The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Unfreezing the Flexnerian Model: introducing longitudinal integrated clerkships in rural communities.

INTRODUCTION: Physician shortages in rural areas remain severe but may be ameliorated by recent expansions in medical school class sizes. Expanding student exposure to rural medicine by increasing the amount of prolonged clinical experiences in rural areas may increase the likelihood of students pursuing a career in rural medicine. This research sought to investigate the perspective of rural physicians on the introduction of a rurally based nine-month Longitudinal Integrated Clerkship (LIC). METHODS: In this mixed-methods study, nine physician leaders were interviewed from five Maine, USA, rural hospitals participating in an LIC. Semi-structured interviews were audiotaped and transcribed. Qualitative analysis techniques were used to code the transcripts and develop themes. Forty-seven participating rural LIC preceptors were also surveyed through an online survey. RESULTS: Four major themes related to implementing the LIC model emerged: (1) melting old ways, (2) overcoming fears, (3) synergy of energy, and (4) benefits all-around. The faculty were very positive about the LIC, with increased job satisfaction, practice morale, and ongoing learning, but concerned about the financial impact on productivity. CONCLUSIONS: The importance of these themes and perceptions are discussed within the three-stage model of change by Lewin. These results describe how the innovative LIC model can conceptually unfreeze the traditional Flexnerian construct for rural physicians. Highlighting the many stakeholder benefits and addressing the anxieties and fears of rural faculty may facilitate the implementation of a rural LIC. Given the net favorable perception of rural faculty of the LIC, this educational model has the potential to play a major role in increasing the rural workforce

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Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

IL-17A is required for airway recruitment of neutrophils but not AHR in NO₂-promoted allergic airway disease.

<p>C57BL/6 mice were exposed to 15ppm NO₂ for 1 hour on day 1. All mice were exposed to OVA on days 1-3 and again during challenge on days 14-16. Treatment groups received either IgG isotype control antibody or anti-IL-17A neutralization antibody one day prior to antigen challenge on day 13. 48 hours following the final antigen challenge, BAL total cells (A) were quantified and macrophages (Macs; B), neutrophils (PMNs; C), and eosinophils (Eos; D) were calculated based on cell fractions. Pulmonary function assessment was performed by invasive forced oscillation technique. The percent baseline and average percent baseline per dose methacholine were calculated for resistance (R; E-F) and elastance (E; G-H), as determined by the single-compartment model [47]. Lungs were removed and snap frozen prior to RNA analysis for <i>Cxcl5</i> (I)<i>, Lcn2</i> (J), <i>Gob5</i> (K), and <i>Muc5ac</i> (L). Statistics were performed by 1-way ANOVA (A-D and I-L) or 2-way ANOVA (E-H) and Tukey post hoc analysis. **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05 compared to non-inflamed unless indicated by brackets. ND, not significantly different from non-inflamed. n = 7 per group (A-H) or n = 5-7 per group (I-L).</p

The endogenously-generated Th17 response in NO₂-promoted allergic airway disease is qualitatively different from the Th17 response generated following Th17 adoptive transfer.

<p>Mice were treated as in Figure 4. Lung single-cell suspensions were restimulated with OVA antigen in the presence or absence of anakinra (Ana; 0.2 μg/mL), Dex (10^-8 M), or anakinra and Dex in combination for 96 hours. Cell supernatants of antigen-restimulated and treated lung cells from mice subjected to NO₂-promoted allergic sensitization and OVA challenge (A-D) or Th17 adoptive transfer (E-H) were analyzed for the production of cytokines by Milliplex. Statistics were performed by 1-way ANOVA and Bonferroni post hoc analysis. **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05 compared to controls (None) unless otherwise indicated by brackets. ND, not significantly different compared to controls. For NO₂/OVA sensitized and challenged mice, n = 6. For Th17 and Th2 adoptively transferred mice, samples from n = 3 mice were pooled prior to <i>in </i><i>vitro</i> culturing, which was performed in triplicate.</p