Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable ...a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation. Stromal fibroblast-specific deletion of mouse orthologs of several candidates resulted in the hyper-proliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients, and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth-suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.
•Mesodermal suppressors of epithelial proliferation identified in C. elegans•Mesoderm-epithelial signaling components are highly conserved across species•Depletion of candidates in murine fibroblasts causes mammary hyper-proliferation•Human orthologs of identified genes are altered in breast cancer stroma
Liu, Dowdle, Khurshid, Sullivan et al. identify mesodermal factors in C. elegans that suppress growth of adjacent epithelial cells. These candidates are shown to have conserved function in murine contexts and to be altered in human breast cancer stroma.
The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control ...in smokers with asthma.
Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 μg per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.
At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow -10.67 L/min, 95% CI -38.70 to 17.37, p = 0.449, but there was an improvement with atorvastatin in asthma quality of life score 0.52, 95% CI 0.17 to 0.87 p = 0.005. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.
Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma.
Clinicaltrials.gov identifier: NCT00463827.
Data on sepsis prevalence on the general wards is lacking on the UK and in the developed world. We conducted a multicentre, prospective, observational study of the prevalence of patients with sepsis ...or severe sepsis on the general wards and Emergency Departments (ED) in Wales. During the 24-hour study period all patients with NEWS≥3 were screened for presence of 2 or more SIRS criteria. To be eligible for inclusion, patients had to have a high clinical suspicion of an infection, together with a systemic inflammatory response (sepsis) and evidence of acute organ dysfunction and/or shock (severe sepsis). There were 5317 in-patients in the 24-hour study period. Data were returned on 1198 digital data collection forms on patients with NEWS≥3 of which 87 were removed, leaving 1111 for analysis. 146 patients had sepsis and 144 patients had severe sepsis. Combined prevalence of sepsis and severe sepsis was 5.5% amongst all in-patients. Patients with sepsis had significantly higher NEWS scores (3 IQR 3-4 for non-sepsis and 4 IQR 3-6 for sepsis patients, respectively). Common organ dysfunctions in severe sepsis were hypoxia (47%), hypoperfusion (40%) and acute kidney injury (25%). Mortality at 90 days was 31% with a median (IQR) hospital free stay of 78 (36-85) days. Screening for sepsis, referral to Critical Care and completion of Sepsis 6 bundle was low: 26%, 16% and 12% in the sepsis group. Multivariable logistic regression analysis identified higher National Early Warning Score, diabetes, COPD, heart failure, malignancy and current or previous smoking habits as independent variables suggesting the diagnosis of sepsis. We observed that sepsis is more prevalent in the general ward and ED than previously suggested before and that screening and effective treatment for sepsis and severe sepsis is far from being operationalized in this environment, leading to high 90 days mortality.
With phosphorus magnetic resonance spectroscopy (31P MRS) energy metabolites can be visualised. In this case study, we report on a patient with stenosis and wall contrast enhancement in the left ...internal carotid and the right vertebral artery, due to giant cell arteritis. 31P MRS revealed a decreased inorganic phosphate-to-phosphocreatine ratio (Pi/PCr) in regions with a prolonged mean transit time (MTT). After systemic therapy and angioplasty of the right vertebral artery, the stenosis and the symptoms improved and the area of prolonged MTT became smaller. However, a new decrease in Pi/PCr in areas that developed moderately prolonged MTT was observed.
Cardiac sympathetic nervous system molecular imaging has demonstrated prognostic value. Compared with meta-
Chydroxyephedrine,
Fflubrobenguane (FBBG) facilitates reliable estimation of SNS ...innervation using similar analytical methods and possesses a more convenient physical half-life. The aim of this study was to evaluate pharmacokinetic and metabolic properties of FBBG in target clinical cohorts.
Blood sampling was performed on 20 participants concurrent to FBBG PET imaging (healthy = NORM, non-ischemic cardiomyopathy = NICM, ischemic cardiomyopathy = ICM, post-traumatic stress disorder = PTSD). Image-derived blood time-activity curves were transformed to plasma input functions using cohort-specific corrections for plasma protein binding, plasma-to-whole blood distribution, and metabolism.
The plasma-to-whole blood ratio was 0.78 ± 0.06 for NORM, 0.64 ± 0.06 for PTSD and 0.60 ± 0.14 for (N)ICM after 20 minutes. 22 ± 4% of FBBG was bound to plasma proteins. Metabolism of FBBG in (N)ICM was delayed, with a parent fraction of 0.71 ± 0.05 at 10 minutes post-injection compared to 0.53 ± 0.03 for PTSD/NORM. While there were variations in metabolic rate, metabolite-corrected plasma input functions were similar across all cohorts.
Rapid plasma clearance of FBBG limits the impact of disease-specific corrections of the blood input function for tracer kinetic modeling.
Rationale
Vascular nitric oxide levels are low in acute stroke and donors such as glyceryl trinitrate have shown promise when administered very early after stroke. Potential mechanisms of action ...include augmentation of cerebral reperfusion, thrombolysis and thrombectomy, lowering blood pressure, and cytoprotection.
Aim
To test the safety and efficacy of four days of transdermal glyceryl trinitrate (5 mg/day) versus sham in patients with ultra-acute presumed stroke who are recruited by paramedics prior to hospital presentation.
Sample size estimates
The sample size of 850 patients will allow a shift in the modified Rankin Scale with odds ratio 0.70 (glyceryl trinitrate versus sham, ordinal logistic regression) to be detected with 90% power at 5% significance (two-sided).
Design
The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is a multicentre UK prospective randomized sham-controlled outcome-blinded parallel-group trial in 850 patients with ultra-acute (≤4 h of onset) FAST-positive presumed stroke and systolic blood pressure ≥120 mmHg who present to the ambulance service following a 999 emergency call. Data collection is performed via a secure internet site with real-time data validation.
Study outcomes
The primary outcome is the modified Rankin Scale measured centrally by telephone at 90 days and masked to treatment. Secondary outcomes include: blood pressure, impairment, recurrence, dysphagia, neuroimaging markers of the acute lesion including vessel patency, discharge disposition, length of stay, death, cognition, quality of life, and mood. Neuroimaging and serious adverse events are adjudicated blinded to treatment.
Discussion
RIGHT-2 has recruited more than 500 participants from seven UK ambulance services.
Status
Trial is ongoing.
Funding
British Heart Foundation.
Registration
ISRCTN26986053.
Societies must transform their dynamics to support the flourishing of life. There is increasing interest in regeneration and regenerative practice as a solution, but also limited cohered ...understanding of what constitutes regenerative systems at social-ecological scales. In this perspective we present a conceptual, cross-disciplinary, and action-oriented regenerative systems framework, the Regenerative Lens, informed by a wide literature review. The framework emphasizes that regenerative systems maintain positive reinforcing cycles of wellbeing within and beyond themselves, especially between humans and wider nature, such that “life begets life.” We identify five key qualities needed in systems to encourage such dynamics: an ecological worldview embodied in human action; mutualism; high diversity; agency for humans and non-humans to act regeneratively; and continuous reflexivity. We apply the Lens to an envisioned future food system to illustrate its utility as a reflexive tool and for stretching ambition. We hope that the conceptual clarity provided here will aid the necessary acceleration of learning and action toward regenerative systems.
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Tourism and Wellness Grimwood, Bryan S. R; Mair, Heather; Caton, Kellee ...
2018, 2018-11-23
eBook
By recognizing tourism as a profound social force, this book engages with notions of power and perspectives of wellness in tourism and contested conceptualizations of tourism spaces and places for ...wellness.
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