders in the public and private sectors

Internationally, citizenship education has come to the fore in the past decade. It may be particularly importantwithin the context of societies with a legacy of political conflict, such as Northern Ireland and the Republic of Ireland, where it is being implemented as part of the statutory curriculum. This article explores understandingsof citizenship education among stakeholders in the private and public sectors in Northern Ireland and the Republic of Ireland with the aim to compare these with curricular conceptualizations of citizenship inboth contexts. Semi-structured interviews were conducted in both societies involving non-governmentalorganizations, political parties, trade unions and the police. Results indicated that levels of awareness aboutcitizenship education varied substantially and understandings mainly reflected current theory and curriculumpractice in citizenship. Commonalities emerged as in both societies similar key concepts were identified whiledifferences transpired over issues relating to national identity and political conflict, which may raise questionsfor history and citizenship education in both societies.

Fighting for shells: how private information about resource value changes hermit crab pre-fight displays and escalated fight behaviour

Pre-fight displays typically provide honest, but sometimes dishonest, information about resource holding potential and may be influenced by assessment of resource value and hence motivation to acquire the resource. These assessments of potential costs and benefits are also predicted to influence escalated fight behaviour. This is examined in shell exchange contests of hermit crabs in which we establish an information asymmetry about a particularly poor quality shell. The poor shell was created by gluing sand to the interior whereas control shells lacked sand and the low value of the poor shell could not be accurately assessed by the opponent. Crabs in the poor shell showed changes in the use of pre-fight displays, apparently to increase the chances of swapping shells. When the fights escalated, crabs in poor shells fought harder if they took the role of attacker but gave up quickly if in the defender role. These tactics appear to be adaptive but do not result in a major shift in the roles taken or outcome. We thus link resource assessment with pre-fight displays, the roles taken, tactics used during escalation and the outcome of these contests.

El significado de la prosopopeya de las Leyes en el "Critón" de Platon

El objeto de este trabajo es realizar un estudio iusfilosófico sobre la aparición de las Leyes (nómoi) personificadas de Atenas en el Critón de Platón. La prosopopeya de las Leyes resulta ser un aspecto central para poder comprender la obra, ya que éstas entablan un diálogo imaginario con Sócrates en el cual instalan diversos argumentos filosóficos para fundamentar la autoridad de la pólis. A los fines de identificar el valor argumentativo de este recurso en la obra, analizaré el significado del nómos en la Atenas del siglo V a. C. y la naturaleza de las Leyes en el contexto general del diálogo. Se busca demostrar la importancia que tienen aquéllas para explicar la decisión de Sócrates de beber la cicuta.