Ibuprofen Ameliorates Fatigue- And Depressive-Like Behavior in Tumor-Bearing Mice

Aims: Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines is associated with skeletal muscle wasting and depressive- and fatigue-like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF. Main methods: Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10 mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue-like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis. Key findings: Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1β and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice. Significance: Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF

Fluoxetine Prevents the Development of Depressive-like Behavior in a Mouse Model of Cancer Related Fatigue

Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine

Losartan Treatment Attenuates Tumor-induced Myocardial Dysfunction

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin–angiotensin–aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Methods and results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8 weeks of age. Simultaneously, mice were administered Losartan (10 mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19 days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation

Childhood intellectual disability and parents' mental health: integrating social, psychological and genetic influences.

BACKGROUND: Intellectual disability has a complex effect on the well-being of affected individuals and their families. Previous research has identified multiple risk and protective factors for parental mental health, including socioeconomic circumstances and child behaviour. AIMS: This study explored whether genetic cause of childhood intellectual disability contributes to parental well-being. METHOD: Children from across the UK with intellectual disability due to diverse genetic causes were recruited to the IMAGINE-ID study. Primary carers completed the Development and Well-being Assessment, including a measure of parental distress (Everyday Feeling Questionnaire). Genetic diagnoses were broadly categorised into aneuploidy, chromosomal rearrangements, copy number variants (CNVs) and single nucleotide variants. RESULTS: Compared with the UK general population, IMAGINE-ID parents (n = 888) reported significantly elevated emotional distress (Cohen's d = 0.546). Within-sample variation was related to recent life events and the perceived impact of children's difficulties. Impact was predicted by child age, physical disability, autistic characteristics and other behavioural difficulties. Genetic diagnosis also predicted impact, indirectly influencing parental well-being. Specifically, CNVs were associated with higher impact, not explained by CNV inheritance, neighbourhood deprivation or family structure. CONCLUSIONS: The mental health of parents caring for a child with intellectual disability is influenced by child and family factors, converging on parental appraisal of impact. We found that genetic aetiologies, broadly categorised, also influence impact and thereby family risks. Recognition of these risk factors could improve access to support for parents, reduce their long-term mental health needs and improve well-being of individuals with intellectual disability.This work was supported by the UK Medical Research Council (grant number G101400 to K.B.), UK Medical Research Council and Medical Research Foundation (grant number MR-N022572-1 to the IMAGINE-ID study; Principle Investigators: David H. Skuse, F Lucy Raymond, Jeremy Hall, Marianne Van den Bree, Michael J. Hall) and the Baily Thomas Charitable Trust (to K.B.)

Key aerodynamic technologies for aircraft engine nacelles

Customer requirements and vision in aerospace dictate that the next generation of civil transport aircraft should have a strong emphasis on increased safety, reduced environmental impact and reduced cost without sacrificing performance. In this context, the School of Mechanical and Aerospace Engineering at the Queen's University of Belfast and Bombardier have, in recent years, been conducting research into some of the key aerodynamic technologies for the next generation of aircraft engine nacelles. Investigations have been performed into anti-icing technology, efficient thrust reversal, engine fire zone safety, life cycle cost and integration of the foregoing with other considerations in engine and aircraft design. A unique correlation for heat transfer in an anti-icing system has been developed. The effect of normal vibration on heat transfer in such systems has been found to be negligible. It has been shown that carefully designed natural blockage thrust reversers without a cascade can reduce aircraft weight with only a small sacrifice in the reversed thrust. A good understanding of the pressure relief doors and techniques to improve the performance of such doors have been developed. Trade off studies between aerodynamics, manufacturing and assembly of engine nacelles have shown the potential for a significant reduction in life cycle cost

Between fixities and flows : Navigating place attachments in an increasingly mobile world

This paper develops a theoretical argument for how place attachments are forged and become dynamically linked to increasingly common mobility practices. First, we argue that mobilities, rather than negating the importance of place, shift our understanding of place and the habitual ways we relate to and bond with places as distinct from a conception of place attachment premised on fixity and stability. Second, we document how the body of research on place attachment has both reinforced and contested 'sedentaristic' assumptions criticized within the so-called 'mobilities turn' in the social sciences. Third, we present a conceptual framework, built around different modes of interrelation between fixity and flow, as a way to re-theorize, link and balance the various studies of place attachment that have grappled with mobility. Finally, we sketch out the main research implications of this framework for advancing our understanding of place attachment in a mobile world.Peer reviewe

The dynamics and high-energy emission of conductive gas clouds in supernova-driven galactic superwinds

In this paper we present high-resolution hydrodynamical models of warm ionized clouds embedded in a superwind, and compare the OVI and soft X-ray properties to the existing observational data. These models include thermal conduction, which we show plays an important role in shaping both the dynamics and radiative properties of the resulting wind/cloud interaction. Heat conduction stabilizes the cloud by inhibiting the growth of K-H and R-T instabilities, and also generates a shock wave at the cloud's surface that compresses the cloud. This dynamical behaviour influences the observable properties. We find that while OVI emission and absorption always arises in cloud material at the periphery of the cloud, most of the soft X-ray arises in the region between the wind bow shock and the cloud surface, and probes either wind or cloud material depending on the strength of conduction and the relative abundances of the wind with respect to the cloud. In general only a small fraction (<1%) of the wind mechanical energy intersecting a cloud is radiated away at UV and X-ray wavelengths, with more wind energy going into accelerating the cloud. Models with heat conduction at Spitzer-levels are found to produce observational properties closer to those observed in superwinds than models with no thermal conduction, in particular in terms of the OVI-to-X-ray luminosity ratio, but cloud life times are uncomfortably short (<1Myr) compared to the dynamical ages of real winds. We experimented with reducing the thermal conductivity and found that even when we reduced conduction by a factor of 25 that the simulations retained the beneficial hydrodynamical stability and low O{\sc vi}-to-X-ray luminosity ratio found in the Spitzer-level conductive models, while also having reduced evaporation rates.Comment: 27 pages, 12 figures (4 in color), MNRAS accepte

Residents' support for tourism development: The role of residents' place image and perceived tourism impacts

Drawing on the triple bottom line approach for tourism impacts (economic, socio-cultural and environmental) and adopting a non-forced approach for measuring residents' perception of these impacts, this study explores the role of residents' place image in shaping their support for tourism development. The tested model proposes that residents' place image affects their perceptions of tourism impacts and in turn their support for tourism development. The results stress the need for a more flexible and resident oriented measurement of tourism impacts, revealing that more favorable perceptions of the economic, socio-cultural and environmental impacts lead to greater support. Moreover, while residents' place image has been largely neglected by tourism development studies, the findings of this study reveal its significance in shaping residents' perception of tourism impacts as well as their level of support. The practical implications of the findings for tourism planning and development are also discussed

Direct rate measurements of eruption plumes at Augustine volcano: A problem of scaling and uncontrolled variables

The March–April 1986 eruption of Augustine Volcano, Alaska, provided an opportunity to directly measure the flux of gas, aerosol, and ash particles during explosive eruption. Most previous direct measurements of volcanic emission rates are on plumes from fuming volcanoes or on very small eruption clouds. Direct measurements during explosive activity are needed to understand the scale relationships between passive degassing or small eruption plumes and highly explosive events. Conditions on April 3, 1986 were ideal: high winds, clear visibility, moderate activity. Three measurements were made: 1) an airborne correlation spectrometer (Cospec) provided mass flux rates of SO2; 2) treated filter samples chemically characterized the plume and 3) a quartz crystal microcascade impactor provided particle size distribution. Atmospheric conditions on April 3 caused the development of a lee wave plume, which allowed us to constrain a model of plume dispersion leading to a forecast map of concentrations of SO2 at greater distances from the vent. On April 3, 1986, the emission rate of SO2 at Augustine was 24,000 t/d, one of the largest direct volcanic rate measurements yet recorded with a Cospec. The results, coupled with analytical results from samples simultaneously collected on filters, allow us to estimate HCl emissions at 10,000 t/d and ash eruption rate at 1.5×106 t/d. Based on other data, this ash eruption rate is about 1/50 of the maximum rate during the March–April activity. Filter samples show that the gas:aerosol proportions for sulfur and chlorine are about 10:1 and 4:1, respectively. By contrast, measurements of Augustine\u27s plume, together with ground-based gas sampling in July 1986 when the volcano was in a posteruptive fuming state, are 380 t/d SO2 and approximately 8000 t/d HCl with no ash emission. The observations of large Cl releases at Augustine support the Cl abundance conclusions of Johnston (1980) based on study of melt inclusions in the 1976 lavas. The results reinforce the need for more measurements during eruptions and for better understanding of scaling of volcanic emissions of various eruptive components