Vascular control mechanisms in normal and lipopolysaccharide-treated rats

The development of sepsis is associated with complex cardiovascular changes, some of which can be micmked in animals by administration of lipopolysaccharide (LPS). Animal models have identified a number of mediators important in these changes. The work described within this thesis aimed to investigate the role of adrenomedullin (AM) and adenosine in regulating vascular function in vivo in normal and LPS-treated rats. Integrated haemodynamics were assessed in Sprague Dawley rats following implantation of pulsed Doppler flow probes, allowing changes in renal, mesenteric and hindquarters vascular conductance to be measured across time. Adrenomedullin (AM), a hypotensive peptide involved in cardiovascular regulation, is upregulated in sepsis. Intermedin (IMD) is related to AM and shares some of its functions. However, the in vivo integrated responses to IMD have yet to be determined. In normal rats, both peptides caused marked vasodilatations in all regions, with hypotension and tachycardia. IMD was a more potent vasodilator than equimolar AM. Next, mechanisms involved in IMD signalling were investigated and compared to AM. Both AM and IMD-mediated renal and mesenteric vasodilatation were attenuated by AM22-52 and some components of IMD were sensitive to L-NAME, suggesting IMD causes both endothelial-dependent and -independent vasodilatations. No role for KATP channels was found, but there was an enhanced response to AM in the presence ofU37883A ; this was due to inhibition of the renin-angiotensin system as assessed by the angiotensin II receptor antagonist losartan. To assess whether vascular sensitivity to AM and IMD was affected in an LPS model of endotoxaemia, rats were treated with LPS and responses to peptides were assessed at 1.5 h, 6 hand 25 h. Vascular hyporesponsiveness to both AM and IMD occurred at 1.5 h, but had returned by 25 h regardless of the LPS administration protocol. Thus, vascular hyporesponsiveness appears to be a common phenomenon during the early stages of LPS-induced endotoxaemia. The role of adenosine was then examined in the haemodynamic sequelae of sepsis, since evidence suggests that adenosine-mediated vasodilatations help to maintain regional perfusion in animal models. In control rats, endogenous adenosine caused bradycardia and vasodilatation, whereas there was evidence of regional vasoconstriction in LPS-treated rats. In control animals, exogenous adenosine caused hypotension, tachycardia and vasodilatation, but in LPStreated rats, the adenosine-induced renal (at 1.5 h) and hindquarters (at 6 h) vasodilatations were abolished. As enhanced A1 receptor-mediated vasoconstriction could explain the results in LPS-treated rats, responsiveness to an At-receptor agonist (CCPA) or antagonist (DPCPX) was assessed. There was no evidence for enhanced vasoconstrictor responsiveness to CCP A in LPS-treated rats, but DPCPX caused renal vasodilatation, consistent with endogenous adenosine mediating renal vasoconstriction. Finally, the effects of a subdepressor infusion of adenosine on the haemodynamic responses to AM and IMD were assessed, and vice versa, to determine whether any synergism exists between these agents. No synergism was found between adenosine and AM, but there was functional antagonism between adenosine and IMD in the mesenteric vasculature. Collectively, these studies suggest that the development of novel cardiovascular therapies for treatment of sepsis should be designed to take into account the vascular region, and the time elapsed from onset

Vascular control mechanisms in normal and lipopolysaccharide-treated rats

The development of sepsis is associated with complex cardiovascular changes, some of which can be micmked in animals by administration of lipopolysaccharide (LPS). Animal models have identified a number of mediators important in these changes. The work described within this thesis aimed to investigate the role of adrenomedullin (AM) and adenosine in regulating vascular function in vivo in normal and LPS-treated rats. Integrated haemodynamics were assessed in Sprague Dawley rats following implantation of pulsed Doppler flow probes, allowing changes in renal, mesenteric and hindquarters vascular conductance to be measured across time. Adrenomedullin (AM), a hypotensive peptide involved in cardiovascular regulation, is upregulated in sepsis. Intermedin (IMD) is related to AM and shares some of its functions. However, the in vivo integrated responses to IMD have yet to be determined. In normal rats, both peptides caused marked vasodilatations in all regions, with hypotension and tachycardia. IMD was a more potent vasodilator than equimolar AM. Next, mechanisms involved in IMD signalling were investigated and compared to AM. Both AM and IMD-mediated renal and mesenteric vasodilatation were attenuated by AM22-52 and some components of IMD were sensitive to L-NAME, suggesting IMD causes both endothelial-dependent and -independent vasodilatations. No role for KATP channels was found, but there was an enhanced response to AM in the presence ofU37883A ; this was due to inhibition of the renin-angiotensin system as assessed by the angiotensin II receptor antagonist losartan. To assess whether vascular sensitivity to AM and IMD was affected in an LPS model of endotoxaemia, rats were treated with LPS and responses to peptides were assessed at 1.5 h, 6 hand 25 h. Vascular hyporesponsiveness to both AM and IMD occurred at 1.5 h, but had returned by 25 h regardless of the LPS administration protocol. Thus, vascular hyporesponsiveness appears to be a common phenomenon during the early stages of LPS-induced endotoxaemia. The role of adenosine was then examined in the haemodynamic sequelae of sepsis, since evidence suggests that adenosine-mediated vasodilatations help to maintain regional perfusion in animal models. In control rats, endogenous adenosine caused bradycardia and vasodilatation, whereas there was evidence of regional vasoconstriction in LPS-treated rats. In control animals, exogenous adenosine caused hypotension, tachycardia and vasodilatation, but in LPStreated rats, the adenosine-induced renal (at 1.5 h) and hindquarters (at 6 h) vasodilatations were abolished. As enhanced A1 receptor-mediated vasoconstriction could explain the results in LPS-treated rats, responsiveness to an At-receptor agonist (CCPA) or antagonist (DPCPX) was assessed. There was no evidence for enhanced vasoconstrictor responsiveness to CCP A in LPS-treated rats, but DPCPX caused renal vasodilatation, consistent with endogenous adenosine mediating renal vasoconstriction. Finally, the effects of a subdepressor infusion of adenosine on the haemodynamic responses to AM and IMD were assessed, and vice versa, to determine whether any synergism exists between these agents. No synergism was found between adenosine and AM, but there was functional antagonism between adenosine and IMD in the mesenteric vasculature. Collectively, these studies suggest that the development of novel cardiovascular therapies for treatment of sepsis should be designed to take into account the vascular region, and the time elapsed from onset

Adding web-based support to exercise referral schemes improves symptoms of depression in people with elevated depressive symptoms:A secondary analysis of the e-coachER randomised controlled trial

Background: Exercise referral schemes (ERS) reduce depression but the additional effect on mental health from web-based behavioural support is unknown. The e-coachER trial reported no effect of augmenting usual ERS with theory-driven web-based behavioural support on moderate to vigorous physical activity (MVPA) at 12 months for patients with chronic physical and mental health conditions. The present study reports the effects of the e-coachER intervention on depression, anxiety and MVPA only among participants with elevated depressive symptoms and investigates whether these were mediated by changes in MVPA and hypothesised cognitive and behavioural processes. Methods: Of the original 450 adults recruited into the e-coachER trial, 205 had at least mild depression, based on the Hospital Anxiety and Depression Scale (HADS), and were included in the present analysis. Data collected included the HADS, accelerometer measured and self-reported MVPA and survey process measures on physical activity action planning, self-monitoring and goal reviewing, and perceived importance, confidence, competence, autonomy and support. Linear mixed models were used to compare groups for change in depression and anxiety at 4 and 12 months using intention-to-treat complete case analysis, controlling for baseline. We also examined whether changes in physical activity and process variables at 4 months mediated changes in depression and anxiety at 12 months. Results: Of the 205 participants, 138 (67%) provided follow-up data at four months and 126 (61%) at 12 months. For those that provided follow-up data, those randomised to e-coachER reported improved levels of depression (−1.36, 95% CI: −2.55 to −0.18) but not anxiety, or MVPA, compared with controls at four months. No differences were observed at 12 months for depression, anxiety or MVPA. Intervention effects on accelerometer-measured or self-reported MVPA did not mediate improvements in depression or anxiety. However, intervention effects on confidence, competence and self-monitoring at four months significantly mediated the reduction in depression scores at four months. Intervention effects on competence and self-monitoring at four months also significantly mediated improvements in anxiety scores at four months. Interpretation: Adding web-based support to usual ERS leads to reductions in depression but not anxiety at four months. Changes in depression and anxiety were influenced by changing people's motivational regulations toward physical activity. The benefit of adding web-based support to usual ERS on mental health appears to be from increasing a sense of confidence, competence and self-monitoring rather than from increasing physical activity in people with elevated depression. ERS should focus more on strengthening motivational regulations than just doing more exercise. Trial registration: ISRCTN15644451.</p

Adding web-based support to exercise referral schemes improves symptoms of depression in people with elevated depressive symptoms:A secondary analysis of the e-coachER randomised controlled trial

Background: Exercise referral schemes (ERS) reduce depression but the additional effect on mental health from web-based behavioural support is unknown. The e-coachER trial reported no effect of augmenting usual ERS with theory-driven web-based behavioural support on moderate to vigorous physical activity (MVPA) at 12 months for patients with chronic physical and mental health conditions. The present study reports the effects of the e-coachER intervention on depression, anxiety and MVPA only among participants with elevated depressive symptoms and investigates whether these were mediated by changes in MVPA and hypothesised cognitive and behavioural processes. Methods: Of the original 450 adults recruited into the e-coachER trial, 205 had at least mild depression, based on the Hospital Anxiety and Depression Scale (HADS), and were included in the present analysis. Data collected included the HADS, accelerometer measured and self-reported MVPA and survey process measures on physical activity action planning, self-monitoring and goal reviewing, and perceived importance, confidence, competence, autonomy and support. Linear mixed models were used to compare groups for change in depression and anxiety at 4 and 12 months using intention-to-treat complete case analysis, controlling for baseline. We also examined whether changes in physical activity and process variables at 4 months mediated changes in depression and anxiety at 12 months. Results: Of the 205 participants, 138 (67%) provided follow-up data at four months and 126 (61%) at 12 months. For those that provided follow-up data, those randomised to e-coachER reported improved levels of depression (−1.36, 95% CI: −2.55 to −0.18) but not anxiety, or MVPA, compared with controls at four months. No differences were observed at 12 months for depression, anxiety or MVPA. Intervention effects on accelerometer-measured or self-reported MVPA did not mediate improvements in depression or anxiety. However, intervention effects on confidence, competence and self-monitoring at four months significantly mediated the reduction in depression scores at four months. Intervention effects on competence and self-monitoring at four months also significantly mediated improvements in anxiety scores at four months. Interpretation: Adding web-based support to usual ERS leads to reductions in depression but not anxiety at four months. Changes in depression and anxiety were influenced by changing people's motivational regulations toward physical activity. The benefit of adding web-based support to usual ERS on mental health appears to be from increasing a sense of confidence, competence and self-monitoring rather than from increasing physical activity in people with elevated depression. ERS should focus more on strengthening motivational regulations than just doing more exercise. Trial registration: ISRCTN15644451.</p

The Grizzly, February 11, 2016

Campus Safety Officers to Increase Reimert Presence • Preparing for More Snow • Ursinus Hires New VP of Admissions • Improv Troupe Set to Perform • UC Hosts Title IX Meeting • International Perspective: School vs. Work • Exploring the 80\u27s • New Spin on SPINT • Opinions: End the 21-Meal Plan; Is it Appropriate to Culturally Appropriate? • More Than Just a Trainer • Women\u27s Swimming Posts Third Perfect Seasonhttps://digitalcommons.ursinus.edu/grizzlynews/1682/thumbnail.jp

Objective cough frequency, airway inflammation, and disease control in asthma

Background Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. Methods Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). Results Eighty-nine subjects with asthma (mean ± SD age, 57 ± 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P &#60; .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. Conclusions Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent independent dimensions of asthma control

Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33–mediated macrophage polarization and emphysema

Heterotrimeric guanine nucleotide–binding protein (G protein) signaling is a ubiquitous signaling system that links hundreds of G protein–coupled receptors (GPCRs) with four G protein signaling pathways. Two of these pathways, one mediated by Gq and G11 and the other by G12 and G13, are implicated in the force-dependent activation of transforming growth factor–β (TGFβ) in lung epithelial cells. Reduced TGFβ activation in alveolar cells leads to emphysema, whereas enhanced TGFβ activation promotes acute lung injury, and idiopathic pulmonary fibrosis, therefore precise control of alveolar TGFβ activation is essential for alveolar homeostasis. Here, we investigated whether the Gq/G11 or G12/G13 pathways in epithelial cells are required to generate TGFβ and suppress alveolar inflammation. Mice deficient in both Gαq and Gα11 developed inflammation primarily due to alternatively activated (M2-polarized) macrophages, enhanced production of matrix metalloprotease 12 (MMP12), and age-related alveolar airspace enlargement consistent with emphysema. We found that mice with impaired Gq/G11 signaling had reduced stretch-mediated generation of TGFβ by epithelial cells and elevated macrophage MMP12 synthesis, but were protected from the effects of ventilator-induced lung injury. Furthermore, synthesis of the pleiotropic cytokine interleukin-33 (IL-33), was increased in these alveolar epithelial cells resulting in the M2-type polarization of alveolar macrophages independently of the effect on TGFβ. Our results suggest that alveolar Gq/G11 signaling maintains alveolar homeostasis and is likely to independently upregulate mechanotransduced epithelial TGFβ activation and downregulate epithelial IL-33 synthesis. Together, these findings suggest that disruption of Gq/G11 signaling promotes inflammatory emphysema, but protects against mechanostransduced lung injury

Integrative Oncology Education: An Emerging Competency for Oncology Providers

A growing number of cancer patients use complementary and alternative therapies during and after conventional cancer treatment. Patients are often reluctant to discuss these therapies with their oncologist, and oncologists may have limited knowledge and confidence on how to advise patients on the appropriate use. Integrative oncology is a patient-centered, evidence-informed field that utilizes mind-body practices, lifestyle modifications and/or natural products interwoven with conventional cancer treatment. It prioritizes safety and best available evidence to offer appropriate interventions alongside conventional care. There are few opportunities for oncologists to learn about integrative oncology. In this commentary, we highlight the Integrative Oncology Scholars (IOS) program as a means to increase competency in this growing field. We provide an overview of several integrative oncology modalities that are taught through this program, including lifestyle modifications, physical activity, and mind-body interventions. We conclude that as more evidence is generated in this field, it will be essential that oncology healthcare providers are aware of the prevalent use of these modalities by their patients and cancer centers include Integrative Oncology trained physicians and other healthcare professionals in their team to discuss and recommend evidence-based integrative oncology therapies alongside conventional cancer treatments to their patients

Rosanna Raymond’s SaVAge K’lub at the eighth Asia Pacific Triennial of Contemporary Art

This visual essay is based on a conversation in June 2016 between artist Rosanna Raymond and academic Karen Jacobs on Raymond’s art work, The SaVAge K’lub, with which she contributed to the eighth Asia Pacific Triennial of Contemporary Art. While this artwork challenges a variety of stereotypical misrepresentations of Pacific people and their arts, it unexpectedly appeared to reinforce certain perceptions too